KRAS inhibitors

Abstract

The present invention provides compounds of the formula: wherein R1, R2, R3, and R4 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients with cancer.

Description

KRAS INHIBITORS Background

[0001] The MAPK / ERK signaling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses including cell proliferation, differentiation, and apoptosis. KRAS protein is an initiator of the MAPK / ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRAS binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRAS is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP). In its GTP-bound active state, KRAS recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRAS-GTP are c-Raf and PI3-kinase. KRAS, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRAS gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK / ERK signal which promotes cancerous cell growth. Missense mutations of KRAS at codon 12 are the most common mutations and markedly diminish GTPase activity.

[0002] Oncogenic KRAS mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations, it has been a difficult therapeutic target. (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] Thus far, work has focused on KRAS G12C mutant inhibitors (e.g., WO2019 / 099524, WO2020 / 081282, WO2020 / 101736, WO2020 / 146613, and WO2021 / 118877 disclose KRAS G12C inhibitors), whereas WO2021 / 041671 discloses small molecules inhibitors of KRAS G12D and WO2017 / 011920 discloses small molecule inhibitors of KRAS G12C, G12D, and G12V.

[0004] There remains a need to provide alternative, small molecule KRAS inhibitors. In particular, there is a need to provide orally deliverable KRAS inhibitors that are useful for treating cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRAS GTP activity. There is also a need to provide small molecule KRAS inhibitors that exhibit greater efficacy at the same or reduced KRAS inhibitory activity. Further, there is a desire to provide KRAS inhibitors that exhibit better pharmacokinetic / pharmacodynamic properties. Even further, there is a desire to provide KRAS inhibitors that exhibit good oral bioavailability and target coverage (KRAS G12V inhibition). Additionally, there is a need to provide KRAS inhibitors that exhibit selective inhibition preference for KRAS G12V mutant over KRAS wild-type and preferably also exhibit selective inhibition preference for KRAS G12V mutant over HRAS or NRAS. Also, there is a need to provide more potent KRAS inhibitors that exhibit increased efficacy with reduced or minimized untoward or undesired effects. The present invention addresses one or more of these needs by providing novel KRAS inhibitors. Summary

[0005] Compounds of Formula I are provided herein: wherein: R1is a group of the formula ; R1b is H, C1-3 alkyl, or cyclopropyl; R1c is C1-3 alkyl, or cyclopropyl;n is 0, 1, or 2; R2 is halogen; R3 is a group of the formula ; Z is -C(R3c)- or -N-; R3a, R3b, and R3care each independently H or halogen; R4 is a group of the formula selected from (i) , whereinR4ais –(CR4cR4d)m–NR4eR4f, R4bis H or methyl; R4c and R4d together with the carbon atom to which they are attached form a cyclopropyl; R4e and R4f are each independently C1-3 alkyl, or R4e and R4f together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; and m is 0 or 1; (ii) , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl;R5band R5care each independently H, C1-6alkyl, C3-5cycloalkyl, or a 3-, 4-, or 5- membered heterocycle containing a heteroatom selected from N, O, and S; or R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or R5aand R5btogether with the atoms to which they are attached form a 4-, 5-, or 6- membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, and R5c is a C1-3 alkyl, and wherein the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3alkyl; and p is 0 or 1; (iii) wherein R6 is H or C1-3 alkyl; R6ais halogen or C1-3alkyl; and q is 0 or 1; or (iv) , wherein R7 is –(CR7aR7b)r-R7c; R7aand R7bare each independently H or C1-3alkyl; R7ca is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1- or 2- heteroatoms independently selected from N, O, or S, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and dimethylamino; or R7c is –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl; and r is 1 or 2; or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein are methods of using the compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. The methods include 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 compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in therapy. Additionally provided herein, are the compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. Also additionally provided herein is the use of compounds of Formula I, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. Detailed Description

[0008] Novel inhibitors of the KRAS gain of function mutation G12V are described herein. These new compounds could address the needs noted above for inhibitors of KRAS GTP activity in gain of function mutants in the treatment of cancers such as lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. Some of these new KRAS G12V mutant inhibitorcompounds are selective to KRAS G12V mutants over wild-type KRAS, preferably they are also selective over hRAS and nRAS. Additionally, some of these new selective KRAS G12V mutant inhibitor compounds are also inhibitors of other mutant types such as KRAS G12C or G12D. Some of these new KRAS G12V mutant inhibitor compounds have good oral bioavailability and good target coverage (KRAS G12V mutant inhibition).

[0009] The present invention provides a compound of Formula I: Formula I wherein R1, R2, R3, and R4 are as defined above, or a pharmaceutically acceptable salt thereof.

[0010] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C1-4 alkyl” or “C1-3 alkyl.” Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl.

[0011] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R3is a group of the formula , wherein preferably R3b is F or Cl, most preferably R3b is F.

[0012] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R3 is a group of the formula, wherein preferably R3b is H or F.

[0013] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R3is a group of the formula , wherein preferably R3b is F.

[0014] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R3 is a group of the formula selected from , , or .

[0015] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

[0016] In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2is F.

[0017] In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2is Cl.

[0018] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula .

[0019] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula .

[0020] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1bis H, methyl, ethyl, isopropyl, or cyclopropyl.

[0021] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1b is H, or methyl, preferably R1b is methyl.

[0022] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1bis C1-3alkyl, preferably R1bis methyl.

[0023] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, n is 0.

[0024] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1bis C1-3alkyl, and n is 0.

[0025] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula .

[0026] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , or .

[0027] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula .

[0028] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, n is 1.

[0029] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, n is 1 and R1cis C1-3alkyl, preferably R1cis methyl.

[0030] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1b is C1-3 alkyl, n is 1 and R1c is C1-3 alkyl, preferably R1b and R1c are methyl.

[0031] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula .

[0032] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , , , or .

[0033] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , or .

[0034] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula .

[0035] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , , , or .

[0036] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula , or .

[0037] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, n is 2 and each R1c is C1-3 alkyl, preferably each R1c is methyl.

[0038] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1bis C1-3alkyl, n is 2 and each R1cis C1-3alkyl, preferably R1band each R1care methyl.

[0039] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula .

[0040] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula , or .

[0041] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula .

[0042] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, n is 1 and R1c is cyclopropyl.

[0043] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1bis C1-3alkyl, n is 1 and R1cis cyclopropyl, preferably R1bis methyl.

[0044] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1is a group of the formula .

[0045] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , , , or .

[0046] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the formula , or .

[0047] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R4ais –(CR4cR4d)m–NR4eR4f; R4bis H or methyl; R4cand R4dtogether with the carbon atom to which they are attached form a cyclopropyl; R4eand R4fare each independently C1-3 alkyl, or R4e and R4f together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; and m is 0 or 1.

[0048] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R4b is H or methyl; and R4e and R4f are each independently C1-3 alkyl, or R4e and R4f together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen.

[0049] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R4bis H or methyl; and R4eand R4fare each independently C1-3 alkyl. In an embodiment, R4 is a group of the formula: ;; or .

[0050] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R4b is H or methyl; and R4e and R4f together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen. In an embodiment, R4is a group of the formula: ;; ; or .

[0051] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R4bis H or methyl; R4eand R4fare each independently C1-3alkyl, or R4e and R4f together with the nitrogen atom to which they are attached form a 4- or5-membered heterocycle optionally substituted with a halogen. In an embodiment, R4bis H or methyl; and R4e and R4f are each independently C1-3 alkyl. In an embodiment, R4b is H; and R4e and R4f are each independently C1-3 alkyl. In an embodiment, R4 is group of the formula: .

[0052] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3alkyl; R5band R5care each independently H, C1-6alkyl, C3-5cycloalkyl, or a 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5band R5c together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3alkyl; or R5aand R5btogether with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, wherein R5c is C1-3 alkyl, and wherein the 5- or 6-membered fused ring is optionally further substituted with a C1-3alkyl; and p is 0 or 1.

[0053] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula, wherein R5ais halogen, hydroxy, C1-3alkyl, C1-3alkoxy, or C1-3alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or a 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; and p is 0 or 1. In an embodiment, R4is group of the formula: ; ; ; ; ; ; ; ; ; NN; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0054] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R5ais halogen, hydroxy, C1-3alkyl, C1-3alkoxy, or C1-3alkoxy-C1-3alkyl; R5band R5ctogether with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; and p is 0 or 1. In an embodiment, R5ais C1-3alkyl; R5band R5ctogether with the nitrogen atom to which they are attached form a morpholinyl group; and p is 0 or 1. In an embodiment, R5a is methyl; R5b and R5c together with the nitrogen atom to which they are attached form a morpholinyl group; and p is 1. In an embodiment, R4is group of the formula: .

[0055] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula , wherein R5aand R5btogether with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, and R5c is a C1-3 alkyl, and wherein the 4-, 5- or 6- membered fused ring is optionally further substituted with a C1-3alkyl. In an embodiment, R5aand R5btogether with the atoms to which they are attached form a 5- or 6-membered heterocyclic fused ring, and R5c is a C1-3 alkyl. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 5-membered heterocyclic fused ring, and R5cis aC1-3alkyl. In an embodiment, R5aand R5btogether with the atoms to which they are attached form a 6-membered heterocyclic fused ring, and R5c is a C1-3 alkyl. In an embodiment, R4 is a group of the formula: ; or .

[0056] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula wherein R6 is H or C1-3 alkyl; R6a is halogen or C1-3 alkyl; and q is 0 or 1. In an embodiment, R6is H; R6ais C1-3alkyl; and q is 1. In an embodiment, R6is H; R6ais methyl; and q is 1. In an embodiment, R6is C1-3alkyl; and q is 0. In an embodiment, R6is methyl; and q is 0. In an embodiment, R4 is a group of the formula: ; ; or .

[0057] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula , wherein R7is –(CR7aR7b)r-R7c; R7aand R7bare each independently H or C1-3alkyl; R7c is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1- or 2-heteroatoms independently selected from N, O, or S, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and dimethylamino; or R7cis –OR7d, wherein R7dis C1-3 alkyl or C1-3 haloalkyl; and r is 1 or 2.

[0058] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a group of the formula, wherein R7is –(CR7aR7b)r-R7c; R7aand R7bare each independently H or C1-3alkyl; R7cis an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and dimethylamino. In an embodiment, r is 1, R7a and R7b are each H, and R7c is an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino. In an embodiment, r is 2, R7a and R7b are each independently H or methyl, and R7cis an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and dimethylamino. In an embodiment, r is 2, R7aand R7bare each independently H, and R7cis an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino. In an embodiment, R4 is a group of the formula: N O O ; ; ; ; ; ; ; ; ; ;

[0059] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein R7 is –(CR7aR7b)r-R7c; R7a and R7b are each independently H or C1-3 alkyl; R7cis –OR7d, wherein R7dis C1-3alkyl or C1-3haloalkyl; and r is 1 or 2. In an embodiment, r is 2, R7aand R7bare each independently H or C1-3alkyl; and R7cis –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl. In an embodiment, R4 is a group of the formula: .

[0060] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula

[0061] The present invention also provides a compound of Formula Ia:Formula Ia wherein R1b, R1c, R2, R3a, R3b, R4, Z, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis halogen, Z is - C(R3c)-, and R3cis H. In an embodiment, n is 0, R2is F, R3ais H, R3bis halogen, Z is - C(R3c)-, and R3c is H. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is halogen, and Z is - N-. In an embodiment, n is 0, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 0, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, Z is - C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis methyl, R2is Cl, R3ais H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is cyclopropyl, R2 isCl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis cyclopropyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1cis cyclopropyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is - C(R3c)-, and R3c is H. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is halogen, and Z is - N-. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is - N-. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, each R1cis methyl, R2is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen.

[0062] The present invention also provides a compound of Formula Ia-1:wherein R1b, R1c, R2, R3a, R3b, R4, Z, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is halogen, Z is - C(R3c)-, and R3c is H. In an embodiment, n is 0, R2 is F, R3a is H, R3b is halogen, Z is - C(R3c)-, and R3cis H. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis halogen, and Z is - N-. In an embodiment, n is 0, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 0, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1cis methyl, R2is Cl, R3ais H, R3bis halogen, Z is - C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1cis cyclopropyl, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis cyclopropyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1cis cyclopropyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is - C(R3c)-, and R3c is H. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is halogen, and Z is - N-. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, each R1cis methyl, R2is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen.

[0063] The present invention also provides a compound of Formula Ib:wherein R1c, R2, R3a, R3b, R4, Z, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 0, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 0, R2is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R2is Cl, R3ais H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H,R3bis halogen, and Z is -N-. In an embodiment, n is 1, R2is Cl, R3ais H, R3bis H, Z is - C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis methyl, R2is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is methyl, R2 is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is cyclopropyl, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis cyclopropyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1cis cyclopropyl, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is H, Z is - C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1c is methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1cis methyl, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen.

[0064] The present invention also provides a compound of Formula Ib-1:wherein R1c, R2, R3a, R3b, R4, Z, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 0, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 0, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 0, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R2is Cl, R3ais H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R2 is Cl, R3a is H, R3b is H, Z is - C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1cis methyl, R2is Cl, R3ais H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is methyl, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1cis methyl, R2is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1c is methyl,R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1cis cyclopropyl, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1cis cyclopropyl, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1c is cyclopropyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1cis cyclopropyl, R2is F, R3ais H, R3bis H, Z is - C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 2, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, each R1cis methyl, R2is Cl, R3ais H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, each R1cis methyl, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, each R1c is methyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, each R1cis methyl, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen.

[0065] The present invention also provides a compound of Formula Ic, Formula Ic-1, Formula Id, Formula Id-1, Formula If, Formula If-1, Formula Ig, or Formula Ig-1:wherein R1b, R1c, R2, R3a, R3b, Z, R4b, R4e, R4f, R5a, R5b, R5c, R6, R6a, R7a, R7b, R7c, n, p, q, and r are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, n is 0, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 0, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1bis methyl), R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 0, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3bis halogen, and Z is -N-. In an embodiment, n is 0, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 0, R1b is H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, andR3cis halogen. In an embodiment, n is 0, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1b is H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 1, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1b is methyl), R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R1cis methyl, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R1c is methyl, R2is F, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1cis methyl, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R1c is methyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1b is H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R1cis methyl, R2is Cl, R3ais H, R3bis H, Z is - C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1bis methyl), R1cis methyl, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R1c is cyclopropyl, R2is Cl, R3ais H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R1c is cyclopropyl, R2 is F, R3a is H, R3bis halogen, Z is -C(R3c)-, and R3cis H. In an embodiment, n is 1, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1b is methyl), R1c is cyclopropyl, R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), R1cis cyclopropyl, R2 is F, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3alkyl, more preferably R1bis methyl), R1cis cyclopropyl, R2is Cl, R3ais H, R3bis H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 1, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1bis methyl), R1cis cyclopropyl, R2is F, R3ais H, R3bis H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, R1b is H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3 alkyl, more preferably R1b is methyl), each R1c is methyl, R2 is F, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is halogen, and Z is -N-. In an embodiment, n is 2, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), each R1cismethyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, R1bis H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1- 3 alkyl, more preferably R1b is methyl), R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen. In an embodiment, n is 2, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), each R1c is methyl, R2 is Cl, R3a is H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1bis methyl), each R1cis methyl, R2is F, R3ais H, R3b is halogen, Z is -C(R3c)-, and R3c is H. In an embodiment, n is 2, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1bis methyl), each R1cis methyl, R2is Cl, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, R1b is H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), each R1cis methyl, R2is F, R3ais H, R3bis halogen, and Z is -N-. In an embodiment, n is 2, R1bis H, C1-3 alkyl, or cyclopropyl (preferably R1b is C1-3 alkyl or cyclopropyl, more preferably R1b is C1-3 alkyl, more preferably R1b is methyl), each R1c is methyl, R2 is Cl, R3a is H, R3b is H, Z is -C(R3c)-, and R3cis halogen. In an embodiment, n is 2, R1bis H, C1-3alkyl, or cyclopropyl (preferably R1bis C1-3alkyl or cyclopropyl, more preferably R1bis C1-3alkyl, more preferably R1b is methyl), each R1c is methyl, R2 is F, R3a is H, R3b is H, Z is -C(R3c)-, and R3c is halogen.

[0066] In the above embodiments of the compounds of Formula I, the chemical drawings are shown flat without chiral information. These compounds often have multiple chiral centers and are contemplated to exist is various forms with various combinations of chiral centers. Additionally, these compounds have various enantiomers, diastereomers, and atropisomers that can exist and are included herein.

[0067] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0068] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0069] In an embodiment of a 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.

[0070] The following are further numbered embodiments of the invention:

[0071] Embodiment 1. A compound of the formula: wherein:R1 is a group of the formulaR1b is H, C1-3 alkyl, or cyclopropyl; R1cis C1-3alkyl, or cyclopropyl; n is 0, 1, or 2; R2 is halogen; R3 is a group of the formula; Z is -C(R3c)- or -N-; R3a, R3b, and R3care each independently H or halogen; R4 is a group of the formula (i) , whereinR4ais –(CR4cR4d)m–NR4eR4f; R4bis H or methyl; R4c and R4d together with the carbon atom to which they are attached form a cyclopropyl; R4eand R4fare each independently C1-3alkyl, or R4eand R4ftogether with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; and m is 0 or 1; (ii) , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5band R5care each independently H, C1-6alkyl, C3-5cycloalkyl, or a 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing afurther heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, wherein R5c is C1-3 alkyl, and wherein the 4-, 5-, or 6- membered fused ring is optionally further substituted with a C1-3 alkyl; and p is 0 or 1; (iii) wherein R6 is H or C1-3 alkyl; R6a is halogen or C1-3 alkyl; and q is 0 or 1; or (iv) , wherein R7 is –(CR7aR7b)r-R7c; R7aand R7bare each independently H or C1-3alkyl; R7cis an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1- or 2-heteroatoms independently selected from N, O, or S, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and dimethylamino; or R7c is –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl; and r is 1 or 2; or a pharmaceutically acceptable salt thereof.

[0072] Embodiment 2. The compound according to embodiment 1, wherein R1b is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 3. The compound according to embodiment 1 or embodiment 2, wherein R1b is methyl, or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 4. The compound according to any one of embodiments 1-3, wherein n is 0, or a pharmaceutically acceptable salt thereof.

[0075] Embodiment 5. The compound according to any one of embodiments 1-3, wherein n is 1 and R1c is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 6. The compound according to any one of embodiments 1-3, wherein n is 1 and R1c is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 7. The compound according to any one of embodiments 1-3, wherein n is 2 and each R1cis C1-3alkyl, or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 8. The compound according to any one of embodiments 1-3, wherein R1is a group of the formula , , , or , or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 9. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula O N HN , or a pharmaceutically acceptable salt thereof.

[0080] Embodiment 10. The compound according to any one of embodiments 1-3, wherein R1is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 11. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0082] Embodiment 12. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0083] Embodiment 13. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula or a pharmaceuticallyacceptable salt thereof.

[0084] Embodiment 14. The compound according to any one of embodiments 1-3, wherein R1is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0085] Embodiment 15. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula, or a pharmaceutically acceptable salt thereof.

[0086] Embodiment 16. The compound according to any one of embodiments 1-3, wherein R1is a group of the formula, or a pharmaceutically acceptable salt thereof.

[0087] Embodiment 17. The compound according to any one of embodiments 1-3, wherein R1is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0088] Embodiment 18. The compound according to any one of embodiments 1-17, wherein R2 is F or Cl, or a pharmaceutically acceptable salt thereof.

[0089] Embodiment 19. The compound according to any one of embodiments 1-18, wherein R2 is F, or a pharmaceutically acceptable salt thereof.

[0090] Embodiment 20. The compound according to any one of embodiments 1-18, wherein R2is Cl, or a pharmaceutically acceptable salt thereof.

[0091] Embodiment 21. The compound according to any one of embodiments 1-20, wherein R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0092] Embodiment 22. The compound according to embodiment 21, wherein R3bis halogen (preferably fluoro), and R3c is H, or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 23. The compound according to embodiment 21, wherein R3b is H, and R3cis halogen, (preferably fluoro), or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 24. The compound according to embodiment 21, wherein R3b is halogen (preferably fluoro), and R3c is halogen, (preferably fluoro), or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 25. The compound according to any one of embodiments 1-20, wherein R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 26. The compound according to embodiment 25, wherein R3bis halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 27. The compound according to any one of embodiments 1-20, wherein R3is a group of the formula ,, or ,or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 28. The compound according to any one of embodiments 1-20, wherein R3 is a group of the formula, or a pharmaceutically acceptable salt thereof.

[0099] Embodiment 29. The compound according to any one of embodiments 1-20, wherein R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 30. The compound according to any one of embodiments 1-20, wherein R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 31. The compound according to any one of embodiments 1-30, wherein R4is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0102] Embodiment 32. The compound according to embodiment 31, wherein R4is a group of the formula, wherein R4b is H or methyl; and R4e and R4f are each independently C1-3alkyl, or R4eand R4ftogether with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 33. The compound according to embodiment 31, wherein R4 is a group of the formula , wherein R4b is H or methyl; and R4e and R4f are each independently C1-3alkyl; or a pharmaceutically acceptable salt thereof.

[0104] Embodiment 34. The compound according to embodiment 31, wherein R4 is a group of the formula , wherein R4bis H or methyl; and R4eand R4ftogether with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; or a pharmaceutically acceptable salt thereof.

[0105] Embodiment 35. The compound according to embodiment 31, wherein R4is a group of the formula , wherein R4bis H or methyl; R4eand R4fare each independently C1-3alkyl, or R4eand R4ftogether with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 36. The compound according to embodiment 35, wherein R4bis H or methyl; and R4e and R4f are each independently C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 37. The compound according to embodiment 35, wherein R4bis H; and R4e and R4f are each independently C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[0108] Embodiment 38. The compound according to embodiment 31, wherein R4 is a group of the formulaor a pharmaceutically acceptable salt thereof.

[0109] Embodiment 39. The compound according to any one of embodiments 1-30, wherein R4is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0110] Embodiment 40. The compound according to embodiment 39, wherein R4 is a group of the formula , wherein R5ais halogen, hydroxy, C1-3alkyl, C1-3alkoxy, or C1-3alkoxy-C1-3alkyl; R5band R5care each independently H, C1-6alkyl, C3-5cycloalkyl, or a 3-,4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0111] Embodiment 41. The compound according to embodiment 39, wherein R4 is a group of the formula , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-3 alkyl, C3 cycloalkyl, or a 5- membered heterocycle containing a heteroatom selected from N, O, and S; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0112] Embodiment 42. The compound according to embodiment 39, wherein R4 is a group of the formula , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-3 alkyl, C3 cycloalkyl, or a tetrahydrofuranyl; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0113] Embodiment 43. The compound according to embodiment 39, wherein R4is a group of the formula , wherein R5ais halogen, hydroxy, C1-3alkyl, C1-3alkoxy, or C1-3alkoxy-C1-3alkyl; R5band R5ctogether with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selectedfrom N, O, and S, wherein the heterocycle is optionally substituted with a C1-3alkyl; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0114] Embodiment 44. The compound according to embodiment 39, wherein R4 is a group of the formula , wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c together with the nitrogen atom to which they are attached form a 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0115] Embodiment 45. The compound according to embodiment 43 or embodiment 44, wherein R5ais C1-3alkyl; R5band R5ctogether with the nitrogen atom to which they are attached form a morpholinyl group; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0116] Embodiment 46. The compound according to any one of embodiments 43-45, wherein R5a is methyl; R5b and R5c together with the nitrogen atom to which they are attached form a morpholinyl group; and p is 1; or a pharmaceutically acceptable salt thereof.

[0117] Embodiment 47. The compound according to embodiment 39, wherein R4is a group of the formula , wherein R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, and R5cis a C1-3alkyl, and wherein the 4-, 5- or 6-membered fused ring is optionally further substituted with a C1-3alkyl; or a pharmaceutically acceptable salt thereof.

[0118] Embodiment 48. The compound according to embodiment 47, wherein R5a and R5b together with the atoms to which they are attached form a 5- or 6-membered heterocyclic fused ring, and R5c is a C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[0119] Embodiment 49. The compound according to embodiment 47, wherein R5a and R5b together with the atoms to which they are attached form a 5-membered heterocyclic fused ring, and R5c is a C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[0120] Embodiment 50. The compound according to embodiment 47, wherein R5a and R5b together with the atoms to which they are attached form a 6-membered heterocyclic fused ring, and R5cis a C1-3alkyl; or a pharmaceutically acceptable salt thereof.

[0121] Embodiment 51. The compound according to embodiment 39, wherein R4 is a group of the formula; ; ; ; ; or ; or a pharmaceutically acceptable salt thereof.

[0122] Embodiment 52. The compound according to any one of embodiments 1-30, wherein R4 is a group of the formula , or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 53. The compound according to embodiment 52, wherein R6is H; R6ais C1-3 alkyl; and q is 1; or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 54. The compound according to embodiment 52, wherein R6is H; R6ais methyl; and q is 1; or a pharmaceutically acceptable salt thereof.

[0125] Embodiment 55. The compound according to embodiment 52, wherein R6 is C1-3 alkyl; and q is 0; or a pharmaceutically acceptable salt thereof.

[0126] Embodiment 56. The compound according to embodiment 52, wherein R6is methyl; and q is 0; or a pharmaceutically acceptable salt thereof.

[0127] Embodiment 57. The compound according to embodiment 52, wherein R4 is a group of the formula ; ; or ; or a pharmaceutically acceptable salt thereof.

[0128] Embodiment 58. The compound according to any one of embodiments 1-30, wherein R4 is a group of the formula, or a pharmaceutically acceptable salt thereof.

[0129] Embodiment 59. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; R7a and R7b are each independently H or C1-3 alkyl; R7c is an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4- oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino; or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 60. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; r is 1, R7a and R7b are each H, and R7c is an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino; or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 61. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; r is 2, R7aand R7bare each independently H or methyl, and R7cis an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4-oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino; or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 62. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; r is 2, R7a and R7b are each independently H, and R7c is an optionally substituted heterocycle selected from pyrrolidine, tetrahydrofuran, dioxane, morpholine, 1,4- oxazepane, piperidine, oxetane, and azetidine, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino; or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 63. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; R7a and R7b are each independently H or C1-3 alkyl; R7c is –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl; and r is 1 or 2; or a pharmaceutically acceptable salt thereof.

[0134] Embodiment 64. The compound according to embodiment 58, wherein R7is – (CR7aR7b)r-R7c; r is 2, R7a and R7b are each independently H or C1-3 alkyl; and R7c is –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0135] Embodiment 65. The compound according to embodiment 58, wherein R4is a group of the formulaor a pharmaceutically acceptable salt thereof.

[0136] Embodiment 66. The compound according to any one of embodiments 1-30, wherein R4 is a group of the formulaoror a pharmaceutically acceptable salt thereof.

[0137] Embodiment 67. The compound according to embodiment 1, selected fromor a pharmaceutically acceptable salt thereof.

[0138] Embodiment 68. A pharmaceutical composition comprising a compound according to any one of embodiments 1-67, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0139] Embodiment 69. A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to embodiment 68, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma,uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

[0140] Embodiment 70. A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of embodiments 1-67, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

[0141] Embodiment 71. The method according to embodiments 69 or 70 wherein the patient has a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0142] Embodiment 72. The method according to embodiments 69 or 70, wherein one or more cells express KRAS G12V mutant protein.

[0143] Embodiment 73. A method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1-67, or a pharmaceutically acceptable salt thereof.

[0144] Embodiment 74. The method according to embodiment 73, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

[0145] Embodiment 75. The method according to any one of embodiments 69-74, 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, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof.

[0146] Embodiment 76. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-67, for use in therapy.

[0147] Embodiment 77. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-67, for use in the treatment of cancer.

[0148] Embodiment 78. The compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 77, wherein the cancer has a KRAS G12V mutation.

[0149] Embodiment 79. The compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 77 or embodiment 78, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

[0150] Embodiment 80. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-67 for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer.

[0151] Embodiment 81. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of a PD-1 inhibitor.

[0152] Embodiment 82. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of a PD-L1 inhibitor.

[0153] Embodiment 83. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of a CDK4 / CDK6 inhibitor.

[0154] Embodiment 84. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of an EGFR inhibitor.

[0155] Embodiment 85. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of an ERK inhibitor.

[0156] Embodiment 86. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of an Aurora A inhibitor.

[0157] Embodiment 87. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of a SHP2 inhibitor.

[0158] Embodiment 88. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of a platinum agent.

[0159] Embodiment 89. The method according to embodiment 75, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 80, wherein the patient is also administered an effective amount of pemetrexed, or pharmaceutically acceptable salts thereof.

[0160] Embodiment 90. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is non-small cell lung cancer.

[0161] Embodiment 91. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is colorectal cancer.

[0162] Embodiment 92. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is pancreatic cancer.

[0163] Embodiment 93. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is cervical cancer.

[0164] Embodiment 94. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is esophageal cancer.

[0165] Embodiment 95. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is endometrial cancer.

[0166] Embodiment 96. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is ovarian cancer.

[0167] Embodiment 97. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is cholangiocarcinoma.

[0168] Embodiment 98. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is stomach adenocarcinoma.

[0169] Embodiment 99. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is invasive ductal carcinoma.

[0170] Embodiment 100. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is uterine carcinosarcoma.

[0171] Embodiment 101. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is a germ cell tumor.

[0172] Embodiment 102. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is bladder cancer.

[0173] Embodiment 103. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is small bowel adenocarcinoma.

[0174] Embodiment 104. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is appendix cancer.

[0175] Embodiment 105. The method according to any one of embodiments 69-75 or 81-89, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 77-89, wherein the cancer is peritoneum cancer.

[0176] The chemical drawings in the compounds above contain indications of chiral aspects of the specific compounds shown. However, the chemical drawings in the compounds above do not contain all the possible chiral features of these compounds and the chiral indications shown are not intended to exclude changes to the chiral aspects shown. Thus, alternate chiral versions of the compounds as well as different combinations of chiral attributes are contemplated and included herein.

[0177] Further provided herein are methods of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. In this method, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. In this method, the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an embodiment the cancer can be non-small cell lung cancer. In an embodiment the cancer can be pancreatic cancer. In an embodiment the cancer can be colorectal cancer. In an embodiment the cancer can be stomach adenocarcinoma. In an embodiment the cancer can be invasive ductal carcinoma. In an embodiment the cancer can be uterine carcinosarcoma. In an embodiment the cancer can be germ cell tumors. In an embodiment the cancer can be bladder cancer. In an embodiment the cancer can be small bowel adenocarcinoma. In an embodiment the cancer can be appendix cancer. In an embodiment the cancer can be peritoneum cancer.

[0178] Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells thatexpress a mutant KRAS G12V protein. In this method, the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRAS G12V mutant protein. This method also includes treating KRAS G12V mutant bearing cancers of other origins.

[0179] Further provided herein is a method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof. In this method, the cancer that has a KRAS G12V mutation can be KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, and KRAS G12V mutant peritoneum cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant non-small cell lung cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant pancreatic cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant colorectal cancer.

[0180] Additionally provided herein is a method of modulating a mutant KRAS G12V enzyme in a patient in need thereof, by administering a compound according to Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment this method comprises inhibiting a human mutant KRAS G12V enzyme.

[0181] Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer that was determined to express the KRAS G12V mutantprotein. The method comprises administering to a patient an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. The G12V mutational status of one or more cancer cells can be determined by a number of 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, e.g. in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine the mutational status (e.g., G12C, G12D, and / or G12V mutational status, in one or more cancer cells or in 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.

[0182] Further provided herein is a compound or a pharmaceutically acceptable salt thereof according to Formula I for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer. For this use in treating cancer, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is cervical cancer. In an embodiment, the cancer is esophageal cancer. In an embodiment, the cancer is endometrial cancer. In an embodiment, the cancer is ovarian cancer. In an embodiment, the cancer is cholangiocarcinoma. In an embodiment, the cancer is colorectal cancer. In an embodiment, the cancer is stomach adenocarcinoma. In an embodiment, the cancer is invasive ductal carcinoma. In an embodiment, the cancer is uterine carcinosarcoma. In an embodiment, the cancer is germ cell tumors. In an embodiment, the cancer is bladder cancer. In an embodiment, the cancer is small bowel adenocarcinoma. In an embodiment, the cancer is appendix cancer. In an embodiment, the cancer is peritoneum cancer. The cancer can have one or more cancer cells that express the mutant KRAS G12V protein such as KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutantcholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, or KRAS G12V mutant peritoneum cancer. Additionally, the cancer can be non-small cell lung cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be pancreatic cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant cervical cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant esophageal cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant endometrial cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant ovarian cancer, and one or more cells express KRAS G12V mutant protein.Further, the cancer can be KRAS G12V mutant cholangiocarcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant stomach adenocarcinoma, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant invasive ductal carcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant uterine carcinosarcoma, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant germ cell tumors, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant bladder cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant small bowel adenocarcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant appendix cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant peritoneum cancer, and one or more cells express KRAS G12V mutant protein. The patient can have a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceuticallyacceptable salt thereof. The patient may have been treated with a different course of treatment prior to being treated as described herein.

[0183] The compounds provided herein according to Formula I, or a pharmaceutically acceptable salt thereof, may also be used in the manufacture of a medicament for treating cancer. When used in the manufacture of a medicament, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is cervical cancer. In an embodiment, the cancer is esophageal cancer. In an embodiment, the cancer is endometrial cancer. In an embodiment, the cancer is ovarian cancer. In an embodiment, the cancer is cholangiocarcinoma. In an embodiment, the cancer is colorectal cancer. In an embodiment, the cancer is stomach adenocarcinoma. In an embodiment, the cancer is invasive ductal carcinoma. In an embodiment, the cancer is uterine carcinosarcoma. In an embodiment, the cancer is germ cell tumors. In an embodiment, the cancer is bladder cancer. In an embodiment, the cancer is small bowel adenocarcinoma. In an embodiment, the cancer is appendix cancer. In an embodiment, the cancer is peritoneum cancer. The cancer can have one or more cancer cells that express the mutant KRAS G12V protein. When the cancer cells express KRAS G12V protein, the cancer can be selected from KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, and KRAS G12V mutant peritoneum cancer.

[0184] Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or apharmaceutically 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, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer. Additionally provided is a combination comprising a compound according to 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, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in the treatment of cancer.

[0185] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a PD-1 or PD-L1 inhibitor, for use in the treatment of cancer. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor can be pembrolizumab; the PD-1 or PD-L1 inhibitor can be nivolumab; the PD-1 or PD-L1 inhibitor can be cemiplimab; the PD-1 or PD-L1 inhibitor can be sintilimab ; the PD-1 or PD-L1 inhibitor can be atezolizumab; the PD-1 or PD-L1 inhibitor can be avelumab; the PD-1 or PD-L1 inhibitor can be durvalumab; or the PD-1 or PD-L1 inhibitor can be lodapilimab.

[0186] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to 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 which the cancer has one or more cells that express a mutant KRAS G12V protein. As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib; the CDK4 / CDK6 inhibitor can be palbociclib; or the CDK4 / CDK6 inhibitor can be ribociclib.

[0187] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additional provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; or the EGFR inhibitor can be cetuximab.

[0188] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or apharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the ERK inhibitor can be LY3214996; the ERK inhibitor can be LTT462; or the ERK inhibitor can be KO-947.

[0189] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the 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.

[0190] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof, and a SHP2 inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a 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 Cefsulodin, and pharmaceutically acceptable salts thereof. Examples of Type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, and pharmaceutically acceptable salts thereof. Additional examples of SHP2 inhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI- 2376, ETS-001, and PCC0208023, and pharmaceutically acceptable salts thereof. This method also includes treating KRAS G12V mutant protein mutant bearing cancers of other origins.

[0191] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use inthe treatment of cancer. As used herein, the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin.

[0192] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein.

[0193] As described herein in paragraphs

[0184] to

[0192] above, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein, or the cancer can be mutant lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein. These methods also include treating KRAS G12V mutant bearing cancers of other origins.

[0194] The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound considered to be acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al.,2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0195] Pharmaceutical compositions containing the compounds of Formula I as described herein may be prepared using pharmaceutically acceptable additives. The term “pharmaceutically acceptable additive(s)” as used herein for the pharmaceutical compositions, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious 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., 22ndEd., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols.

[0196] As used herein, the term “effective amount” refers to an amount that is a dosage, which is effective in achieve a desired therapeutic result such as treating a disorder or disease, like a cancerous lesion or progression of abnormal cell growth and / or cell division. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of patient to be treated; the patient’s size, age, gender, and general health; the degree of involvement or stage and / or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of other concomitant medication.

[0197] A treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need. Pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. The tablet, capsule, or solution can include a compound of the present invention in an amount effective for treating a patient in need of treatment with cancer.

[0198] As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, controlling, delaying, reducing, stopping, reversing, preventing, or ameliorating the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and / or cell division. Treating does not necessarily indicate a total elimination of all disorder or disease symptoms.

[0199] As used herein, the term "patient" refers to a mammal in need of treatment. Specifically, the patient can be a human that is in need of treatment with cancer, for example, KRAS G12V mutant protein mutant bearing cancers.

[0200] Certain abbreviations are defined as follows: “ACN“ refers to acetonitrile; “AcOH” or “HOAc” refer to acetic acid; “aq.” refers to aqueous; “conc.” refers to concentrated; “DCM” refers to dichloromethane; “DIBAL-H” refers to diisobutylaluminum hydride; “DIEA” and “DIPEA” refer to N,N-diisopropyl ethylamine; “DMAP” refers to 4- dimethylaminopyridine; “DMEA” refers to N,N-dimethylethylamine; “DMF” refers to N,N- dimethylformamide; “DMSO” refers to dimethylsulfoxide; “ELISA” refers to enzyme-linked immunosorbent assay; “ERK” refers to extracellular signal-regulated kinases; “Et” refers to an ethyl group; “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; “GDP” refers to guanosine diphosphate; “GTP” refers to guanosine triphosphate; “h” refers to hour or hours; “Hex” or “hex” refers to hexane or hexanes; “HPLC” refers to high-performance liquid chromatography; “IPA” refers to isopropyl alcohol; “IPAm” refers to isopropyl amine; “KOAc” refers to potassium acetate; “LC-ES / MS” refers to liquid chromatograph- electrospray mass spectrometry; “LC-MS” refers to liquid chromatography mass spectrometry; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MAPK” refers to mitogen-activated protein kinases; “mCPBA” refers to 3-chloro-peroxybenzoic acid; “Me” refers to a methyl group; “MeOH” refers to methanol; “min” refers to minute or minutes; “MTBE” refers to methyl tert-butyl ether; “NMP” refers to 1-methylpyrrolidin-2-one; “Pd(OAc)2 refers to palladium (II) acetate; “RT” refers to room temperature; “sat.” refers to saturated; “SCX” refers to strong cation exchange; “TBAF” refers to tetrabutylammonium fluoride; “tBu” refers to the tert-butyl group; “t-BuOH” refers to tert-butanol or tert-butylalcohol; “TEA” refers to triethylamine; “TFA” refers to trifluoracetic acid; “THF” refers to tetrahydrofuran; “XantPhos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; “XPhos” refers to 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl.

[0201] Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of compounds listed below, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley- Interscience, 1994). The molecules described herein include compounds that are atropisomers and which can exist in different conformations or as different rotomers. Atropisomers are compounds that exist in different conformations arising from restricted rotation about a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier to rotation about the single bond is sufficiently high that the rate of interconversion is slow enough to allow the individual rotomers to be separated from each other. This description is intended to include all of the isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that could be made using the compounds disclosed herein. In the molecules described herein, only molecules in which the absolute conformation of a chiral center (or atropisomer conformation) is known have used naming conventions or chemical formula that are drawn to indicate the chirality or atropisomerism. Those of skill in the art will readily understand when other chiral centers are present in the molecules described herein and be able to identify the same.

[0202] Compounds of any one of Formula I that are chemically capable of forming salts are readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, i.e., removing the protecting group. Examples, 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 andDevelopment, 4: 427-435 (2000); and Berge, S.M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0203] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the Schemes, Preparations, and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Preparation 1 Methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate

[0204] A solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 eq.) in THF (5 mL) was flushed with N2 and charged with NaH (60 mass%) in mineral oil (0.101 g, 2.53 mmol, 1.24 eq.) at RT. Gas evolution was observed, and a precipitate formed in the flask. The reaction was stirred at RT for 20 min. A solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) in THF (5 mL) was added slowly via syringe over ~2 min. The reaction was stirred at RT for 9 h. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 eq.) and sodium hydride (60 mass%) in mineral oil (0.050 g, 1.3 mmol, 0.6 eq.) were added and stirring was continued at RT for ~18 h. The mixture was diluted with EtOAc and washed with sat. aq. NH4Cl and brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with 2% MTBE / Hex to obtain the title compound (0.346 g, 59%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.23 – 8.19 (dd, J= 4.49, 8.9 Hz, 1H), 8.05 (s, 1H), 7.62 (t, J= 9.0 Hz, 1H), 3.93 (s, 3H).Preparation 2 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid

[0205] A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 eq.) in MeOH (130 mL) and THF (130 mL) was charged with 5N NaOH (66 mL, 330 mmol, 5 eq.) and stirred at RT for 40 min. The mixture was concentrated and H2O (500 mL) was added. The pH was adjusted to ~2 with 5N HCl. The mixture was extracted with EtOAc (2 x 500mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The solids were dried under vacuum at 50 °C to afford the title compound (17.6 g, 96%) as a white solid. MS (ES) m / z=229 (M-1-CO2). Preparation 3 tert-Butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0206] 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 eq.) and diphenylphosphoryl azide (1.5 mL, 6.9 mmol, 1.3 eq.) and heated at 95 °C for 1 h. The mixture was cooled and concentrated. The residue was purified on silica, eluting with MTBE / Hex (4% to 20%) to obtain the title compound (0.987 g, 52%) as a white solid. MS (ES) m / z=290 (M+1). Preparation 4tert-Butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0207] A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.90 mmol) and bis(neopentyl glycolato)diboron (4.02 g, 17.8 mmol, 2 eq.) and KOAc (2.62 g, 26.7 mmol, 3 eq.) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 min. To the mixture was added Pd(ddpf)Cl2(0.69 g, 0.90 mmol, 0.1eq.). The reaction was sonicated for 3 min, then put through a vacuum / N2refill cycle (3x) and was heated at 100 °C for 3 h. The mixture was cooled to RT, filtered through diatomaceous earth and was rinsed with 1:4 EtOAc / Hex. The filtrate was concentrated and the residue was purified on silica (0- 40% MTBE / Hex) to obtain the title compound (2.95 g, 87%) as a white solid.1H 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). Preparation 5 tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0208] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A solution of 2-(4- chloro-5-fluoropyridin-3-yl)acetonitrile (11.8 g, 56.1 mmol) in DMF (112 mL) was cooled to 0 °C. Potassium tert-butoxide (7.00 g, 61.1 mmol) was added. After 15 min, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was poured into a mixture of ice / water (1.5 L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (60 °C) overnight and separated from the diatomaceous earth to give ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 79%) as a solid. MS (ES) m / z=266 (M+1).

[0209] 2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3- cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0 °C. NaOH (5 M in water, 90 mL) was added dropwise over 15 min. The reaction mixture was heated to 105 °C for 1 h, then cooled to room temperature. The reaction mixture was poured into a mixture of ice / water (1.8 L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (50 °C) overnight and separated from the diatomaceous earth to give crude 2-amino-7-fluoro- thieno[3,2-c]pyridine-3-carbonitrile.

[0210] tert-Butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL) and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0 °C.4- dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the remaining material was diluted with DCM (400 mL) and 5% aq. citric acid (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2- yl)carbamate (7.5 g, 58%) as a brown solid. MS (ES) m / z=294 (M+1).

[0211] 2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide.3- Chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of tert-butyl (3- cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature overnight, then cooled to 0 °C for ~15 min. Solids were collected by filtration and dried in a vacuum oven (60 °C). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 0-6% MeOH in DCM. Fractions containing desired material were combined with the solids from the filtration and concentrated to give tert-butyl N-(3-cyano-7-fluoro-5- oxido-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS (ES) m / z=310 (M+1).

[0212] tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. Asuspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0 °C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, at 45 °C for 90 min, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of sat. aq. NaHCO3 (500 mL), NaOH (5 M in water, 40 mL), and ice. Solid NaHCO3was added to the stirred mixture to maintain pH ~6-7. Once bubbling ceased, the phases were separated. The aqueous phase was extracted 3x with DCM. The combined organic phases were dried over MgSO4 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 50- 100% DCM in hexanes. Fractions containing desired material were concentrated to give the title compound (3.87 g, 69%) as a white solid. MS (ES) m / z=328 (M+1). Preparation 6 5-Fluoroisobenzofuran-1(3H)-one

[0213] To a stirred mixture of (2-bromo-5-fluorophenyl)methanol (500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 eq.) in ACN (2500 mL) was added Pd(OAc)2(10.95 g, 48.77 mmol, 0.02 eq.) and XantPhos (42.33 g, 73.16 mmol, 0.03 equiv.) at RT, then stirred for 3 days at 120 °C under 10 atm of carbon monoxide. The reaction was cooled to RT and concentrated. The residue was diluted with H2O (1,000 mL), then extracted with EtOAc (2 x 2000 mL). The combined organic layers were washed with brine (2 x 1,000 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (1,100 mL) and then filtered. The filter cake was dried at 50 °C for ~18 h to obtain the title compound as a yellow solid (300 g, 81%). MS (ES) m / z=153 (M+1).Preparation 7 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one

[0214] To a stirred mixture of 5-fluoroisobenzofuran-1(3H)-one (300 g, 1.97 mol) in H2SO4(1,500 mL) was added HNO3(273.38 g, 4.348 mol, 2.2 eq.) dropwise at 65 °C. The reaction was stirred for 1 h then cooled to RT.1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (2,255.43 g, 7.88 mol, 4 eq.) was added in portions over 20 min and was stirred at RT for ~18 h. The mixture was poured onto ice / water (pre-treated with 3 kg Na2SO3) and filtered. The filter cake was dissolved in EtOAc (3,000 mL), washed with sat. aq. Na2CO3 (2 x 1,000 mL), brine (2 x 1,000 mL), dried over anhydrous Na2SO4 and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (660 mL) and was filtered and dried at 50 °C for ~18 h to obtain the title compound as a yellow solid (270 g, 49%) which was used in a subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 5.51 (s, 2H). Preparation 8 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran

[0215] To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one (270 g, 978 mmol) in DCM (2,500 mL) was added DIBAL-H (1M in THF, 1,467 mL, 1.467 mol, 1.5 eq.) dropwise at -78 °C under N2. The reaction was stirred for 5 h at -78 °C, then was quenched with 5N NaOH (300 mL) at -78 °C. The resulting mixture was allowed to warm to RT, then was concentrated. The residue was diluted with EtOAc (2,500 mL), washed with brine (2 x 1,000 mL) and dried over anhydrous Na2SO4 and concentrated. The residue was trituratedwith 10:1 hexanes / EtOAc (550 mL) and filtered. The solids were dried (190 g, 683.4 mmol) then dissolved in DCM (1,500 mL) and treated dropwise with Et3SiH (662 mL, 4.10 mol, 6 eq.) at 0 °C. The reaction was stirred for 20 min at 0 °C. TFA (152 mL, 2.05 mol, 3 eq.) was added dropwise at 0 °C. The ice bath was removed, and the reaction was stirred at RT for ~18 h. The reaction was concentrated to an oil, which was diluted with EtOAc (2,000 mL), washed with sat. aq. Na2CO3 (2 x 500 mL) and brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain the title compound (110 g, 42%) which was used in a subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J= 6.2 Hz, 1H), 5.18 – 5.15 (m, 2H), 5.11 – 5.06 (m, 2H). Preparation 9 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine

[0216] To a stirred mixture of 4-bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 eq.) in EtOH (1,000 mL) and H2O (200 mL) was added Fe (117.22 g, 2.09 mol, 5 eq.) in portions at RT, then stirred for ~ 18 h at 80 °C. The mixture was filtered and concentrated. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (2 x 1,000 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica (25% to 50% EtOAc / Hex) to afford the title compound (70 g, 72%) as a yellow solid. MS (ES) m / z=231 (M+1). Preparation 10 (4-Chloro-1,2-phenylene)dimethanol

[0217] To a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 eq., 2.5 M in THF) in THF (1 L) was added 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 eq.) in THF (500 mL) dropwise at -20 °C under N2. The resulting mixture was stirred for 30 min at 45 °C under N2. The reaction was quenched by the addition of H2O (1.5 L) and 15% NaOH (500 mL) at RT. The mixture was filtered, and the filter cake was washed with MTBE (3 x 250 mL). The filtrate was extracted with MTBE (3 x 1.5 L). The combined organic layers were washed with brine (2 x 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (219.5 g, 93%) as an off-white solid.1H 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, 2H), 4.54 (s, 2H), 4.49 (s, 2H). Preparation 11 5-Chloro-1,3-dihydroisobenzofuran

[0218] To a stirred mixture of (4-chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 eq.) in ACN (3 L) was added NaOMe (137.4 g, 2.544 mol, 2 eq.) in portions at RT. The resulting mixture was stirred for ~18 h at 80 °C under N2. The mixture was concentrated under reduced pressure, diluted with H2O (2 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica (10:1 to 8:1 hex / EtOAc) to obtain the title compound (165 g, 82%) as a light-brown solid.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). Preparation 12 5-Chloro-6-nitro-1,3-dihydroisobenzofuran

[0219] A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) at -10 °C was charged with a solution of KNO3 (64.74 g, 640 mmol, 0.9 eq.) in H2SO4 (200 mL) dropwise at -5 °C – 0 °C. The resulting mixture was stirred for additional 30 min at 0 °C and then was slowly added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H2O (3 x 1 L). The filter cake was dried in vacuo to afford the title compound (110 g, 77 %) as a light-brown solid which was used in a subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07 – 5.02 (m, 4H). Preparation 13 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran

[0220] To a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4(700 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, 1 eq.) in portions at -10 °C. The mixture was stirred for 1 h at -10 °C then slowly was added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H2O (3 x 0.5 L). The filter cake was dried in vacuo and purified on silica (10:1 to 5:1 Hex / EtOAc) to obtain the title compound (83.5 g, 47.9%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=1.1 Hz,1H), 5.19 (dt, J=2.3, 1.1 Hz, 2H), 5.08(t, 2H). Preparation 14 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine

[0221] To a stirred mixture of 4-bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 eq.) in EtOH (200 mL) and H2O (40 mL) was added Fe (44.52 g, 797.2 mmol, 6 equiv.) in portions at RT. The resulting mixture was stirred for ~18 h at 80 °C. The resulting mixture was filtered hot and the filter cake was washed with EtOAc (3 x 500 mL). The filtrate was concentrated under reduced pressure and was purified on silica (15:1 to 10:1 Hex / EtOAc) to obtain the title compound (25 g, 76%) as a light-yellow solid. MS (ES) m / z=248 (M+1). Preparation 15 Ethyl N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate

[0222] A solution of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL) was charged with ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 eq.) slowly via addition funnel and subsequently stirred at RT for ~ 4 h. The solids were filtered. The filtrate was concentrated, suspended in DCM (100 mL) and hexanes (350 mL) and stirred at RT. The resultant filtered solids and previous filtered solids were dried under vacuum at 50 °C for 2 h. The batches were combined to obtain the title compound (32.6 g, quantitative) as a white solid. MS (ES) m / z=363 (M+1).Preparation 16 Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate

[0223] 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner analogous to the method of Preparation 15 to afford the title compound (14 g, 92%) as a white solid. MS (ES) m / z=379 (M+1). Preparation 17 Ethyl (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate

[0224] A 2L 3-necked RBF, equipped with an overhead stirrer, dropping funnel and thermocouple was charged with a suspension of ethyl N-[(7-bromo-6-fluoro-1,3- dihydroisobenzofuran-5-yl)carbamothioyl]carbamate (32.6 g, 89.8 mmol) and acetone (450 mL). To this was added solid K2CO3 (37.2 g, 269 mmol, 3.00 eq.) in several portions, followed by the dropwise addition of EtI (7.2 mL, 90 mmol, 1.0 eq.) over 20 min. The mixture was stirred at RT for ~18 h. The solids were filtered and the filtrate was concentrated and partitioned between DCM (500 mL) and H2O (500 mL). The organics were further washed with brine and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica (0 to 30% EtOAc / Hex) to obtain the title compound (30.9 g, 85.6%) as a white solid. MS (ES) m / z=391 (M+1).Preparation 18 Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate

[0225] Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate was used in a manner analogous to the method of Preparation 17 to afford the title compound (15.4 g, crude) as a brown solid. MS (ES) m / z=407 (M+1). Preparation 19 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0226] A 2L 4-necked RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet and thermocouple and was purged with N2. NMP (anhydrous, 300 mL) was added. The mixture was heated to 175 °C. In a second flask, ethyl (((7-bromo-6-fluoro-1,3- dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate (22.63 g, 57.83 mmol) and NMP (anhydrous, 100 mL) were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask had reached 175 °C, the contents of the second flask were poured into the dropping funnel and were added dropwise but rapidly to the hot NMP. After 30 min, the heat was turned off and the reaction cooled to 45 °C. H2O (500 mL) was slowly added and the mixture was stirred at RT for 1 h. The solids were filtered, rinsed with H2O (300 mL) and dried under vacuum at 50 °C for ~18 h to afford the title compound (15.2 g, 73%) as an off-white solid. MS (ES) m / z=363 (M+1).Preparation 20 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0227] Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5- yl)amino)(ethylthio)methylene)carbamate was used in a manner analogous to the method of Preparation 19 to afford the title compound (11.4 g, 86%) as a white solid. MS (ES) m / z=361 (M+1). Preparation 21 6-Bromo-3-(ethylthio)-5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydrofuro[3,4- f]quinazolin-1(2H)-one

[0228] A mixture of 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (30.1 g, 87.3 mmol) in DMF was heated to ~70 °C to dissolve the solids, then cooled to 40 °C. To the mixture was added diisopropylethylamine (30.4 mL, 175 mmol) and 2- (chloromethoxyethyl)trimethyl silane (23.2 mL, 131 mmol). The reaction mixture was stirred for 1 h at 40 °C, then cooled to room temperature and diluted with water (1 L) and EtOAc (500 mL). The layers were separated and the organic layer was washed with brine (2 x 500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (49.2 g, 85% purity) as a yellow oil. MS (ES) m / z=475 (M+1). Preparation 22 6-Bromo-5-chloro-3-(ethylthio)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydrofuro[3,4-f]quinazolin-1(2H)-one

[0229] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol was used in a manner analogous to the method of Preparation 21 to afford the title compound (10.5 g, 96%) as a pink solid. MS (ES) m / z=491 (M+1). Preparation 23 6-Bromo-3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofuro[3,4-f]quinazoline

[0230] To a 0 °C mixture of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazoline (6.50 g, 17.9 mmol) and 2-(trimethylsilyl)ethan-1-ol (3.04 mL, 21.5 mmol) in THF (60 mL) was added potassium tert-butoxide (2.68 mL, 23.2 mmol) in three portions. The mixture was stirred at room temperature. After 1 h, the mixture was diluted with saturated aqueous ammonium chloride, then extracted with methyl-THF (200 mL). The organics were dried over magnesium sulfate and concentrated under reduced pressure to give the crude title compound (7.5 g, 94%) as a white solid. MS (ES) m / z=445 (M+1). Preparation 24 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

[0231] A 5L 3-necked RBF, equipped with a dropping funnel, thermocouple and an overhead stirrer was charged with a solution of DMF (50 mL, 646 mmol, 4 eq.) in DCM (1,000 mL) and was placed in an ice / water bath and cooled to ~4 °C. Oxalyl chloride (50.0 mL, 576 mmol, 4 eq.) was added dropwise via addition funnel over ~40 min. When the addition was complete, the reaction was stirred at ~4 °C for 15 min. Solid 6-bromo-3-(ethylthio)-5-fluoro- 7,9-dihydrofuro[3,4-f]quinazolin-1-ol (50.4 g, 140 mmol) was added in several portions to the reaction mixture and the resulting suspension was stirred at ~4 °C for 30 min. The ice bath was removed and the reaction was allowed to warm to RT and stir for 1 h. Then H2O (1 L) was added and the mixture was stirred for 15 min. The mixture was partitioned and the organic layer was washed with brine (1 L) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with DCM / Hex (60% to 90%) to obtain the title compound (45.1g, 89%) as a white solid. MS (ES) m / z=363 (M+1). Preparation 25 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline

[0232] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol was used in a manner analogous to the method of Preparation 24 to afford the title compound (0.81 g, 77%) as a yellow solid. MS (ES) m / z=382 (M+1). Preparation 26 tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate

[0233] 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (0.80 g, 2.32 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate (1.12 g, 2.78 mmol) and cesium carbonate (2.27 g, 6.95 mmol) were combined in DMF (12 mL) and the mixture was degassed by sparging with argon for 10 min. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (Pd-117, 0.166 g, 0.232 mmol) was added and the mixture was heated to 100 °C. After 24 h, the mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain the title compound (0.96 g, 74%) as a yellow solid. MS (ES) m / z=557 (M+1).

[0234] The following compounds in Table 1 were prepared in similar manner as described in Preparation 26. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 1: MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- 27 f]quinazolin-6-yl)-3- 573 cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamatetert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- 281cyano-7- 573 fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 2 tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- hydroxy-7,9- 29 dihydrofuro[3,4- 532 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 302tetrahydrofuro[3,4- 662 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 1 tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 31 tetrahydrofuro[3,4- 678 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamatetert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 323tetrahydrofuro[3,4- 678 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 1 1 Prep-Chiral-HPLC; Phenomenex Lux Cellulose-5, 30 x 150 mm, 18-30% (1:1 methanol:ethanol) in heptane, 42.5 mL / min 2 Chiral SFC; Chiralpak IC, 50 x 250 mm, 25% (methanol w / 0.2% dimethylethylamine) in CO2, 300 g / min 3 Chiral SFC; Chiralpak IC, 20 x 250 mm, 25% (isopropanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min Preparation 33 tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2-yl)carbamate

[0235] A mixture of tert-butyl (4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at -40 °C. Sulfurisocyanatidic chloride (0.184 mL, 2.12 mmol) was slowly added and the mixture was allowed to warm to 0 °C. After consumption of the starting material (monitored by LCMS), the mixture was cooled to 0 °C. DMF (4 mL) was slowly added. Upon reaction completion (monitored by LCMS), the mixture was diluted with DCM (20 mL) and saturated aq. ammonium chloride (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3x 30 mL). The combined organics were passed through a hydrophobic frit and concentrated under reduced pressure to obtain the crude title compound. MS (ES) m / z=557 (M+1).

[0236] The following compounds in Table 2 were prepared in similar manner as described in Preparation 33. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 2: MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-1- oxo-2-((2- (trimethylsilyl)ethoxy)me 341thyl)-1,2,7,9- 687 tetrahydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 35 tetrahydrofuro[3,4- 703 f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 362tetrahydrofuro[3,4- 703 f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate 1 Clean atropisomer, chiral purification from Preparation 302Clean atropisomer, chiral purification from Preparation 32 Preparation 37 tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0237] 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-5-fluoro-1-(2- (trimethylsilyl)ethoxy)-7,9-dihydrofuro[3,4-f]quinazoline. A mixture of 6-bromo-3- (ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofuro[3,4-f]quinazoline (30.59 g, 68.68 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (26.37 g, 116.8 mmol), potassium acetate (20.22 g, 206.0 mmol), and Pd-117 (CAS 205319-06-8; 0.738 g, 1.03 mmol) in 1,4-dioxane (343 mL) was degassed (direct nitrogen sparge). The mixture was then stirred at 90 °C for 16 h, cooled, and filtered through diatomaceous earth to give crude 6- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)- 7,9-dihydrofuro[3,4-f]quinazoline in 1,4-dioxane.

[0238] tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A mixture of tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (22.51 g, 68.68 mmol), dipotassium phosphate (35.89 g, 206.0 mmol) in water (206 mL), and XPhos Pd(crotyl)Cl (CAS 1798782-02-1; 2.31 g, 3.43 mmol) in 1,4-dioxane (172 mL) was degassed (direct nitrogen sparge). The mixture was then stirred at 90 °C and the solution of 6-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9- dihydrofuro[3,4-f]quinazoline (32.86 g, 68.68 mmol) in 1,4-dioxane (~340 mL) was added dropwise. The mixture was stirred at 90 °C for 30 min, cooled, and concentrated underreduced pressure. The residue was diluted with water (500 mL) and ethyl acetate (1 L). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with MTBE (200 mL) and stirred for 16 h. The solids were filtered and dried at 45 °C to obtain the title compound (89% purity, 23.24 g, 46%). MS (ES) m / z=658 (M+1).

[0239] The following compounds in Table 3 were prepared in similar manner as described in Preparation 37. Different coupling conditions, such as base, ligands or palladium sources may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 3: MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 38 tetrahydrofuro[3,4- 704 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy)me thyl)-1,2,7,9- 391tetrahydrofuro[3,4- 704 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate, Atropisomer 1 1 Chiral SFC; Chiralpak ID, 20 x 250 mm, 35% (isopropanol w / 0.5% dimethylethylamine) in CO2, 80 mL / minPreparation 40 tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2-yl)carbamate

[0240] To a mixture of tert-butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-oxo-2-((2- (trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofuro[3,4-f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2-yl)carbamate (19.2 g, 26.3 mmol) in THF (192 mL) was added activated molecular sieves (4 angstrom, 38 g), followed by tetrabutylammonium fluoride (1M in THF, 105 mL, 105 mmol). The reaction mixture was heated for 9 h at a bath temperature of 80 °C, then cooled to room temperature. Additional activated molecular sieves (4 angstrom, 17 g) were added, and the reaction mixture was heated overnight at a bath temperature of 80 °C, then cooled to room temperature. The mixture was filtered and the filter cake was washed with EtOAc. The combined filtrates were concentrated under reduced pressure, diluted with 2-methyltetrahydrofuran (300 mL), and washed with water (3 x 300 mL). The combined aqueous layers were extracted with 2-methyltetrahydrofuran (300 mL). The combined organic layers were washed with 5% aqueous citric acid (300 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified on silica, eluting with 0-60% EtOAc in cyclohexane to obtain the title compound (9.42 g) as a yellow foam. MS (ES) m / z=557 (M+1). Clean atropisomer, chiral purification from Preparation 30.

[0241] The following compounds in Table 4 were prepared in similar manner as described in Preparation 40. Different deprotection conditions, such as cesium fluoride in DMF, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 4:MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- 41 f]quinazolin-6-yl)-3- 573 cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- 421f]quinazolin-6-yl)-3- 573 cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- 43 f]quinazolin-6-yl)-3- 574 cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- 442f]quinazolin-6-yl)-3- 574 cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 1 Clean atropisomer, chiral purification from Preparation 32 1 Clean atropisomer, chiral purification from Preparation 39

[0242] The following compounds in Table 5 were prepared in similar manner as described in Preparation 24. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.Table 5: MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (3-cyano-4- (1,5-dichloro-3- (ethylthio)-7,9- 451dihydrofuro[3,4- 591 f]quinazolin-6-yl)-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(1-chloro-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- 46 f]quinazolin-6-yl)-3- 575 cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate 1 Clean atropisomer, chiral purification from Preparation 28 Preparation 47 (6S)-3-Amino-1,6-dimethylpiperidin-2-one

[0243] (S)-1,6-Dimethylpiperidin-2-one. To a solution of (S)-6-methylpiperidin-2-one (0.500 g, 4.42 mmol) in THF (5 mL) was added sodium hydride (60 wt% in mineral oil; 0.212 g, 5.30 mmol). The mixture was stirred at room temperature for 30 min, then cooled to 0 °C. A solution of iodomethane (0.41 mL, 6.63 mmol) in THF (0.3 mL) was added dropwise and the mixture was stirred at 0 °C for 5 min, then warmed to room temperature and stirred overnight. The mixture was diluted with water (5 mL) and extracted with EtOAc and DCM. The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude (S)-1,6-dimethylpiperidin-2-one as a white solid. MS (ES) m / z=128 (M+1).

[0244] (6S)-3-Chloro-1,6-dimethylpiperidin-2-one. A solution of (S)-1,6-dimethylpiperidin- 2-one (0.600 g, 4.72 mmol) in THF (2 mL) was cooled to -78 °C. Lithium diisopropylamide (2.0M in THF / heptane / ethylbenzene; 3.07 mL, 6.13 mmol) was added. The mixture was stirred at -78 °C for 20 min, then a solution of tosyl chloride (2.70 g, 14.2 mmol) in THF (0.5 mL) was slowly added. The mixture was stirred at -78 °C for 90 min. The mixture was diluted with water and extracted with DCM. The organics were dried over anhydrous Na2SO4 and purified on silica, eluting with 0-40% MeOH in DCM to obtain crude (6S)-3-chloro-1,6- dimethylpiperidin-2-one as a brown oil. MS (ES) m / z=162 (M+1).

[0245] (6S)-3-Amino-1,6-dimethylpiperidin-2-one. A solution of (6S)-3-chloro-1,6- dimethylpiperidin-2-one (0.250 g, 1.55 mmol) in acetonitrile (5 mL) and ammonium hydroxide (5 mL) was heated under microwave irradiation at 80°C for 22 h. The mixture was concentrated under reduced pressure to give the title compound (0.220 g, crude) as a brown oil. MS (ES) m / z=143 (M+1).

[0246] The following compounds in Table 6 were prepared in similar manner as described in Preparation 47. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 6: MS Preparation Chemical Name Structure (ES) m / z (M+1) (6R)-3-Amino-1,6- 48 dimethylpiperidin-2-one 143 3-Amino-1,5- 49 dimethylpiperidin-2-one 143 3-Amino-1,5,5- 50 trimethylpiperidin-2-one 1573-Amino-6-cyclopropyl- 51 1-methylpiperidin-2-one 169 Preparation 52 tert-Butyl (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0247] To a mixture of tert-butyl (3-cyano-4-(1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.454 g, 0.768 mmol) and (R)- 3-amino-1-methylpiperidin-2-one hydrochloride (0.190 g, 1.15 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.67 mL, 3.84 mmol). The mixture was stirred at rt. After 16 h, the mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% EtOAc in heptane to obtain the title compound (0.473 g, 90%) as a white solid. MS (ES) m / z=683 (M+1). Clean atropisomer, chiral purification from Preparation 28.

[0248] The following compounds in Table 7 were prepared in similar manner as described in Preparation 52. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 7: MS Preparation Chemical Name Structure (ES) m / z (M+1)tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((1,5,5- trimethyl-2-oxopiperidin- 3-yl)amino)-7,9- 531dihydrofuro[3,4- 711 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3-(ethylthio)- 5417,9-dihydrofuro[3,4- 697 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3-(ethylthio)- 5517,9-dihydrofuro[3,4- 723 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-1- (((R)-1-methyl-2- oxopiperidin-3- 56 yl)amino)-7,9- 667 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate1Clean atropisomer, chiral purification from Preparation 28 Preparation 57 tert-Butyl (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0249] To a mixture of tert-butyl (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (2.06 g, 3.59 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (3.74 g, 7.19 mmol), and (R)-3-amino-1-methylpiperidin-2-one hydrochloride (0.710 g, 4.31 mmol) in acetonitrile (36 mL) was added diisopropylethylamine (3.71 mL, 21.6 mmol). The mixture was stirred at RT overnight. The mixture was diluted with water (40 mL) and the volatiles were removed under reduced pressure. The resulting material was extracted with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified on silica, eluting with 30-80% EtOAc in hexanes to obtain the title compound (2.5 g, 100%) as a yellow solid. MS (ES) m / z=683 (M+1).

[0250] The following compounds in Table 8 were prepared in similar manner as described in Preparation 57. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 8: MS Preparation Chemical Name Structure (ES) m / z (M+1)tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-1- (((R)-1-methyl-2- oxopiperidin-3- 581yl)amino)-7,9- 667 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 592dihydrofuro[3,4- 683 f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 60 dihydrofuro[3,4- 684 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 613dihydrofuro[3,4- 684 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate1Clean atropisomer, chiral purification from Preparation 30 2 Clean atropisomer, chiral purification from Preparation 32 3 Clean atropisomer, chiral purification from Preparation 39 Preparation 62 tert-Butyl (4-(5-chloro-3-(ethylsulfonyl)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0251] To a solution of tert-butyl (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate (0.473 g, 0.692 mmol) in DCM (5 mL) was added mCPBA (70 wt%; 0.375 g, 1.52 mmol) portionwise at 0 °C. The mixture was stirred at 0 °C for 30 min, then at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude material was purified on silica, eluting with 0-100% EtOAc in DCM to obtain the title compound (0.365 g, 74%) as a white solid. MS (ES) m / z=715 (M+1). Clean atropisomer, chiral purification from Preparation 28.

[0252] The following compounds in Table 9 were prepared in similar manner as described in Preparation 62. Different oxidation conditions, such as hydrogen peroxide and hexaammonium heptamolybdate tetrahydrate in ethanol and DCM, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 9:MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((1,5,5- trimethyl-2-oxopiperidin- 3-yl)amino)-7,9- 631dihydrofuro[3,4- 743 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3- (ethylsulfonyl)-7,9- 641dihydrofuro[3,4- 729 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3- (ethylsulfonyl)-7,9- 651dihydrofuro[3,4- 755 f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamatetert-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 1-(((R)-1-methyl-2- oxopiperidin-3- 66 yl)amino)-7,9- 699 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 67 dihydrofuro[3,4- 715 f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 1-(((R)-1-methyl-2- oxopiperidin-3- 682yl)amino)-7,9- 699 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 693dihydrofuro[3,4- 715 f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamatetert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 70 dihydrofuro[3,4- 716 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 714dihydrofuro[3,4- 716 f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 1-(2- (trimethylsilyl)ethoxy)- 72 7,9-dihydrofuro[3,4- 690 f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- hydroxy-7,9- dihydrofuro[3,4- 73 f]quinazolin-6-yl)-3- 605 cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate1Clean atropisomer, chiral purification from Preparation 282Clean atropisomer, chiral purification from Preparation 30 3 Clean atropisomer, chiral purification from Preparation 32 4 Clean atropisomer, chiral purification from Preparation 39 Preparation 74 tert-Butyl (2S)-2-methyl-3-morpholinopyrrolidine-1-carboxylate

[0253] To a solution of tert-butyl (S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.00 g, 5.02 mmol), morpholine (0.656 g, 7.53 mmol), and acetic acid (0.29 mL, 5.02 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride (1.70 g, 8.03 mmol). The mixture was stirred at room temperature. After 12 h, the mixture was diluted with DCM (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure to give the crude title compound (1.3 g, 96%). MS (ES) m / z=271 (M+1). Preparation 75 tert-Butyl (S)-3-(methyl((R)-tetrahydrofuran-3-yl)amino)pyrrolidine-1-carboxylate

[0254] (R)-N-methyltetrahydrofuran-3-amine (0.381 g, 3.77 mmol) and diisopropylethylamine (0.72 mL, 4.14 mmol) were added to tert-butyl (R)-3- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.500 g, 1.88 mmol). The reaction mixture was stirred for 16 h at 85 °C. The mixture was cooled to room temperature and diluted with MeOH (1 mL). The material was purified on strong cation exchange media (25 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain the crude title compound. MS (ES) m / z=271 (M+1).Preparation 76 tert-Butyl (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1-carboxylate

[0255] tert-Butyl (2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (0.500 g, 2.50 mmol), acetone (0.275 mL, 3.74 mmol), and sodium triacetoxyborohydride (1.59 g, 7.49 mmol) were dissolved in methanol (6 mL). The mixture was heated at 50 °C. After 18 h, the mixture was cooled, concentrated under reduced pressure, and diluted with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with EtOAc (3 x 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 (0.600 g) as a colorless oil. MS (ES) m / z=243 (M+1).

[0256] The following compounds in Table 10 were prepared in similar manner as described in Preparation 76. Different reductive amination conditions, such as sodium cyanoborohydride with sodium dihydrogen phosphate, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 10: MS Preparation Chemical Name Structure (ES) m / z (M+1) tert-Butyl (2S,3S)-3- (dimethylamino)-2- 77 methylpyrrolidine-1- 229 carboxylate tert-Butyl (3S,4S)-3- (dimethylamino)-4- 78 methoxypyrrolidine-1- 245 carboxylatetert-Butyl (3R,4R)-3- (dimethylamino)-4- 79 methoxypyrrolidine-1- 245 carboxylate tert-Butyl (3S,4R)-3- hydroxy-4- 80 (isopropyl(methyl)amino) 259 pyrrolidine-1-carboxylate tert-Butyl (3R,4S)-3- (dimethylamino)-4- 81 hydroxypyrrolidine-1- 231 carboxylate tert-Butyl (3S,4R)-3- (dimethylamino)-4- 82 hydroxypyrrolidine-1- 231 carboxylate tert-Butyl (3S,4S)-3- fluoro-4- 83 (isopropylamino)pyrrolid 247 ine-1-carboxylate tert-Butyl (3S,4R)-3- fluoro-4- 84 (isopropylamino)pyrrolid 247 ine-1-carboxylate tert-Butyl (3R,4S)-3- fluoro-4- 85 (isopropylamino)pyrrolid 247 ine-1-carboxylate tert-Butyl (3R,4S)-3- fluoro-4- 86 (isopropyl(methyl)amino) 261 pyrrolidine-1-carboxylate tert-Butyl (3R,4S)-3- (isopropylamino)-4- 87 methylpyrrolidine-1- 243 carboxylatetert-Butyl (3R,4S)-3- (isopropyl(methyl)amino) 88 -4-methylpyrrolidine-1- 257 carboxylate tert-Butyl (3R,4R)-3- (dimethylamino)-4- 89 fluoropyrrolidine-1- 233 carboxylate tert-Butyl (3S,4S)-3- (dimethylamino)-4- 90 fluoropyrrolidine-1- 233 carboxylatetert-Butyl (3R,4S)-3- (dimethylamino)-4- 91 fluoropyrrolidine-1- 233 carboxylate tert-Butyl (2S,4R)-4- (dimethylamino)-2- 92 methylpyrrolidine-1- 229 carboxylate tert-Butyl (2R,4S)-4- (dimethylamino)-2- 93 methylpyrrolidine-1- 229 carboxylate tert-Butyl (2S,4S)-4- (dimethylamino)-2- 94 methylpyrrolidine-1- 229 carboxylate tert-Butyl (2R,4R)-4- (dimethylamino)-2- 95 methylpyrrolidine-1- 229 carboxylate tert-Butyl 3-(1- (dimethylamino)cyclopro 96 pyl)azetidine-1- 241 carboxylatetert-Butyl (2S,4S)-4- (dimethylamino)-2- 97 (methoxymethyl)pyrrolid 259 ine-1-carboxylate Preparation 98 (2S,3S)-N-Isopropyl-2-methylpyrrolidin-3-amine dihydrochloride

[0257] To a mixture of tert-butyl (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1- carboxylate (0.600 g, 2.48 mmol) in DCM (3 mL) was added HCl (4M in 1,4-dioxane; 3 mL). The mixture was stirred at room temperature. After 6 h, the mixture was concentrated under reduced pressure to give the crude title compound (0.533 g) as a yellow solid. MS (ES) m / z=143 (M+1).

[0258] The following compounds in Table 11 were prepared in similar manner as described in Preparation 98. Different acidic conditions, such as trifluoroacetic acid, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 11: MS Preparation Chemical Name Structure (ES) m / z (M+1) (2S,3S)-N,N,2- 99 Trimethylpyrrolidin-3- 129 amine dihydrochloride (3S,4S)-4-Methoxy-N,N- 100 dimethylpyrrolidin-3- 145 amine dihydrochloride(3R,4R)-4-Methoxy-N,N- 101 dimethylpyrrolidin-3- 145 amine (3S,4R)-4- (Isopropyl(methyl)amino 102 )pyrrolidin-3-ol dihyrdrochloride (3S,4R)-4- 103 (Dimethylamino)pyrrolid 131 in-3-ol (3R,4S)-4- 104 (Dimethylamino)pyrrolid 131 in-3-ol 4-((2S,3S)-2- Methylpyrrolidin-3- 105 yl)morpholine 171 dihydrochloride (3S,4S)-4-Fluoro-N- 106 isopropylpyrrolidin-3- 147 amine (3R,4S)-4-Fluoro-N- 107 isopropylpyrrolidin-3- 147 amine (3S,4R)-4-Fluoro-N- 108 isopropylpyrrolidin-3- 147 amine (3S,4R)-4-Fluoro-N- 109 isopropyl-N- 161 methylpyrrolidin-3-amine (3R,4S)-N-Isopropyl- 110 N,4-dimethylpyrrolidin- 157 3-amine(3R,4R)-4-Fluoro-N,N- 111 dimethylpyrrolidin-3- amine dihydrochloride (3S,4S)-4-Fluoro-N,N- 112 dimethylpyrrolidin-3- 133 amine(3R,4S)-4-Fluoro-N,N- 113 dimethylpyrrolidin-3- 133 amine(3R,5S)-N,N,5- 114 Trimethylpyrrolidin-3- 129 amine (3S,5R)-N,N,5- 115 Trimethylpyrrolidin-3- 129 amine dihydrochloride (3S,5S)-N,N,5- 116 Trimethylpyrrolidin-3- 129 amine dihydrochloride (3R,5R)-N,N,5- 117 Trimethylpyrrolidin-3- 129 amine dihydrochloride 1-(Azetidin-3-yl)-N,N- 118 dimethylcyclopropan-1- 141 amine (S)-N-Methyl-N-((R)- 119 tetrahydrofuran-3- 171 yl)pyrrolidin-3-amine 4-((2S)-2- Methylpyrrolidin-3- 120 yl)morpholine 171 dihydrochloride(3S,5S)-5- (Methoxymethyl)-N,N- 121 dimethylpyrrolidin-3- 159 amine dihydrochloride Preparation 122 (R)-(4-Methyl-1,4-oxazepan-3-yl)methanol

[0259] A mixture of (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-3-carboxylic acid (1.00 g, 4.08 mmol and lithium aluminum hydride (1M in THF; 10 mL, 10 mmol) in THF (5 mL) was stirred under nitrogen at 50 °C for 3 h, then at RT overnight. The mixture was diluted with EtOAc (20 mL), followed by water (0.40 mL), aqueous NaOH (2M, 0.40 mL), and water (1.2 mL). The mixture was stirred at RT for 30 min, then filtered through diatomaceous earth to remove the resulting solids. The filtrate was concentrated under reduced pressure and the crude residue was purified on strong cation exchange media (10 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain the title compound (0.542 g, 92%) as a colorless oil. Preparation 123 (S)-(4-Methyl-1,4-oxazepan-3-yl)methanol

[0260] (R)-4-(tert-butoxycarbonyl)-1,4-oxazepane-3-carboxylic acid was used in a manner analogous to the method of Preparation 122 to afford the crude title compound (0.538 g, 91%) as a colorless oil. Preparation 124 tert-Butyl (4-(5-chloro-3-((4-hydroxytetrahydrofuran-2-yl)methoxy)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate

[0261] To a solution of 5-(hydroxymethyl)tetrahydrofuran-3-ol (0.0064 g, 0.054 mmol) in DMF (2 mL) was added sodium hydride (60 wt% in mineral oil; 0.0022 g, 0.054 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. A solution of tert-butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.035 g, 0.049 mmol) in DMF (1 mL) was added dropwise. The mixture was stirred at room temperature for 12 h, then quenched with water (2 mL). The crude mixture was purified by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in water (0.1% formic acid), to give the title compound (0.025 g; 69%). MS (ES) m / z=739 (M+1). Clean atropisomer, chiral purification from Preparation 28. Preparation 125 tert-Butyl (4-(5-chloro-3-((2S)-4-hydroxy-2-methylpyrrolidin-1-yl)-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate

[0262] tert-Butyl (4-(5-chloro-3-(ethylsulfonyl)-1-(((R)-1-methyl-2-oxopiperidin-3- yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2- yl)carbamate (0.150 g, 0.210 mmol), (5S)-5-methylpyrrolidin-3-ol (0.087 g, 0.629 mmol), CsF (0.016 g, 0.105 mmol), and diisopropylethylamine (0.53 mL, 3.15 mmol) were combined in acetonitrile (4 mL) and stirred at 75 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 10-100% acetonitrile in 10 mM aqueous ammonium bicarbonate with 5% MeOH, to give the title compound (0.080 g; 53%). MS (ES) m / z=722 (M+1). Clean atropisomer, chiral purification from Preparation 28.

[0263] The following compounds in Table 12 were prepared in similar manner as described in Preparations 124 and 125. Different bases, such as lithium bis(trimethylsilyl)amide, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 12: MS Prep Chemical Name Structure (ES) m / z (M+1) tert-Butyl (3-cyano-7-fluoro-4- (5-fluoro-3-(((2R,4R)-4-fluoro- 1-methylpyrrolidin-2- 1265yl)methoxy)-1-hydroxy-7,9- 629 dihydrofuro[3,4-f]quinazolin- 6-yl)thieno[3,2-c]pyridin-2- yl)carbamatetert-Butyl (3-cyano-4-(3-(((R)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- 1275hydroxy-7,9-dihydrofuro[3,4- 647 f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (3-cyano-4-(3-(((S)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- 1285hydroxy-7,9-dihydrofuro[3,4- 647 f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-hydroxy-2- methylpyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 1291yl)amino)-7,9-dihydrofuro[3,4- 722 f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3- ((3R,4R)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 1301yl)amino)-7,9-dihydrofuro[3,4- 753 f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-1-(((R)- 1-methyl-2-oxopiperidin-3- yl)amino)-3-(((S)- tetrahydrofuran-2-yl)methoxy)- 13117,9-dihydrofuro[3,4- 723 f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((2S,4S)-4-(dimethylamino)-2- (methoxymethyl)pyrrolidin-1- yl)-1-(((R)-1-methyl-2- 1321oxopiperidin-3-yl)amino)-7,9- 779 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-((1,5,5-trimethyl-2- oxopiperidin-3-yl)amino)-7,9- 1331749 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-1-((1,5- dimethyl-2-oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin-1-yl)- 13417,9-dihydrofuro[3,4- 735 f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-1-((6- cyclopropyl-1-methyl-2- oxopiperidin-3-yl)amino)-3-(3- (dimethylamino)azetidin-1-yl)- 13517,9-dihydrofuro[3,4- 761 f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-hydroxy-7,9- 136 dihydrofuro[3,4-f]quinazolin- 611 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3-((S)- 3-(dimethylamino)pyrrolidin- 1-yl)-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9- 1372dihydrofuro[3,4-f]quinazolin- 735 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4S)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 1382yl)amino)-7,9-dihydrofuro[3,4- 753 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3-(3-(1- (dimethylamino)cyclopropyl)a zetidin-1-yl)-1-(((R)-1-methyl- 2-oxopiperidin-3-yl)amino)- 13927,9-dihydrofuro[3,4- 761 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3R,4S)-3-fluoro-4- (isopropylamino)pyrrolidin-1- yl)-1-(((R)-1-methyl-2- 1402oxopiperidin-3-yl)amino)-7,9- 767 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-((S)- 3- (isopropyl(methyl)amino)pyrro lidin-1-yl)-1-(((R)-1-methyl-2- 1412oxopiperidin-3-yl)amino)-7,9- 763 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-((3- hydroxytetrahydrofuran-2- yl)methoxy)-1-(((R)-1-methyl- 142 2-oxopiperidin-3-yl)amino)- 2, 67,9-dihydrofuro[3,4- 739 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3- ((2S,4R)-4-(dimethylamino)-2- methylpyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 1432yl)amino)-7,9-dihydrofuro[3,4- 749 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-((S)- 2-methoxypropoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 1442yl)amino)-7,9-dihydrofuro[3,4- 711 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4S)-3-fluoro-4- (isopropylamino)pyrrolidin-1- yl)-1-(((R)-1-methyl-2- 1452oxopiperidin-3-yl)amino)-7,9- 767 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(3-([1,3'- biazetidin]-1'-yl)-5-chloro-1- (((R)-1-methyl-2-oxopiperidin- 3-yl)amino)-7,9- 1462dihydrofuro[3,4-f]quinazolin- 733 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3- ((3R,4S)-3-(dimethylamino)-4- hydroxypyrrolidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin- 14723-yl)amino)-7,9- 751 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4R)-3-(dimethylamino)-4- hydroxypyrrolidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin- 14823-yl)amino)-7,9- 751 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-(((R)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-1-(((R)-1-methyl- 14922-oxopiperidin-3-yl)amino)- 772 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-(((S)- 4-methyl-1,4-oxazepan-3- yl)methoxy)-1-(((R)-1-methyl- 2-oxopiperidin-3-yl)amino)- 15027,9-dihydrofuro[3,4- 766 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-1-(((R)- 1-methyl-2-oxopiperidin-3- yl)amino)-3-(1- methylhexahydropyrrolo[3,4- 151 2, 7b]pyrrol-5(1H)-yl)-7,9- 747 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4S)-3-(dimethylamino)-4- methoxypyrrolidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin- 15223-yl)amino)-7,9- 765 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(3-(((S)-1,4- dioxan-2-yl)methoxy)-5- chloro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9- 1532dihydrofuro[3,4-f]quinazolin- 739 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3R,4S)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 1542yl)amino)-7,9-dihydrofuro[3,4- 753 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3-(3- (diethylamino)azetidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin- 3-yl)amino)-7,9- 155 dihydrofuro[3,4-f]quinazolin- 749 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4R)-3-fluoro-4- (isopropylamino)pyrrolidin-1- yl)-1-(((R)-1-methyl-2- 1562oxopiperidin-3-yl)amino)-7,9- 767 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3-(((R)- 4-methyl-1,4-oxazepan-3- yl)methoxy)-1-(((R)-1-methyl- 2-oxopiperidin-3-yl)amino)- 15727,9-dihydrofuro[3,4- 766 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-1-(((R)- 1-methyl-2-oxopiperidin-3- yl)amino)-3-(2-(piperidin-1- yl)ethoxy)-7,9- 1582dihydrofuro[3,4-f]quinazolin- 750 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino)pyrro lidin-1-yl)-1-(((R)-1-methyl-2- 1592oxopiperidin-3-yl)amino)-7,9- 779 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3R,4S)-3- (isopropyl(methyl)amino)-4- methylpyrrolidin-1-yl)-1-(((R)- 16021-methyl-2-oxopiperidin-3- 777 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(5-chloro-1-(((R)- 1-methyl-2-oxopiperidin-3- yl)amino)-3-(((S)- tetrahydrofuran-2-yl)methoxy)- 16127,9-dihydrofuro[3,4- 723 f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-(3- (dimethylamino)azetidin-1-yl)- 5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9- 162 dihydrofuro[3,4-f]quinazolin- 705 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-4-(3-(3- (dimethylamino)-3- methylazetidin-1-yl)-5-fluoro- 1-(((R)-1-methyl-2- 1633oxopiperidin-3-yl)amino)-7,9- 719 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-(3-(1- (dimethylamino)cyclopropyl)a zetidin-1-yl)-5-fluoro-1-(((R)- 1-methyl-2-oxopiperidin-3- 1643yl)amino)-7,9-dihydrofuro[3,4- 745 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((3S,4S)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-5-fluoro- 1-(((R)-1-methyl-2- 1653oxopiperidin-3-yl)amino)-7,9- 737 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-((S)- 3- (ethyl(methyl)amino)pyrrolidin -1-yl)-5-fluoro-1-(((R)-1- 1663methyl-2-oxopiperidin-3- 733 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-(3-((R)-3- fluoropyrrolidin-1-yl)azetidin- 1-yl)-1-(((R)-1-methyl-2- 1673oxopiperidin-3-yl)amino)-7,9- 749 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3-(2- 1683morpholinoethoxy)-7,9- 736 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-((S)- 3-(diethylamino)pyrrolidin-1- yl)-5-fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3-yl)amino)- 16937,9-dihydrofuro[3,4- 747 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3- ((2S)-2-methyl-3- 170 morpholinopyrrolidin-1-yl)- 775 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-5-fluoro-4 (5-fluoro-3-((S)-3- (isopropyl(methyl)amino)pyrro lidin-1-yl)-1-(((R)-1-methyl-2 1713oxopiperidin-3-yl)amino)-7,9- 747 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4 (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3-(4 methyloctahydro-1H- 172 3, 8pyrrolo[3,2-b]pyridin-1-yl)- 745 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4 (5-fluoro-3-((3R,4S)-3-fluoro- 4-(isopropylamino)pyrrolidin- 1-yl)-1-(((R)-1-methyl-2- 1733751 oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4 (5-fluoro-3-((S)-3- methoxypyrrolidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin 17433-yl)amino)-7,9- 706 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)-1-(((R)-1-methyl-2- 1753oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-((S)-3-(methyl((R)- tetrahydrofuran-3- yl)amino)pyrrolidin-1-yl)-1- 1763(((R)-1-methyl-2-oxopiperidin- 775 3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-(((2R,4R)-4-fluoro- 1-methylpyrrolidin-2- yl)methoxy)-1-(((R)-1-methyl- 17732-oxopiperidin-3-yl)amino)- 738 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (4-(3-([1,3'- biazetidin]-1'-yl)-5-fluoro-1- (((R)-1-methyl-2-oxopiperidin- 3-yl)amino)-7,9- 1783dihydrofuro[3,4-f]quinazolin- 717 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-4-(3-(3- (cyclopropyl(methyl)amino)py rrolidin-1-yl)-5-fluoro-1-(((R)- 1-methyl-2-oxopiperidin-3- 1793yl)amino)-7,9-dihydrofuro[3,4- 745 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4-(5-fluoro-3-((3R,4S)-3-fluoro- 4- (isopropyl(methyl)amino)pyrro 1803lidin-1-yl)-1-(((R)-1-methyl-2- 765 oxopiperidin-3-yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3-(3- (pyrrolidin-1-yl)azetidin-1-yl)- 1813731 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3- (((S)-1-morpholinopropan-2- 1823yl)oxy)-7,9-dihydrofuro[3,4- 750 f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-4-(3- ((3S,4S)-3-(dimethylamino)-4- methoxypyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 1833oxopiperidin-3-yl)amino)-7,9- 749 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-((3- (dimethylamino)oxetan-3- yl)methoxy)-5-fluoro-1-(((R)- 1-methyl-2-oxopiperidin-3- 184 yl)amino)-7,9-dihydrofuro[3,4- 736 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-((3R,4S)-3- (isopropyl(methyl)amino)-4- methylpyrrolidin-1-yl)-1-(((R)- 18531-methyl-2-oxopiperidin-3- 761 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((2R,4S)-4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 1863oxopiperidin-3-yl)amino)-7,9- 733 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-4-(3- ((2S,4S)-4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 1873oxopiperidin-3-yl)amino)-7,9- 733 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3-(3- methyl-3-(pyrrolidin-1- 1883yl)azetidin-1-yl)-7,9- 745 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-(((R)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1-(((R)- 18931-methyl-2-oxopiperidin-3- 756 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-((S)-2- methoxypropoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 1903yl)amino)-7,9-dihydrofuro[3,4- 695 f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(3-(((R)-1,4- dioxan-2-yl)methoxy)-5- fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9- 1913dihydrofuro[3,4-f]quinazolin- 723 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-((R)-3- (isopropyl(methyl)amino)pyrro lidin-1-yl)-1-(((R)-1-methyl-2- 1923oxopiperidin-3-yl)amino)-7,9- 747 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((3R,4R)-3-(dimethylamino)-4- methoxypyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 1933oxopiperidin-3-yl)amino)-7,9- 749 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-3- (((R)-4-methylmorpholin-2- 1943yl)methoxy)-7,9- 736 dihydrofuro[3,4-f]quinazolin- 6-yl)benzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-4-(3-(((S)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1-(((R)- 19531-methyl-2-oxopiperidin-3- 756 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-(((2S,4R)-4- methoxy-1-methylpyrrolidin-2- yl)methoxy)-1-(((R)-1-methyl- 19632-oxopiperidin-3-yl)amino)- 750 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-(((2S,4S)-4-fluoro- 1-methylpyrrolidin-2- yl)methoxy)-1-(((R)-1-methyl- 19732-oxopiperidin-3-yl)amino)- 738 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3-((R)- 3-(dimethylamino)pyrrolidin- 1-yl)-5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- 1983yl)amino)-7,9-dihydrofuro[3,4- 719 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (3-cyano-5-fluoro-4- (5-fluoro-3-((2S,3S)-3- (isopropylamino)-2- methylpyrrolidin-1-yl)-1-(((R)- 19931-methyl-2-oxopiperidin-3- 747 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 200 oxopiperidin-3-yl)amino)-7,9- 733 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((2R,4R)-4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl-2- 2013oxopiperidin-3-yl)amino)-7,9- 733 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate tert-Butyl (3-cyano-4-(3- ((3R,4S)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-5-fluoro- 1-(((R)-1-methyl-2- 2023oxopiperidin-3-yl)amino)-7,9- 737 dihydrofuro[3,4-f]quinazolin- 6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamatetert-Butyl (4-(5-chloro-3-((3- (dimethylamino)oxetan-3- yl)methoxy)-1-(((R)-1-methyl- 2-oxopiperidin-3-yl)amino)- 203 7,9-dihydrofuro[3,4- 753 f]quinazolin-6-yl)-3-cyano-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3S,4S)-3-(dimethylamino)-4- methoxypyrrolidin-1-yl)-1- (((R)-1-methyl-2-oxopiperidin- 20443-yl)amino)-7,9- 766 dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3R,4R)-3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin-3- 205 754 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (4-(5-chloro-3- ((3R,4S)-3- (isopropyl(methyl)amino)-4- methylpyrrolidin-1-yl)-1-(((R)- 206 1-methyl-2-oxopiperidin-3- 778 yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorothieno[3,2-c]pyridin-2- yl)carbamate1Clean atropisomer, chiral purification from Preparation 282Clean atropisomer, chiral purification from Preparation 323Clean atropisomer, chiral purification from Preparation 304Clean atropisomer, chiral purification from Preparation 395Synthesized from Preparation 72; the protecting group was removed during the reaction. 6 A mix of trans isomers on the tetrahydrofuran. 7 A mix of cis isomers on the hexahydropyrrolopyrrole. 8 A mix of cis isomers on the octahydropyrrolopyridine.

[0264] The following compounds in Table 13 were prepared in similar manner as described in Preparation 57. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Table 13: MS Prep Chemical Name Structure (ES) m / z (M+1) tert-Butyl (3-cyano-7-fluoro- 4-(5-fluoro-3-(((2R,4R)-4- fluoro-1-methylpyrrolidin-2- yl)methoxy)-1-(((R)-1- 207 methyl-2-oxopiperidin-3- 739 yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)thieno[3,2-c]pyridin-2- yl)carbamate tert-Butyl (3-cyano-4-(3- (((R)-4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1-(((R)- 208 1-methyl-2-oxopiperidin-3- 757 yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)-7-fluorothieno[3,2- c]pyridin-2-yl)carbamatetert-Butyl (3-cyano-4-(3-(((S)- 4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1-(((R)- 209 1-methyl-2-oxopiperidin-3- 757 yl)amino)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1- yl)-1-(((R)-1-methyl-2- oxopiperidin-3-yl)amino)-7,9- 210 dihydrofuro[3,4-f]quinazolin- 721 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate Example 1 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3- carbonitrile

[0265] tert-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-(((2R,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)-1-(((R)-1-methyl-2-oxopiperidin-3-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin- 6-yl)thieno[3,2-c]pyridin-2-yl)carbamate (0.353 g, 0.478 mmol) was added to a mixture of DCM (3.5 mL) and trifluoroacetic acid (0.74 mL). The mixture was stirred at room temperature. After 2 h, the mixture was concentrated under reduced pressure. The materialwas purified on strong cation exchange media (10 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 35-55% acetonitrile in aqueous ammonium bicarbonate buffer (pH 9), to give the title compound (0.094 g; 31%). MS (ES) m / z=639 (M+1).

[0266] The following compounds in Table 14 were prepared in similar manner as described in Example 1. Different acidic conditions, such as HCl in 1,4-dioxane, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Isomer separation methods may be found as footnotes. Table 14: MS Example Chemical Name Structure (ES) m / z (M+1) 2-Amino-4-(3-(((R)-4,4- difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- (((R)-1-methyl-2- 2 oxopiperidin-3- 657 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile2-Amino-4-(3-(((S)-4,4- difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- (((R)-1-methyl-2- 3 oxopiperidin-3- 657 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 2-Amino-4-(5-chloro-3- ((4- hydroxytetrahydrofuran- 2-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 41 , 5yl)amino)-7,9- 639 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 2-Amino-4-(5-chloro-3- ((4- hydroxytetrahydrofuran- 2-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 51 , 5yl)amino)-7,9- 639 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 32-amino-4-(5-chloro-3- ((2S)-4-hydroxy-2- methylpyrrolidin-1-yl)-1- (((R)-1-methyl-2- oxopiperidin-3- 61 , 6yl)amino)-7,9- 622 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 2-amino-4-(5-chloro-3- ((2S)-4-hydroxy-2- methylpyrrolidin-1-yl)-1- (((R)-1-methyl-2- oxopiperidin-3- 71 , 6yl)amino)-7,9- 622 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 2-Amino-4-(5-chloro-3- ((2S,3S)-3-hydroxy-2- methylpyrrolidin-1-yl)-1- (((R)-1-methyl-2- oxopiperidin-3- 81yl)amino)-7,9- 622 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- fluoropyrrolidin-1-yl)-1- (((R)-1-methyl-2- 91oxopiperidin-3- 653 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-3-(((S)- tetrahydrofuran-2- 101yl)methoxy)-7,9- 623 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((2S,4S)-4- (dimethylamino)-2- (methoxymethyl)pyrrolid in-1-yl)-1-(((R)-1- 111methyl-2-oxopiperidin-3- 679 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((1,5,5-trimethyl- 2-oxopiperidin-3- 121 , 7yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((1,5,5-trimethyl- 2-oxopiperidin-3- 131 , 7yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 2-Amino-4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 141 , 81-yl)-7,9- 635 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 12-Amino-4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 151 , 81-yl)-7,9- 635 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 2-Amino-4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 161 , 81-yl)-7,9- 635 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 2-Amino-4-(5-chloro-1- ((1,5-dimethyl-2- oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 171 , 81-yl)-7,9- 635 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 42-Amino-4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 181 , 91-yl)-7,9- 661 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 2-Amino-4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 191 , 91-yl)-7,9- 661 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 2-Amino-4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 201 , 91-yl)-7,9- 661 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 32-Amino-4-(5-chloro-1- ((6-cyclopropyl-1- methyl-2-oxopiperidin-3- yl)amino)-3-(3- (dimethylamino)azetidin- 211 , 91-yl)-7,9- 661 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 2210yl)amino)-7,9- 621 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 2310yl)amino)-7,9- 621 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 22-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-1-yl)-1-(((R)-1-methyl- 2-oxopiperidin-3- 242yl)amino)-7,9- 635 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- fluoropyrrolidin-1-yl)-1- (((R)-1-methyl-2- 252oxopiperidin-3- 653 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- (3-(1- (dimethylamino)cyclopro pyl)azetidin-1-yl)-1- (((R)-1-methyl-2- 262oxopiperidin-3- 661 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-3- ((3R,4S)-3-fluoro-4- (isopropylamino)pyrrolid in-1-yl)-1-(((R)-1- methyl-2-oxopiperidin-3- 272yl)amino)-7,9- 667 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((S)-3- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin- 2823-yl)amino)-7,9- 663 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3- hydroxytetrahydrofuran- 2-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 292 , 11yl)amino)-7,9- 639 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 12-Amino-4-(5-chloro-3- ((3- hydroxytetrahydrofuran- 2-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 302 , 11yl)amino)-7,9- 639 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 2-Amino-4-(5-chloro-3- ((2S,4R)-4- (dimethylamino)-2- methylpyrrolidin-1-yl)-1- (((R)-1-methyl-2- 312oxopiperidin-3- 649 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((S)-2-methoxypropoxy)- 1-(((R)-1-methyl-2- oxopiperidin-3- 322yl)amino)-7,9- 611 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-3- ((3S,4S)-3-fluoro-4- (isopropylamino)pyrrolid in-1-yl)-1-(((R)-1- methyl-2-oxopiperidin-3- 332yl)amino)-7,9- 667 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 4-(3-([1,3'-Biazetidin]-1'- yl)-5-chloro-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 342dihydrofuro[3,4- 633 f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 1-(((R)-1-methyl-2- 352oxopiperidin-3- 651 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 1-(((R)-1-methyl-2- 362oxopiperidin-3- 651 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- (((R)-4,4-difluoro-1- methylpyrrolidin-2- yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 372yl)amino)-7,9- 672 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- (((S)-4-methyl-1,4- oxazepan-3-yl)methoxy)- 1-(((R)-1-methyl-2- oxopiperidin-3- 382yl)amino)-7,9- 666 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-3-(1- methylhexahydropyrrolo[ 392 , 123,4-b]pyrrol-5(1H)-yl)- 647 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 2-Amino-4-(5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-3-(1- methylhexahydropyrrolo[ 402 , 123,4-b]pyrrol-5(1H)-yl)- 647 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 2-Amino-4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- methoxypyrrolidin-1-yl)- 1-(((R)-1-methyl-2- 412oxopiperidin-3- 665 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile4-(3-(((S)-1,4-Dioxan-2- yl)methoxy)-5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-7,9- 422dihydrofuro[3,4- 639 f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- fluoropyrrolidin-1-yl)-1- (((R)-1-methyl-2- 432oxopiperidin-3- 653 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- (3- (diethylamino)azetidin-1- yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 4413yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 12-Amino-4-(5-chloro-3- (3- (diethylamino)azetidin-1- yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 4513yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 2-Amino-4-(5-chloro-3- ((3S,4R)-3-fluoro-4- (isopropylamino)pyrrolid in-1-yl)-1-(((R)-1- methyl-2-oxopiperidin-3- 462yl)amino)-7,9- 667 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- (((R)-4-methyl-1,4- oxazepan-3-yl)methoxy)- 1-(((R)-1-methyl-2- oxopiperidin-3- 472yl)amino)-7,9- 666 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-3-(2- 482(piperidin-1-yl)ethoxy)- 650 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amin-4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin- 4923-yl)amino)-7,9- 679 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (isopropyl(methyl)amino) -4-methylpyrrolidin-1- yl)-1-(((R)-1-methyl-2- 502oxopiperidin-3- 677 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(5-chloro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-3-(((S)- tetrahydrofuran-2- 512yl)methoxy)-7,9- 623 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 5214dihydrofuro[3,4- 605 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 5314dihydrofuro[3,4- 605 f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 22-Amino-4-(3-(3- (dimethylamino)-3- methylazetidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 543yl)amino)-7,9- 619 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-(3-(1- (dimethylamino)cyclopro pyl)azetidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 553yl)amino)-7,9- 645 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-((3S,4S)- 3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 563yl)amino)-7,9- 637 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(3-((S)-3- (ethyl(methyl)amino)pyrr olidin-1-yl)-5-fluoro-1- (((R)-1-methyl-2- oxopiperidin-3- 573yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-3-(3-((R)-3- fluoropyrrolidin-1- yl)azetidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin- 5833-yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(2- 593morpholinoethoxy)-7,9- 636 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-((S)-3- (diethylamino)pyrrolidin- 1-yl)-5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- 603yl)amino)-7,9- 647 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-((2S)-2- methyl-3- 6115morpholinopyrrolidin-1- 675 yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 1 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-((2S)-2- methyl-3- 6215morpholinopyrrolidin-1- 675 yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 2 2-Amino-5-fluoro-4-(5- fluoro-3-((S)-3- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin- 6333-yl)amino)-7,9- 647 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(4- methyloctahydro-1H- 643 , 16pyrrolo[3,2-b]pyridin-1- 645 yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 1 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(4- methyloctahydro-1H- 653 , 16pyrrolo[3,2-b]pyridin-1- 645 yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 2 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- fluoro-4- (isopropylamino)pyrrolid in-1-yl)-1-(((R)-1- 663methyl-2-oxopiperidin-3- 651 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile2-Amino-5-fluoro-4-(5- fluoro-3-((S)-3- methoxypyrrolidin-1-yl)- 1-(((R)-1-methyl-2- oxopiperidin-3- 673yl)amino)-7,9- 606 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-3-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 683yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-3-((S)-3- (methyl((R)- tetrahydrofuran-3- yl)amino)pyrrolidin-1- yl)-1-(((R)-1-methyl-2- 693oxopiperidin-3- 675 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile2-Amino-5-fluoro-4-(5- fluoro-3-(((2R,4R)-4- fluoro-1- methylpyrrolidin-2- yl)methoxy)-1-(((R)-1- 703methyl-2-oxopiperidin-3- 638 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 4-(3-([1,3'-Biazetidin]-1'- yl)-5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- yl)amino)-7,9- 713dihydrofuro[3,4- 617 f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-(3- (cyclopropyl(methyl)ami no)pyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 723 , 17yl)amino)-7,9- 645 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 12-Amino-4-(3-(3- (cyclopropyl(methyl)ami no)pyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 733 , 17yl)amino)-7,9- 645 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- fluoro-4- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((R)- 7431-methyl-2-oxopiperidin- 665 3-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(3- (pyrrolidin-1-yl)azetidin- 7531-yl)-7,9- 631 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(((S)-1- morpholinopropan-2- 763yl)oxy)-7,9- 650 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-((3S,4S)- 3-(dimethylamino)-4- methoxypyrrolidin-1-yl)- 5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- 773yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-((3- (dimethylamino)oxetan- 3-yl)methoxy)-5-fluoro- 1-(((R)-1-methyl-2- oxopiperidin-3- 7818yl)amino)-7,9- 636 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 12-Amino-4-(3-((3- (dimethylamino)oxetan- 3-yl)methoxy)-5-fluoro- 1-(((R)-1-methyl-2- oxopiperidin-3- 7918yl)amino)-7,9- 636 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropyl(methyl)amino) -4-methylpyrrolidin-1- yl)-1-(((R)-1-methyl-2- 803oxopiperidin-3- 661 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-((2R,4S)- 4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 813yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-4-(3-((2S,4S)- 4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 823yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(3-methyl-3- (pyrrolidin-1-yl)azetidin- 8331-yl)-7,9- 645 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-(((R)-4,4- difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- (((R)-1-methyl-2- 843oxopiperidin-3- 656 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-5-fluoro-4-(5- fluoro-3-((S)-2- methoxypropoxy)-1- (((R)-1-methyl-2- oxopiperidin-3- 853yl)amino)-7,9- 595 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 4-(3-(((R)-1,4-Dioxan-2- yl)methoxy)-5-fluoro-1- (((R)-1-methyl-2- oxopiperidin-3- yl)amino)-7,9- 863dihydrofuro[3,4- 623 f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-3-((R)-3- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((R)- 1-methyl-2-oxopiperidin- 8733-yl)amino)-7,9- 647 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile2-Amino-4-(3-((3R,4R)- 3-(dimethylamino)-4- methoxypyrrolidin-1-yl)- 5-fluoro-1-(((R)-1- methyl-2-oxopiperidin-3- 883yl)amino)-7,9- 649 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- yl)amino)-3-(((R)-4- methylmorpholin-2- 893yl)methoxy)-7,9- 636 dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-(((S)-4,4- difluoro-1- methylpyrrolidin-2- yl)methoxy)-5-fluoro-1- (((R)-1-methyl-2- 903oxopiperidin-3- 656 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-5-fluoro-4-(5- fluoro-3-(((2S,4R)-4- methoxy-1- methylpyrrolidin-2- yl)methoxy)-1-(((R)-1- 913methyl-2-oxopiperidin-3- 650 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-5-fluoro-4-(5- fluoro-3-(((2S,4S)-4- fluoro-1- methylpyrrolidin-2- yl)methoxy)-1-(((R)-1- 923methyl-2-oxopiperidin-3- 638 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-((R)-3- (dimethylamino)pyrrolidi n-1-yl)-5-fluoro-1-(((R)- 1-methyl-2-oxopiperidin- 9333-yl)amino)-7,9- 619 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile2-Amino-5-fluoro-4-(5- fluoro-3-((2S,3S)-3- (isopropylamino)-2- methylpyrrolidin-1-yl)-1- (((R)-1-methyl-2- 943oxopiperidin-3- 647 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 9519yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 9619yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 22-Amino-4-(3-((2R,4R)- 4-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 973yl)amino)-7,9- 633 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- fluoropyrrolidin-1-yl)-5- fluoro-1-(((R)-1-methyl- 2-oxopiperidin-3- 983yl)amino)-7,9- 637 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 2-Amino-4-(5-chloro-3- ((3- (dimethylamino)oxetan- 3-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 9920yl)amino)-7,9- 653 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 12-Amino-4-(5-chloro-3- ((3- (dimethylamino)oxetan- 3-yl)methoxy)-1-(((R)-1- methyl-2-oxopiperidin-3- 10020yl)amino)-7,9- 653 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 2-Amino-4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- methoxypyrrolidin-1-yl)- 1-(((R)-1-methyl-2- 1014oxopiperidin-3- 666 yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 2-Amino-4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- fluoropyrrolidin-1-yl)-1- (((R)-1-methyl-2- oxopiperidin-3- 10221yl)amino)-7,9- 654 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 12-Amino-4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- fluoropyrrolidin-1-yl)-1- (((R)-1-methyl-2- oxopiperidin-3- 10321yl)amino)-7,9- 654 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (isopropyl(methyl)amino) -4-methylpyrrolidin-1- yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 10422yl)amino)-7,9- 678 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (isopropyl(methyl)amino) -4-methylpyrrolidin-1- yl)-1-(((R)-1-methyl-2- oxopiperidin-3- 10522yl)amino)-7,9- 678 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 21Clean atropisomer, chiral purification from Preparation 282Clean atropisomer, chiral purification from Preparation 323Clean atropisomer, chiral purification from Preparation 304Clean atropisomer, chiral purification from Preparation 395Reverse Phase; C18, 29-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol), to give four Diastereomers; a small amount of Diastereomers 2 and 4 were isolated. Diastereomer refers to clean isomers on the tetrahydrofuran.6Reverse Phase; C18, 40-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomer refers to clean isomers on the pyrrolidine.7Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 x 150 mm, 10-100% (ethanol w / 0.1% isopropylamine) in heptane, 42.5 mL / min. Enantiomer refers to a clean isomer at the 3- position of the piperidinone.8Reverse Phase; C18, 41-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol), to give Diastereomer 1, a mix of two diastereomers, and Diastereomer 4. Diastereomers 2 and 3 were further separated with Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 x 150 mm, 15-100% ethanol in heptane, 42.5 mL / min. Diastereomer refers to clean isomers on the piperidinone.9Reverse Phase; C18, 50-100% (95:5 acetonitrile:water) in (95:510 mM aqueous ammonium bicarbonate pH 10:methanol), to give Diastereomer 1, Diastereomer 2, and a mix of two diastereomers. Diastereomers 3 and 4 were further separated with Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 15-50% (ethanol w / 0.1% isopropylamine) in heptane, 42.5 mL / min. Diastereomer refers to clean isomers on the piperidinone.10Chiral SFC; Chiralpak IH, 20 x 250 mm, 30% (methanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min11Reverse Phase; C18, 35-70% acetonitrile in 20 mM aqueous ammonium bicarbonate pH 9. Isomer refers to clean trans isomers on the tetrahydrofuran.12Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 15% (1:1 methanol:ethanol w / 0.1% isopropylamine) in heptane, 50 mL / min. Isomer refers to clean cis isomers on the hexahydropyrrolopyrrole.13Chiral SFC; Chiralpak IH, 20 x 250 mm, 30% (ethanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min14Prep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-100% ethanol in heptane, 37.5 mL / min15Reverse Phase; C18, 43-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol)16Chiral SFC; Chiralpak IG, 20 x 250 mm, 45% (ethanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min. Isomer refers to clean cis isomers on the octahydropyrrolopyridine.17Chiral SFC; Chiralpak IC, 20 x 250 mm, 45% (isopropanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min. Enantiomer refers to a clean isomer on the pyrrolidine.18Reverse Phase; C18, 27-100% acetonitrile in (10 mM ammonium acetate in 95:5water:methanol) 19Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 x 150 mm, 10-100% (1:1 methanol:ethanol) in heptane, 40 mL / min 20Reverse Phase; C18, 26-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) 21Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-100% (ethanol w / 0.1% isopropylamine) in heptane, 42.5 mL / min 22Chiral SFC; (S,S)-Whelk-O, 20 x 250 mm, 45% (ethanol w / 0.5% dimethylethylamine) in CO2, 80 mL / min Biological Assays

[0267] The following assays demonstrate that the exemplified compounds are potent inhibitors of KRAS G12V and inhibit growth of certain tumors in vitro and / or in vivo. Cellular Phospho-ERK AlphaLISA®Assay for KRAS Inhibition

[0268] The purpose of these assays is to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells with amplified KRAS and expressing activating KRAS G12 mutations (Table 1A). Cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations, or amplification of the KRAS gene. Table 1A: Cell Line Information Cell Line Name RAS Mutation / Features Assay Seeding Density (Cells / Well) MKN45 WT KRAS Amplification / Human Gastric Cancer 20,000 SW620 KRAS G12V / Human Colorectal Cancer 20,000

[0269] The compounds’ activity is determined by measuring changes in the phosphorylation levels of the downstream effector Extracellular Signal-regulated Kinase-1 and 2 (ERK1 / 2) in the compound treated cells. Phosphorylation levels of ERK-1 / 2 are measured using theAlphaLISA®SureFire®Ultra™ p-ERK 1 / 2 (Thr202 / Tyr204) Assay Kit (#ALSU-PERK- A50K, PerkinElmer®Waltham, MA). The AlphaLISA®assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cellular lysates using bead-based Alpha technology. The assay kit contains two antibodies, one that binds the phospho-Thr202 / Tyr204 epitope on ERK-1 / 2, and another one that recognizes a separate site on the protein. One of these antibodies is biotinylated and associated with streptavidin-coated Alpha Donor beads, the other antibody is conjugated to AlphaLISA®Acceptor beads. When ERK-1 / 2 is phosphorylated in cellular lysate, the Donor and Acceptor beads are brought into proximity with each other. When the Donor bead is excited by 600 nm wavelength light, a photosensitizer inside the bead converts ambient oxygen to an excited singlet state. When the Acceptor bead is within 200 nm of this reaction, the singlet oxygen reacts with the Acceptor leading to a chemiluminescent emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1 / 2 in the lysate. The AlphaLISA®SureFire®Ultra™p-ERK 1 / 2 (Thr202 / Tyr204) Assay Kit contains AlphaLISA®antibody-conjugated Donor and Acceptor Beads, Lysis buffer concentrate, and a set of proprietary buffers (Activation Buffer, Reaction Buffer 1, Reaction Buffer 2, and Dilution Buffer).

[0270] To perform the assays, test compounds and controls are acoustically dispensed (Labcyte ECHO®, San Jose, CA) into a white 384-well assay plate (Proxiplate-384, PerkinElmer #6008280) in a 10-point 3-fold dilution series in 30 nL DMSO. Cells are then added to the assay plate in 8 µL per well assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO # 10082-147) at a cell line specific density (Table 1A). The final compound concentrations range from 0.5 to 10,000 nM and the final DMSO concentration is 0.375% in each well. Maximum signal control wells contain 0.375% DMSO only (negative control), and minimum signal control wells contain 10,000 nM control compound (positive control). Cells in suspension are incubated with the test and reference compounds for 2 h at 37°C / 5 % CO2. Following the 2 h incubation, cells are lysed by adding 2 µL of the AlphaLISA®Lysis buffer concentrate (5X) supplemented with protease / phosphatase inhibitor cocktail (Thermo Scientific # 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm on a multi-plate shaker (Heidolph, Schwabach, Germany) for 30 min at room temperature toinduce cell lysis. During the lysis, the AlphaLISA®Acceptor beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA®Reaction Buffers 1 and 2 with a 1:25 dilution of AlphaLISA®Activation Buffer). Following cell lysis, plates are centrifuged briefly, and 5 µL per well prepared Acceptor beads are added. The plate is then covered and incubated in the dark for 2 h at room temperature. During the Acceptor bead incubation, Donor beads are prepared by diluting the Alpha streptavidin Donor beads 1:50 in AlphaLISA®Dilution buffer. Following the Acceptor bead incubation, 5 µL per well of Donor bead mixture is added to the plates. Plates are then covered and allowed to incubate in the dark at room temperature for 2 h. 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 optics cube.

[0271] Raw signal obtained from the AlphaLISA®assay is analyzed using Genedata Screener®17.0.3. Within the program, data is normalized to 32 wells treated with inhibition control (max inhibition / positive control) and 32 wells treated with 0.375% DMSO only (minimum inhibition / negative control) to calculate the % Activity of the compound:% Activity values are fit to a four-parameter non-linear logistic equation using Genedata Screener®17.0.3. to -determine IC50 values:Where y = % Activity, Bottom = minimum asymptote, Top = maximum asymptote, x = compound concentration, IC50= the compound concentration where half maximal activity is achieved, and h = the Hill Coefficient.

[0272] Compounds of Examples 1-4, 6, 8-12, 14, 15, 18, 19, 23-43, 45-52, 54-61, 63, 64, 66- 78, 80-94, 96-99, 101, 102 and 104 were tested in the SW620 Cellular Phospho-ERK AlphaLISA® Assay and exhibited an ability to reduce levels of phosphorylated ERK-1 / 2 in cells expressing KRAS indicating inhibition of constitutive RAS activity in cells expressing KRAS G12V with a relative IC50 of <50 nM. Compounds of Examples 1-12, 14, 15, 18, 19, 23-43, 45-52, 54-94, 96-99, 101, 102, 104 and 105 were tested in both assays above (SW620,and MKN 45 Cellular Phospho-ERK AlphaLISA® Assays) and showed a significant (i.e., greater than 5-fold) selective inhibition preference for KRAS G12V mutant over KRAS wild- type. Further, the compounds of Examples 1-4, 6, 8-12, 14, 23-43, 45-50, 52, 54-69, 71-78, 80-91, 96, 98, 99, 101, 102, 104 and 105 showed a greater than 10-fold selective inhibition preference for KRAS G12V mutant over KRAS wild-type.

[0273] This data shows that compounds of Formula I as described herein are potent inhibitors of KRAS human cancer cells expressing KRAS demonstrating the ability to inhibit KRAS G12V mutants with a significant selective inhibition preference for the KRAS G12V mutant over KRAS WT. Table 1B: Abbreviations KRAS Kirsten Rat Sarcoma Virus ERK Extracellular Signal-Regulated Kinase AlphaLISA Alpha-Linked Immunosorbent Assay DMSO Dimethyl Sulfoxide HBSS Hank’s Balanced Salt Solution FBS Fetal Bovine Serum CO2Carbon Dioxide

Claims

1. What is Claimed is 1. A compound of the formula: wherein: R1 is a group of the formula ; R1b is H, C1-3 alkyl, or cyclopropyl; R1c is C1-3 alkyl, or cyclopropyl; n is 0, 1, or 2; R2 is halogen; R3 is a group of the formula ; Z is -C(R3c)- or -N-; R3a, R3b, and R3care each independently H or halogen; R4is a group of the formula (i) , whereinR4ais –(CR4cR4d)m–NR4eR4f; R4b is H or methyl; R4c and R4d together with the carbon atom to which they are attached form a cyclopropyl; R4e and R4f are each independently C1-3 alkyl, or R4e and R4f together with the nitrogen atom to which they are attached form a 4- or 5-membered heterocycle optionally substituted with a halogen; and m is 0 or 1; (ii) , wherein R5ais halogen, hydroxy, C1-3alkyl, C1-3alkoxy, or C1-3alkoxy-C1-3alkyl; R5band R5care each independently H, C1-6alkyl, C3-5cycloalkyl, or a 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5band R5ctogether with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or R5aand R5btogether with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, wherein R5c is C1-3 alkyl, and wherein the 4-, 5-, or 6- membered fused ring is optionally further substituted with a C1-3alkyl; and p is 0 or 1; (iii) whereinR6is H or C1-3alkyl; R6a is halogen or C1-3 alkyl; and q is 0 or 1; or (iv) , wherein R7 is –(CR7aR7b)r-R7c; R7a and R7b are each independently H or C1-3 alkyl; R7cis an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle containing 1- or 2-heteroatoms independently selected from N, O, or S, wherein the heterocycle is optionally substituted with 1-3 groups independently selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and dimethylamino; or R7c is –OR7d, wherein R7d is C1-3 alkyl or C1-3 haloalkyl; and r is 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1b is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein R1bis methyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein n is 0, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-3, wherein n is 1 and R1cis C1-3alkyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-3, wherein n is 1 and R1c is cyclopropyl, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1-3, wherein n is 2 and each R1c is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1-3, wherein R1is a group of the formula, , , or , or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1-3, wherein R1is a group of the formula O N HN , , , or , or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-9, wherein R2 is F or Cl, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1-10, wherein R2is F, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1-10, wherein R2 is Cl, or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1-12, wherein R3is a group of the formula , or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein R3bis halogen, and R3cis H, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 13, wherein R3bis H, and R3cis halogen, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 13, wherein R3bis halogen, and R3cis halogen, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1-12, wherein R3 is a group of the formula , or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17, wherein R3bis halogen, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1-12, wherein R3is a group of the formula ,, or ,or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1-19, wherein R4 is a group of the formula , or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20, wherein R4 is a group of the formula; ; ; ; ; N N ;; or ; or a pharmaceutically acceptable saltthereof.

22. The compound according to any one of claims 1-19, wherein R4is a group of the formula , or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 22, wherein R4is a group of the formula ; ; ; ; ; NN; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;; ; ; ; ; or ; or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1-19, wherein R4is a group of the formula , or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 24, wherein R4is a group of the formula ; ; or ; or a pharmaceutically acceptable salt thereof.

26. The compound according to any one of claims 1-19, wherein R4 is a group of the formula , or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26, wherein R4is a group of the formula ; ; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ; or ; or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 1, selected from; ; ; ; ; ; ; ;; ; ; ; and ; or a pharmaceutically acceptable salt thereof.

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

30. A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 29 or an effective amount of a compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterinecarcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

31. The method according to claim 30, wherein the patient has a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

32. The method according to claim 30, wherein one or more cells express KRAS G12V mutant protein.

33. A method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

34. The method according to any one of claims 30-33, 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, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof.

35. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-28, for use in therapy.

36. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-28, for use in the treatment of cancer.

37. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 36 wherein the cancer has a KRAS G12V mutation.

38. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 36 or 37, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.

39. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-28 for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer.

40. The method according to any one of claims 30-34, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any of one claims 36-39, wherein the cancer is non-small cell lung cancer.

41. The method according to any one of claims 30-34, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any of one claims 36-39, wherein the cancer is colorectal cancer.

42. The method according to any one of claims 30-34, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any of one claims 36-39, wherein the cancer is pancreatic cancer.

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