Substituted fused azines as KRAS G12D inhibitors

Abstract

The present invention relates to R1, R2, R3, R 4a , R 4b , R 4c wherein R, R, X, Y, and Z are as described herein, and pharma- ceutically acceptable salts thereof, and methods of using these compounds and pharma- ceutically acceptable salts thereof to treat patients with cancer.

Description

[Background technology]

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

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

[0003] To date, research has focused on KRas G12C mutant inhibitors (e.g., WO 2019 / 099524, WO 2020 / 081282, WO 2020 / 101736, and WO 2020 / 146613 disclose KRas G12C inhibitors), while WO 2021 / 041671 discloses KRas G12D small molecule inhibitors and WO 2017 / 011920 discloses KRas G12C, G12D, and G12V small molecule inhibitors.

[0004] There remains a need to provide alternative small molecule KRas inhibitors. In particular, there is a need to provide more potent, orally deliverable KRas inhibitors useful in the treatment of cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. There is also a need to provide small molecule KRas inhibitors that exhibit higher efficacy with the same or reduced KRas inhibitory activity. Furthermore, it is desirable to provide KRas inhibitors that exhibit better pharmacokinetic / pharmacodynamic properties. There is also a need to provide more potent KRas inhibitors that exhibit increased efficacy with reduced or minimized adverse or undesirable effects. The present invention addresses one or more of these needs by providing novel KRas inhibitors. Summary of the Invention

[0005] A compound of formula I: [ka] Pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided herein. X is -O- or -S-; Y is -C(CN)- or -N-; Z is -C(H)- or -N-; R1 is H, azetidine, pyrrolidine, piperidine, or N-linked piperazine, and azetidine, pyrrolidine, piperidine, or N-linked piperazine is C 1-4 Alkyl or C 1-4 Optionally substituted with heteroalkyl, C 1-4 Alkyl, C 1-4 Heteroalkyl is optionally substituted with halogen or oxo, and azetidine, pyrrolidine, piperidine, or N-linked piperazine is C 1-4 Alkyl or C 1-4 Azetidine, pyrrolidine, piperidine, or N-linked piperazine, optionally bridged by a heteroalkyl, is 1-4 Alkyl or C 1-4 optionally fused with a heteroalkyl to form a bicyclic ring; R2 is H, -O-CH2-R7, or -O-CH(CH3)-R7, and R7 is azetidine, pyrrolidine, or tetrahydrofuran, and the azetidine, pyrrolidine, or tetrahydrofuran may further include one or more halogens, hydroxyl, C 1-4 Alkyl or C 1-4 Optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and the azetidine, pyrrolidine, or tetrahydrofuran is C 1-4 optionally fused with an alkyl to form a bicyclic ring, when R2 is H, R1 is not H, R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted 1 to 3 times by R8 -C 1-6-OC optionally substituted 1 to 3 times by alkyl or R8 1-6 is alkyl, R 4a , R 4b , and R 4c are each independently H, halogen, or -C optionally substituted 1 to 3 times with R 1-6 is alkyl, R6 is H, -CH2OH, -CH2-O-CH3; R8 is independently halogen, oxo, hydroxy, -C 1-4 Alkyl or -OC 1-4 It is an alkyl.

[0006] Methods of using the compounds of formula I, pharma- ceutical acceptable salts thereof, and pharmaceutical compositions thereof for the treatment of cancer, particularly lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of formula I, or a pharma- ceutical acceptable salt thereof.

[0007] Also provided herein are compounds of formula I, and pharma- ceutically acceptable salts thereof, for use in therapy.Further provided herein are compounds of formula I, and pharma- ceutically acceptable salts thereof, for use in the treatment of cancer, particularly lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.A compound of formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, particularly lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0009] The present invention provides a compound of formula 1, or a pharma- ceutically acceptable salt thereof: [ka] In formula I, X can be -O- or -S-; Y can be -C(CN)- or -N-; Z can be -C(H)- or -N-; R1 can be H, azetidine, pyrrolidine, piperidine, or N-linked piperazine, and azetidine, pyrrolidine, piperidine, or N-linked piperazine is C 1-4 Alkyl or C 1-4 Optionally substituted with heteroalkyl, C 1-4 Alkyl, C 1-4 Heteroalkyl is optionally substituted with halogen or oxo, and azetidine, pyrrolidine, piperidine, or N-linked piperazine is C 1-4 Alkyl or C 1-4 Azetidine, pyrrolidine, piperidine, or N-linked piperazine, optionally bridged by a heteroalkyl, is 1-4 Alkyl or C 1-4 optionally fused with a heteroalkyl to form a bicyclic ring; R2 can be H, -O-CH2-R7, or -O-CH(CH3)-R7, where R7 is azetidine, pyrrolidine, or tetrahydrofuran, and the azetidine, pyrrolidine, or tetrahydrofuran can have one or more halogens, hydroxyl, C 1-4 Alkyl or C 1-4 Optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and the azetidine, pyrrolidine, or tetrahydrofuran is C 1-4 optionally fused with an alkyl to form a bicyclic ring, when R2 is H, R1 is not H, R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted 1 to 3 times by R8 -C 1-6 -OC optionally substituted 1 to 3 times by alkyl or R8 1-6 may be alkyl, R 4a , R 4b , and R 4c are each independently H, halogen, or -C optionally substituted 1 to 3 times with R 1-6 may be alkyl, R6 can be H, -CH2OH, -CH2-O-CH3; R8 is independently halogen, oxo, hydroxy, -C 1-4 Alkyl or -OC 1-4 It may be alkyl.

[0010] In one embodiment, the present invention provides a compound of formula II: [ka] In the formula, R1, R3, R4, R5, R7, X, Y, and Z are as defined above, and A is -CH2- or -CH(CH3)-, or a pharma- ceutically acceptable salt thereof.

[0011] In another embodiment, the present invention provides a compound of formula III: [ka] The present invention provides a compound, or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R6, and Z are as defined above.

[0012] In a further embodiment, the present invention provides a compound of formula IV: [ka] The present invention provides a compound, or a pharma- ceutically acceptable salt thereof, wherein R1, R6, R7, and Z are as defined above, and A is -CH2- or -CH(CH3).

[0013] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means a saturated linear or branched monovalent hydrocarbon radical of 1 to 6 carbon atoms, e.g., "-C1-6 alkyl" or "-C1-4 alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, pentyl, and hexyl. As used herein, the term "oxo" means an oxygen double-bonded to a carbon, i.e., a ketone. As used herein, the term heteroalkyl means a saturated linear or branched monovalent hydrocarbon radical containing 2 to 4 carbon atoms and at least one heteroatom, e.g., "-C2-4 heteroalkyl". Examples of heteroatoms include, but are not limited to, nitrogen and oxygen. Where zero is indicated, for example, in the case of -C0-3 alkyl-cyclopropyl, the alkyl component of the substituent may be absent, and thus, when R3 or R5 of formula I is a cyclopropyl group without an alkyl leading group, the substituent is -C0-3 alkyl-cyclopropyl, as described for R3 or R5. 0-3 It will be illustrated by an alkyl-cyclopropyl substituent (ie, the substituent will be -C0-cyclopropyl).

[0014] For R1, azetidine, pyrrolidine, piperidine, or N-linked piperazine is C 1-4 Alkyl or C 2-4 As used herein, the term "bridged" with respect to an R group means that the R group is 1-4 Alkyl or C 2-4 It is meant that the heteroalkyl is bicyclic, linked to two non-adjacent atoms of an azetidine, pyrrolidine, piperidine, or N-linked piperazine ring. Examples of bridged N-linked piperazine ring groups include: [ka] Examples include:

[0015] As used herein, the term "fused" with respect to an R group means that the R group is 1-4 Alkyl or C 2-4 This means that the heteroalkyl is bicyclic, linking two adjacent atoms of an azetidine, pyrrolidine, piperidine, or N-linked piperazine ring. Examples of fused R groups include: [ka] Examples include:

[0016] In R1, the azetidine, pyrrolidine, and piperidine groups are not specified as being bonded through a carbon or nitrogen, and may be bonded through either a carbon or a nitrogen. Similarly, the C 1-4 Alkyl or C 1-4 The heteroalkyl substitution can be on carbon or on a heteroatom.

[0017] For R7, azetidine, pyrrolidine, or tetrahydrofuran is C 1-4 As used herein, the term "fused" with respect to an R7 group refers to an R7 group that is optionally fused to an alkyl group to form a bicyclic ring. 1-4This means that the alkyl is bicyclic, linking two adjacent atoms of an azetidine, pyrrolidine, or tetrahydrofuran ring. Examples of fused R7 groups include: [ka] Examples include:

[0018] In R7, the azetidine, pyrrolidine, or tetrahydrofuran group is not specified as being attached through a carbon or a nitrogen, and may be attached through either a carbon or a nitrogen. Similarly, the C 1-4 Alkyl or C 1-4 The alkenyl substitution may be on a carbon or heteroatom.

[0019] In certain embodiments of a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, X is --S--.

[0020] In another embodiment of the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, Y is --C(CN)--.

[0021] In further embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, Z is --N--.

[0022] In additional embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is H.

[0023] In another embodiment of a compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is azetidine, pyrrolidine, piperidine, or N-linked piperazine.

[0024] In further embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is an N-linked piperazine.

[0025] In additional embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0026] In another embodiment of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0027] In further embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0028] In additional embodiments of the compound of Formula I or III, or a pharma- ceutically acceptable salt thereof, R2 is --O--CH2--R7.

[0029] In another embodiment of the compound of Formula II or IV, or a pharma- ceutically acceptable salt thereof, R7 is pyrrolidine.

[0030] In further embodiments of the compound of Formula I or III, or a pharma- ceutically acceptable salt thereof, R2 is [ka] It is.

[0031] In additional embodiments of the compound of Formula I or III, or a pharma- ceutically acceptable salt thereof, R2 is [ka] It is.

[0032] In another embodiment of the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, R and R are each independently a halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted 1 to 3 times by R8 -C 1-6 -OC optionally substituted 1 to 3 times by alkyl or R8 1-6 It is an alkyl.

[0033] In further embodiments of the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, R3 is F.

[0034] In additional embodiments of the compound of Formula I or III, or a pharma- ceutically acceptable salt thereof, R 4c is F or -CH3.

[0035] In another embodiment of the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, R5 is Cl.

[0036] In further embodiments of the compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, X is S, Y is -C(CN)-, R is F, and R 4a is H and R 4b is H and R 4c is F and R5 is Cl.

[0037] In additional embodiments of the compound of formula III or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0038] In another embodiment of the compound of formula III or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0039] In further embodiments of the compound of formula III or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0040] In additional embodiments of the compound of formula III or IV, or a pharma- ceutically acceptable salt thereof, R1 is [ka] It is.

[0041] In another embodiment of the compound of Formula II or IV, or a pharma- ceutically acceptable salt thereof, A is -CH2-.

[0042] In further embodiments of the compound of any of Formula I, II, III, or IV, or a pharma- ceutically acceptable salt thereof, R6 is H.

[0043] Examples of compounds described herein include the compounds in Table 1 and pharma- ceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0044] Preferred examples of the compounds described herein include the compounds in Table 2 and pharma- ceutically acceptable salts thereof. [Table 2]

[0045] Also provided herein is a pharmaceutical composition comprising a compound according to any one of Formulas I-IV, or a pharma-ceutically acceptable salt thereof, and a pharma-ceutically acceptable carrier, diluent, or excipient.

[0046] Further provided herein is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof.The cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, gastric cancer, or esophageal cancer.The cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.Even more specifically, the cancer can be non-small cell lung cancer.

[0047] 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 any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. In this method, the cancer can be non-small cell lung cancer, wherein the cancer has one or more cells expressing KRas G12D mutant protein. Also, in this method, the cancer is colorectal cancer, wherein the cancer has one or more cells expressing KRas G12D mutant protein. Furthermore, in this method, the cancer is mutant pancreatic cancer, wherein the cancer has one or more cells expressing KRas G12D mutant protein. Additionally, in this method, the present invention includes a method of treating cancer of other origins having KRas G12D mutant.

[0048] Further provided herein is a method of treating a patient having a cancer with a KRas G12D mutation, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-IV, or a pharma- ceutically acceptable salt thereof.

[0049] Additionally provided herein is a method of modulating mutant KRas G12D enzyme in a patient in need thereof by administering a compound according to any one of Formulas I-IV, or a pharma- ceutically acceptable salt thereof.Preferably, the method comprises inhibiting human mutant KRas G12D enzyme.

[0050] Also provided herein is a method of treating cancer in a patient in need thereof, the patient having a cancer determined to express KRas G12D mutant protein. The method comprises administering to the patient an effective amount of a compound according to any one of Formulae I-IV, or a pharma- ceutically acceptable salt thereof. The G12D mutation status of one or more cancer cells can be determined by several assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained and subjected to sequencing and / or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, for example, in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine mutation status (e.g., G12D mutation status in one or more cancer cells or circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, as well as pyrosequencing and multi-analyte profiling.

[0051] Further provided herein is a compound or a pharma- ceutically acceptable salt thereof according to any one of formulas I-IV for use in therapy. The compound or a pharma- ceutically acceptable salt thereof may be for use in the treatment of cancer. Preferably, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. More preferably, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. Even more preferably, the cancer is non-small cell lung cancer. The cancer may have one or more cancer cells expressing mutant KRas G12D protein. Preferably, the cancer is selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer. Additionally, the cancer may be non-small cell lung cancer, and one or more cells expressing G12D mutant protein. Further, the cancer may be colorectal cancer, and one or more cells express KRas G12D mutant protein. Additionally, the cancer may be pancreatic cancer, and one or more cells express KRas G12D mutant protein. The patient may have a cancer that is determined to have one or more cells that express KRas G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof. The patient may have been treated with a different course of treatment prior to being treated as described herein.

[0052] The compounds provided herein according to any one of formulas I-IV, or pharma- ceutically acceptable salts thereof, may also be used to manufacture a medicament for the treatment of cancer.Preferably, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer.More preferably, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer.Even more preferably, the cancer is non-small cell lung cancer.The cancer may have one or more cancer cells expressing mutant KRas G12D protein.When the cancer cells express KRas G12D protein, the cancer may be selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer.

[0053] 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 any one of Formulas I-IV, or a pharma- ceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein.Further provided herein is a compound according to any one of Formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, in simultaneous, separate, or sequential combination with a PD-1 or PD-L1 inhibitor, a CD4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharma- ceutically acceptable salt thereof. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-IV, or a pharma- ceutically acceptable salt thereof, and one or more of a PD-1 or PD-L1 inhibitor, a CD4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer.

[0054] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with a PD-1 or PD-L1 inhibitor for use in the treatment of cancer. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor for simultaneous, separate or sequential use in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor may be pembrolizumab, the PD-1 or PD-L1 inhibitor may be nivolumab, the PD-1 or PD-L1 inhibitor may be cemiplimab, the PD-1 or PD-L1 inhibitor may be sintilimab, the PD-1 or PD-L1 inhibitor may be atezolizumab, the PD-1 or PD-L1 inhibitor may be avelumab, the PD-1 or PD-L1 inhibitor may be durvalumab, or the PD-1 or PD-L1 inhibitor may be lodapilimab. As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, the cancer may be colorectal cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer may be mutant pancreatic cancer, where the cancer has one or more cells that express a KRas G12D mutant protein. The methods described herein also include methods of treating cancers of other origins that have a KRas G12D mutant.

[0055] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein.Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Additionally, a combination is provided comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of a cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib, the CDK4 / CDK6 inhibitor can be palbociclib, or the CDK4 / CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein, the cancer can be colorectal cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein, and the cancer can be mutant pancreatic cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. The methods described herein also include treating cancers of other origins that harbor the KRas G12D mutation.

[0056] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib, the EGFR inhibitor can be afatinib, the EGFR inhibitor can be gefitinib, and the EGFR inhibitor can be cetuximab. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, or the cancer can be colorectal cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12D mutant protein. The methods described herein also include methods of treating cancers of other origins that have KRas G12D mutant.

[0057] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer. As used herein, the ERK inhibitor can be LY3214996, the ERK inhibitor can be LTT462, or the ERK inhibitor can be KO-947. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, the cancer can be colorectal cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, and the cancer can be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12D mutant protein. The methods described herein also include treating cancers of other origins that have KRas G12D mutant.

[0058] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate or sequential use in the treatment of cancer. As used herein, Aurora A inhibitors include alisertib, tozasertib, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-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, (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 pharma- ceutical acceptable salt thereof. In one embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid.As described herein, the cancer can be non-small cell lung cancer, the cancer can have one or more cells expressing KRas G12D mutant protein, the cancer can be colorectal cancer, the cancer can have one or more cells expressing KRas G12D mutant protein, the cancer can be mutant pancreatic cancer, the cancer can have one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutant.

[0059] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, may be a type I SHP2 inhibitor or a type II SHP2 inhibitor. Examples of type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and cefsulodin, and pharmaceutically acceptable salts thereof. Examples of type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TN0155, 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 pharma- ceutically acceptable salts thereof.As described herein, the cancer may be non-small cell lung cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein; the cancer may be colorectal cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein; the cancer may be mutant pancreatic cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein.The methods also include treating cancers of other origins that harbor the KRas G12D mutation.

[0060] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein, in simultaneous, separate, or sequential combination with a platinum agent, or a pharma- ceutically acceptable salt thereof. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the platinum agent may be cisplatin, the platinum agent may be carboplatin, or the platinum agent may be oxaliplatin. As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells expressing a KRas G12D mutant protein, the cancer may be colorectal cancer, where the cancer has one or more cells expressing a KRas G12D mutant protein, and the cancer may be mutant pancreatic cancer, where the cancer has one or more cells expressing a KRas G12D mutant protein. The methods described herein also include treating cancers of other origins that have a KRas G12D mutant.

[0061] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of formulas I-IV, or a pharma- ceutically acceptable salt thereof, and pemetrexed for simultaneous, separate, or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. As described herein, the cancer has one or more cells expressing mutant KRas G12D protein. Additionally, a platinum agent may be administered to the patient (the platinum agent may be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer may be colorectal cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer may be a mutant pancreatic cancer, where the cancer has one or more cells that express a KRas G12D mutant protein. The methods described herein also include treating cancers of other origins that have a KRas G12D mutant.

[0062] The term "pharmaceutical acceptable salt" as used herein refers to a salt of a compound that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutical acceptable salts and the general methodology for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P.Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M.Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0063] Pharmaceutical compositions containing the compounds of formulas I-IV described herein may be prepared using pharma- ceutically acceptable excipients. The term "pharma- ceutically acceptable excipients" as used herein for pharmaceutical compositions refers to one or more carriers, diluents, and excipients that are compatible with other excipients of the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation are described in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22 nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharma- ceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugars, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycols.

[0064] As used herein, the term "effective amount" refers to an amount that is an effective dose in the treatment of a disorder or disease, such as a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. The attending physician, as one skilled in the art, can easily determine the effective amount by using conventional techniques and observing the results obtained under similar circumstances. The daily dosage of treatment is usually in the range of about 1 mg per day or twice a day to 1000 mg per day or twice a day, more preferably 100 mg per day or twice a day to 900 mg per day or twice a day. Factors to be considered in determining the effective amount or dosage of a compound include: whether the compound or a salt thereof is administered; if used, co-administration of other drugs; the type of patient being treated; the size, age, and general health of the patient; the extent or involvement or severity of the disorder; the response of the individual patient, the mode of administration, the bioavailability characteristics of the preparation being administered, the selected dosing regimen; and the use of other concomitant drugs.

[0065] The treating physician, veterinarian, or other medical professional will be able to determine the effective amount of the compound for treating the patient in need of treatment. Preferred pharmaceutical compositions can be formulated as tablets or capsules for oral administration, liquids for oral administration, or liquids for injection. The tablets, capsules, or solutions can contain an effective amount of the compound of the present invention to treat a patient in need of cancer treatment.

[0066] As used herein, the terms "treating," "treat," or "treatment" include slowing, alleviating, or reversing the progression or severity of an existing symptom, disorder, or condition, which in particular can include slowing the growth of cancerous lesions or the progression of abnormal cell proliferation and / or cell division.

[0067] As used herein, the term "patient" refers to a mammal in need of treatment. Preferably, the patient is a human in need of treatment for cancer, e.g., cancer with a KRas G12D mutation.

[0068] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AIBN" refers to azobisisobutyronitrile, "Boc-Gly-OH" refers to N-(tert-butoxycarbonyl)glycine, "DCM" refers to dichloromethane, "DIEA" refers to N,N-diisopropylethylamine, "(dippf)Rh(cod)BF4" refers to [1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, "DMAP" refers to 4-dimethylaminopyridine, "DMEA" refers to N,N-dimethylethylamine, "DMEM" refers to Dulbecco's modified Eagle's medium, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethylsulfoxide, and "DNA" refers to deoxyribonucleic acid. "DPEPhosPdCl2" refers to dichlorobis(diphenylphosphinophenyl)etherpalladium(II), "DTT" refers to dithiothreitol, "EDTA" refers to ethylenediaminetetraacetic acid, "EGTA" refers to ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid, "ELISA" refers to enzyme-linked immunosorbent assay, "ERK" refers to extracellular signal-regulated kinase, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol, "FBS" refers to fetal bovine serum, "GDP" refers to guanosine diphosphate, "GTP" refers to guanosine triphosphate, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,"(5-b)pyridinium 3-oxide hexafluorophosphate," "HPLC" refers to high performance liquid chromatography, "HRP" refers to horseradish peroxidase, "IPA" refers to isopropyl alcohol, "IPAm" refers to isopropylamine, "KOAc" refers to potassium acetate, "LC-ES / MS" refers to liquid chromatography-electrospray mass spectrometry, "LC / MS" refers to liquid chromatography-mass spectrometry, "L-prolinol" refers to [(2S)-pyrrolidin-2yl]methanol, "MAPK" refers to mitogen-activated protein kinase, "mCPBA" refers to 3-chloro-peroxybenzoic acid, "MeOH" refers to methanol, "MTBE" refers to methyl tert-butyl ether, "NaOMe" refers to sodium methoxide, "NBS" refers to N-bromosuccinimide, "NCS" refers to N-chlorosuccinimide, "N-chlorosuccinimide ... "N-methyl-L-prolinol" refers to [(2S)-1-methylpyrrolidin-2-yl]methanol, "NMP" refers to 1-methylpyrrolidin-2-one, "PCR" refers to polymerase chain reaction, "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), "RPMI" refers to Roswell Park Memorial Institute, "SCX" refers to strong cation exchange, and "SPE" refers to 1,1'-bis(diphenylphosphino)ferrocene. refers to solid phase extraction, SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, "TBDMSCl" refers to tert-butyldimethylsilyl chloride, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, and XPhos: 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl.

[0069] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The molecules described herein include compounds that are atropisomers and can exist in different conformations or as different rotamers. Atropisomers are compounds that exist in different conformations resulting from restricted rotation around a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier for rotation around a single bond is high enough and the interconversion rate is slow enough to separate the individual rotamers from each other. This description is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible for or can be made using the compounds disclosed herein. In the molecules described herein, only those molecules for which the absolute configuration (or atropisomeric configuration) of the chiral center is known use the naming convention or chemical formula drawn to indicate chirality or atropisomerism. Those skilled in the art will be able to easily understand and identify when other chiral centers are present in the molecules described herein.

[0070] Any one of the compounds of formulas I-IV that can chemically form salts can be easily converted to and isolated as pharma- ceutically acceptable salts. Salt formation can occur upon addition of a pharma- ceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., removal of a protecting group. Examples of reactions and conditions for salt formation can be found in Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0071] The compounds of the present invention or their salts may be prepared by various procedures, some of which are illustrated in the following preparations and examples. The specific synthetic steps of each of the described routes may be combined in different ways or combined with steps of different routes to prepare the compounds or salts of the present invention. The products of each step in the following preparations may be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0072] Preparation 1 1-tert-Butyl 2-methyl(2S,3S)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate [ka]

[0073] To a stirred mixture of 1-tert-butyl 2-methyl(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (500.00 mg, 2.039 mmol, 1.00 equiv) and imidazole (416.33 mg, 6.117 mmol, 3.00 equiv) in DCM (20.00 mL) was added TBDMSCl (768.13 mg, 5.098 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH / NH4OH (150:10:1 to 50:10:1) to give the product (600 mg, 82%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ4.45-4.36(m,1H),3.97-3.86(m,1H),3.66(d,3H),3.48-3.34 (m,2H),2.03-1.91(m,1H),1.80-1.69(m,1H),1.36(d,9H),0.86(s,9H),0.07(s,6H).

[0074] Preparation 2 [(2R,3S)-3-[(tert-butyldimethylsilyl)oxy]-1-methylpyrrolidin-2-yl]methanol [ka]

[0075] To a stirred solution of 1-tert-butyl 2-methyl(2S,3S)-3-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate (540 mg, 1.5 mmol, 1.0 equiv) in THF (10 mL) was added LiAlH4 (4.5 mL, 4.5 mmol, 3.0 equiv, 1M in THF) at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with H2O at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH / NH4OH (100:10:1 to 50:10:1) to give the product (120 mg, 32.55%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ4.09-3.99(m,1H),3.44-3.25(m,2H),2.86-2.77(m,1H),2.43-2.31(m,1H) ),2.27(s,3H),2.13-2.06(m,1H),1.90-1.71(m,1H),1.55-1.38(m,1H),0.82(s,9H),0.01(s,6H).

[0076] Preparation 3 [2-(hydroxymethyl)-1-methylpyrrolidin-2-yl]methanol [ka]

[0077] [2-(hydroxymethyl)pyrrolidin-2-yl]methanol (500.00 mg, 3.812 mmol, 1.00 equiv) and HCHO (343.35 mg, 11.435 mmol, 3.00 equiv) in MeOH (10.00 mL) were stirred at room temperature for 0.5 h. Then NaBH3CN (479.07 mg, 7.623 mmol, 2.00 equiv) was added slowly at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with H2O (5 ml) at 0 °C. The resulting mixture was diluted with H2O. The resulting mixture was extracted with EtOAc (200 ml x 3). The combined organic layer was washed with saturated aqueous NaCl solution (100 ml x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel eluting with DCM / MeOH / NH4OH (100:10:1 to 100:20:1) to give the product (400 mg, 72.3%) as a yellow oil. LC-MS: (ES+H,m / z)[M+H] + =146.1. 1 H NMR (400MHz, DMSO-d6+D2O) δ3.32-3.19(m,4H),2.66(t,2H),2.25(s,3H),1.62-1.48(m,4H).

[0078] Preparations 4 and 5 tert-Butyl (2S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (isomer 1) tert-Butyl (2S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (isomer 2) [ka]

[0079] To a solution of tert-butyl (2S)-2-acetylpyrrolidine-1-carboxylate (5.0 g, 23.4 mmol, 1.00 equiv) in THF (100 mL) was added LiAlH4 in THF (46.89 mL, 46.89 mmol, 2.00 equiv. 1.0 M in THF) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with H2O (3 mL) and concentrated under reduced pressure. The residue was purified on silica gel, eluting with toluene / acetone (30:1 to 20:1) to give tert-butyl (S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate, isomer 1 (1.6 g, 31.7%) as a colorless oil, and tert-butyl (S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate, isomer 2 (2.0 g, 39.6%) as a colorless oil. Isomer 1: 1 H NMR(300MHz,CDCl3)δ3.97-3.87(m,2H),3.56-3.45(m,1H),3.33-3.26(m,1H),2. 10-1.94 (m, 1H), 1.88-1.76 (m, 1H), 1.66-1.53 ​​(m, 2H), 1.49 (s, 9H), 1.10 (d, 3H). Isomer 2: 1 H NMR(300MHz,CDCl3)δ3.75-3.72(m,2H),3.51-3.47(m,1H),3.30-3.25(m,1H),2. 01-1.90(m,1H),2.04-1.68(m,2H),1.61-1.51(m,1H),1.49(s,9H),1.13(d,3H).

[0080] Preparation 6 1-[(2S)-1-Methylpyrrolidin-2-yl]ethanol, isomer 1 [ka]

[0081] To a stirred mixture of tert-butyl (S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate, isomer 1 (700.00 mg, 3.25 mmol, 1.00 equiv) in THF (200 mL), LiAlH4 (6.5 mL, 6.50 mmol, 2 equiv, 1M in THF) was added dropwise at 0 °C under N2 atmosphere. The mixture was then stirred at 70 °C for 2 h. The resulting mixture was quenched with H2O (3 mL) and concentrated under reduced pressure. The residue was purified on silica gel and eluted with DCM / MeOH / NH4OH (100:5:2 to 90:10:2) to give the product 1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (300 mg, 71.4%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ3.91-3.87(m,1H),3.19-2.95(m,1H),2.33(s,3H),2.30-2. 22(m,1H),2.18-2.06(m,1H),1.83-1.72(m,1H),1.75-1.59(m,3H),1.12(d,3H).

[0082] Preparation 7 1-[(2S)-1-Methylpyrrolidin-2-yl]ethanol, isomer 2 [ka]

[0083] To a stirred solution of tert-butyl (S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate, isomer 2 (600 mg, 2.79 mmol, 1.0 equiv) in THF, LiAlH4 (5.57 mL, 5.57 mmol, 2 equiv. 1M in THF) was added dropwise at 0 °C under N2 atmosphere. The mixture was then stirred at 70 °C for 2 h. The resulting mixture was quenched with H2O (3 mL) and concentrated under reduced pressure. The residue was purified on silica gel and eluted with DCM / MeOH / NH4OH (100:5:2 to 90:10:2) to give the product 1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (220 mg 61.1%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ3.91-3.87(m,1H),3.19-2.95(m,1H),2.33(s,3H),2.30-2. 22(m,1H),2.18-2.06(m,1H),1.83-1.72(m,1H),1.75-1.59(m,3H),1.12(d,3H).

[0084] Preparation 8 [(2S)-1,2-Dimethylpyrrolidin-2-yl]methanol [ka]

[0085] To a stirred solution of tert-butyl (2S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (700.00 mg, 3.251 mmol, 1.00 equiv) in THF (15.00 mL) was added LiAlH4 (3.90 mL, 3.901 mmol, 1.20 equiv, 1 M solution in THF) at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O (0.1 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH / NH3H2O ​​(150:10:1 to 100:10:1) to give the product (190 mg, 45.23%) as a light brown oil. 1H NMR(400MHz,DMSO-d6)δ4.21(s,1H),3.18(s,2H),2.84-2.78(m,1H),2.54-2.47(m,1H) ),2.17(s,3H),1.84-1.76(m,1H),1.67-1.53(m,2H),1.44-1.33(m,1H),0.84(s,3H).

[0086] Preparation 9 tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate [ka]

[0087] To a stirred mixture of (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (2.00 g, 8.72 mmol, 1.0 equiv) in THF (20 mL) was added BH3-THF (43.62 mL, 43.62 mmol, 5.00 equiv, 1.0 M in THF) dropwise at 0 °C under N2 atmosphere. The mixture was then stirred overnight. The resulting mixture was quenched with MeOH (8 mL) and concentrated under reduced pressure. The residue was purified on silica gel and eluted with DCM / MeOH (30:1 to 15:1) to give the product (1.5 g, 79.8%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ3.90-3.83(m,1H),3.67-3.60(m,1H),3.60-3.56(m,1H),3.51-.3.39(m,1H),2 .15-1.97(m,2H),1.53-1.44(m,1H),1.40(s,9H),1.35-1.27(m,1H),1.08-0.95(m,1H),0.95(d,3H).

[0088] Preparation 10 (2S,4S)-1,4-Dimethylpyrrolidin-2-yl]methanol [ka]

[0089] To a stirred mixture of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (1.50 g, 6.97 mmol, 1.00 equiv) in THF (20 mL) was added LiAlH4 (13.93 mL, 13.93 mmol, 2.00 equiv, 1M in THF) dropwise under N2 atmosphere at 0 °C. The mixture was stirred at 70 °C for 2 h. The resulting mixture was quenched with H2O (3 mL) and concentrated under reduced pressure. The residue was purified on silica gel and eluted with DCM / MeOH / NH4OH (100:5:2 to 90:10:2) to give the product (600 mg, 66.6%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ3.61-3.57(m,1H),3.37-3.34(m,1H),2.85-2.78(m,1H),2.70-2.60(m,1H),2.46-2.40( m,1H),2.37-2.30(m,1H),2.23(s,3H),2.17-2.07(m,1H),2.05-2.01(m,1H),1.39-1.31(m,1H),0.98(d,3H).

[0090] Preparation 11 (2S,4R)-1,4-Dimethylpyrrolidin-2-yl]methanol [ka]

[0091] To a stirred mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (300.00 mg, 1.31 mmol, 1.00 equiv) in THF (10.0 mL) was added LiAlH4 (5.23 mL, 5.23 mmol, 4.0 equiv, 1M in THF) dropwise under N2 atmosphere at -20 °C. The mixture was stirred at -20 °C for 2 h and then at 55 °C for an additional 2 h. The resulting mixture was quenched with MeOH (8 mL) and concentrated under reduced pressure. The residue was purified on silica gel and eluted with DCM / MeOH / NH4OH (45:1.5:1 to 45:3:1) to give the product (90 mg, 53.2%) as a colorless oil. 1H NMR(400MHz,CDCl3)δ3.58-3.52(m,1H),3.42-3.26(m,1H),3.14-3.05(m,1H),2.48-2.39( m,1H),2.26(s,3H),2.16-2.03(m,1H),1.95-1.80(m,2H),1.46-1.34(m,1H),0.92(d,3H).

[0092] Preparation 12 [(1R,2S,5S)-3-Methyl-3-azabicyclo[3.1.0]hexan-2-yl]methanol [ka]

[0093] To a stirred mixture of (1R,2S,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 1.32 mmol, 1.0 equiv) in THF (20 mL) was added LiAlH4 (6.60 mL, 6.60 mmol, 5.0 equiv, 1M in THF) dropwise at -40°C under N2 atmosphere. The resulting mixture was stirred at -40°C for 2 h under N2 atmosphere. The resulting mixture was then stirred at 50°C for 4 h under N2 atmosphere. The reaction was quenched with MeOH (1 mL) at 0°C. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography, eluting with DCM / MeOH / NH4OH (100:10:0.5 to 100:20:0.5) to give the product (90 mg, 53.6%) as a colorless oil. LC-MS: (ES+H,m / z):[M+H] + =128.4. 1 H NMR(400MHz,CDCl3)δ3.78(dd,1H),3.74-3.64(m,2H),3.13(d,1H),2.64-2.57(m,1H),2.53(dd ,1H),2.31(s,3H),1.54-1.43(m,1H),1.38-1.29(m,1H),0.85-0.77(m,1H),0.41-0.35(m,1H).

[0094] Preparation 13 [(1S,2S,5R)-3-Methyl-3-azabicyclo[3.1.0]hexan-2-yl]methanol [ka]

[0095] To a stirred mixture of (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (450 mg, 1.98 mmol, 1.0 equiv) in THF (10 mL) was added LiAlH4 (7.92 mL, 7.92 mmol, 4.0 equiv, 1M in THF) dropwise under N2 atmosphere at -20 °C. The mixture was stirred at -20 °C for 2 h and then at 55 °C for an additional 2 h. The resulting mixture was quenched with MeOH (8 mL) and concentrated under reduced pressure. The residue was purified on silica gel eluted with DCM / MeOH / NH4OH (90:3:0.5 to 90:6:0.5) to give the product (200 mg, 79.4%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ3.58-3.52(m,1H),3.45-3.41(m,1H),3.26-3.21m,1H),2.64-2.58(m,1H),2.46- 2.42(m,1H),2.29(s,3H),1.45-1.39(m,1H),1.35-1.28(m,1H),0.72-0.67(m,1H),0.19-0.16(m,1H).

[0096] Preparation 14 ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol [ka]

[0097] To a stirred solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (20.0 g, 80.9 mmol, 1.0 equiv.) in THF (200 mL) was added LiAlH4 (485.3 mL, 485.3 mmol, 6.0 equiv., 1M in THF) dropwise under N2 atmosphere at -50°C. The resulting mixture was stirred at -50°C for 1 h under N2 atmosphere. The resulting mixture was then stirred at 70°C for 2 h under N2 atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give the product (2.94 g, 27.30%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ5.22-5.00(m,1H),3.72(dd,1H),3.60-3.41(m,2H),3.10(s,1H),2.84-2.55(m,2H),2.41(s,3H),2.19-2.00(m,2H).

[0098] 19 F NMR(377MHz, CDCl3)δ-170.22.

[0099] Preparation 15 [(2S)-1-[2-(oxan-2-yloxy)ethyl]pyrrolidin-2-yl]methanol [ka]

[0100] [(2S)-pyrrolidin-2-yl]methanol (500 mg, 4.94 mmol, 1.0 equiv.) and 2-(2-bromoethoxy)oxane (1.09 g, 5.19 mmol, 1.05 equiv.) and K2CO3 (1.37 g, 9.89 mmol, 2.0 equiv.) in ACN (10 mL) were stirred at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C under N2 atmosphere for 8 h. The mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with saturated aqueous NaCl (3 x 50 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM:MeOH=15:1 to 5:1) to give the product (1.05 g, 93%) as a yellow oil. 1 H NMR(400MHz,CDCl3+D2O)δ4.63(dd,1H),3.91-3.80(m,2H),3.63-3.59(m,1H),3.54-3.47(m,2H),3.38-3.33(m,1H),3.23(ddd,1H) ),3.03-2.97(m,1H),2.69(td,1H),2.62-2.55(m,1H),2.39-2.33(m,1H),1.89-1.81(m,2H),1.78-1.69(m,4H),1.61-1.50(m,4H).

[0101] Preparation 16 [(2S)-1-(2-fluoroethyl)pyrrolidin-2-yl]methanol [ka]

[0102] [(2S)-pyrrolidin-2-yl]methanol (2.015 g, 19.92 mmol) and 1-bromo-2-fluoro-ethane (5.0 g, 39 mmol) were combined in DMEA (6.4 mL, 59 mmol) and stirred at room temperature for about 18 hours. The mixture was charged with LiOH (1.00 g, 41.7 mmol) followed by HO (0.1 mL) and stirred at room temperature for 15 minutes. MeOH (2 mL) was then added followed by DCM (4 mL) and stirred at room temperature for 1 hour. DCM (100 mL) was then added, filtered and concentrated. The residue was purified via silica gel chromatography eluting with 100% ACN to 90% ACN / 10% 2M NH3 in MeOH to give the product (1.78 g, 61%) as a white solid. MS (ES) m / z=148 (M+1).

[0103] Preparation 17 6-Bromo-2,3-difluorobenzenemethanol [ka]

[0104] 6-Bromo-2,3-difluorobenzaldehyde (20.0 g, 88.7 mmol) was dissolved in MeOH (250 mL) and NaBH4 (6.70 g, 177 mmol) was added portionwise. After cooling the exothermic reaction to ambient temperature (ca. 1 h), the reaction mixture was poured into saturated aqueous NH4Cl and extracted three times with DCM. The combined organic extracts were washed with H2O and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dried under high vacuum overnight to give the product (19.5 g, 97%) as a white solid. 1 H NMR (CDCl3) δ7.37(1H,m),7.07(1H,m),4.88(2H,m),2.13(1H,m).

[0105] Preparation 18 Methyl (6-bromo-2,3-difluorophenyl)methanesulfonate [ka]

[0106] 6-Bromo-2,3-difluorobenzenemethanol (19.5 g, 85.7 mmol) was dissolved in THF (200 mL) and DIEA (18.0 mL, 103 mmol) was added. The mixture was cooled to 0° C. and then treated with methanesulfonic anhydride (17.1 g, 94.2 mmol). After stirring at ambient temperature for 18 h, the mixture was diluted with EtOAc:MTBE (1:1) and washed with cold H2O. The layers were separated and the aqueous layer was extracted twice with EtOAc:MTBE (1:1). The combined organics were washed with H2O and saturated NaCl solution, dried over MgSO4 and K2CO3, filtered, and concentrated in vacuo to give the product (26.0 g, quantitative) as a yellow oil. 1 H NMR (CDCl3) δ7.44(1H,m),7.18(1H,m),5.43(2H,d),3.12(3H,s).

[0107] Preparation 19 2-(6-Bromo-2,3-difluoro-phenyl)acetonitrile [ka]

[0108] A mixture of methyl (6-bromo-2,3-difluorophenyl)methanesulfonate (26.0 g, 82.0 mmol) and KCN (6.06 g, 90.3 mmol) in EtOH (200 mL) and H2O (40.0 mL) was refluxed for 0.5 h and then cooled to ambient temperature. The solvent was removed in vacuo and the residue was suspended in DCM. The mixture was washed with H2O, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography eluting with 10-100% DCM / hexane to give the product (17.9 g, 94%). 1 H NMR (CDCl3) δ7.44(1H,m),7.15(1H,m),3.91(2H,d).

[0109] Preparation 20 Ethyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate [ka]

[0110] A solution of 2-(6-bromo-2,3-difluoro-phenyl)acetonitrile (17.9 g, 77.2 mmol) in DMF (200 mL) was cooled in an ice bath and then treated portionwise with tBuOK (9.30 g, 81.2 mmol). After the addition, the mixture was stirred for 10 min and ethoxycarbonyl isothiocyanate (9.80 mL, 81.4 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 h and then heated at 100° C. for 0.5 h. The mixture was then cooled in an ice bath for 10 min and H2O (500 mL) was added slowly with stirring. The resulting precipitate was collected by filtration, rinsed with H2O and hexanes, and air-dried. The solid was further dried in a vacuum oven at 60° C. overnight to give the product (24.5 g, 84%). ES / MS m / z 340.8 [MH] - .

[0111] Preparation 21 2-Amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0112] A mixture of ethyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (24.5 g, 71.4 mmol), DMSO (100 mL), and 5N NaOH (80.0 mL, 400 mmol) was refluxed for 4 h. The mixture was cooled to ambient temperature and treated with cold H2O with vigorous stirring. The resulting precipitate was collected by filtration, washed with H2O, and dried overnight in a vacuum oven at 65 °C to give the product (15.5 g, 80%). ES / MS m / z 268.8 [MH] - .

[0113] Preparation 22 tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate [ka]

[0114] A mixture of 2-amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile (16.0 g, 57.8 mmol) and DIEA (15.0 mL, 86.0 mmol) in DCM (100 mL) and DMF (100 mL) was stirred at room temperature for 5 min. DMAP (700 mg, 5.73 mmol) was added followed by di-tert-butyl dicarbonate (14.5 g, 64.4 mmol) and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and further dried under high vacuum. The residue was treated with 10% aqueous citric acid (200 mL) and 1:1 EtOAc:MTBE (200 mL). After stirring for 15 min, the resulting precipitate was collected by filtration, washed with H2O followed by Et2O and dried in a vacuum oven at 60 °C overnight to give the title compound (17.6 g) as a yellow solid. The layers of the filtrate were separated and the aqueous layer was extracted with 1:1 EtOAc:MTBE (200 mL). The organic layers were combined, washed with saturated aqueous NaHCO3, followed by saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to give a crude yellow solid which was recrystallized from EtOAc / hexanes to give an additional 2 g of the title compound (total product yield 19.6 g, 91%). ES / MS (m / z): 370.8 (M+H).

[0115] Preparation 23 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate [ka]

[0116] tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (16.0 g, 41.4 mmol) and bis(neopentylglycolato)diboron (37.0 g, 157 mmol) were dissolved in 1,4-dioxane (300 mL) under N2. KOAc (12.2 g, 124 mmol) was added and the mixture was sparged with N2 at 50 °C for 1 h. DPEPhosPdCl2 (3.0 g, 4.2 mmol) was added and the flask was heated at 95 °C for 1 h. The mixture was then cooled to room temperature, concentrated in vacuo to approximately 100 mL, diluted with heptane (200 mL), stirred for 10 min, filtered through diatomaceous earth, and rinsed with heptane and heptane:MTBE (1:1). The filtrate was concentrated, dissolved in minimal DCM, filtered through a pad of silica gel, and rinsed with EtOAc:heptane (1:1). The filtrate was washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography eluting with 5-50% (20% acetone in DCM) / hexanes to give the product (13.0 g, 78%). 1 H NMR (DMSO-d6) δ11.6(1H,s),7.61(1H,m),7.20(1H,m),3.78(4H,s),1.54(9H,s),1.03(6H,s).

[0117] Preparation 24 (6-Bromo-2-fluoro-3-methyl-phenyl)methanol [ka]

[0118] 6-Bromo-2-fluoro-3-methyl-benzaldehyde (see U.S. Patent Application Publication No. 2015 / 0126449(A1), Example 120A, page 63) was used in a manner similar to the method of Preparation 17 to give the title compound (13.42 g, 92.2%). 1H NMR (400.13MHz, CDCl3) δ7.29(dd,J=8.1,1.0Hz,1H),7.05(dd,J=8.1,8.1Hz,1H),4.87(d,J=2.2Hz,2H),2.27(d,J=2.1Hz,3H).

[0119] Preparation 25 (6-bromo-2-fluoro-3-methyl-phenyl)methanesulfonate methyl [ka]

[0120] (6-Bromo-2-fluoro-3-methyl-phenyl)methanol was used in an essentially similar manner to the method of Preparation 18 to give the title compound (19 g, quantitative). 1 H NMR (400.13MHz, CDCl3) δ7.35(dd,J=8.1,1.0Hz,1H),7.16(dd,J=8.1,8.1,1H),5.44(d,J=2.1Hz,2H),3.10(s,3H),2.29(d,J=1.9Hz,3H).

[0121] Preparation 26 2-(6-Bromo-2-fluoro-3-methyl-phenyl)acetonitrile [ka]

[0122] Methyl (6-bromo-2-fluoro-3-methyl-phenyl)methanesulfonate was used in a manner similar to the method of Preparation 19 to give the title compound (8.45 g, 62.2%). 1 H NMR (400.13MHz, CDCl3) δ7.33(dd,J=8.1,1.2Hz,1H),7.11(dd,J=8.1,8.1Hz,1H),3.88(d,J=1.8Hz,2H),2.28(d,J=2.1Hz,3H).

[0123] Preparation 27 Ethyl N-(4-bromo-3-cyano-7-methyl-benzothiophen-2-yl)carbamate [ka]

[0124] A solution of 2-(6-bromo-2-fluoro-3-methyl-phenyl)acetonitrile (6.45 g, 28.3 mmol) in DMF (70 mL) was cooled in an ice-water bath and then treated with NaH (60% in mineral oil, 1.24 g, 31.1 mmol). The mixture was stirred for 20 min and ethoxycarbonyl isothiocyanate (3.51 mL, 29.7 mmol) was added. The resulting mixture was heated at 80° C. overnight. The mixture was cooled to room temperature and quenched with H2O. The precipitate was collected by filtration and dried in a vacuum oven at 60° C. overnight. The slightly tan solid was diluted with DCM (50 mL), heated to boiling, and sonicated to break down the remaining solid. The resulting white solid was collected by filtration to give the product (2.72 g, 28%). ES / MS (m / z): 339.0 (M+H).

[0125] Preparation 28 2-Amino-4-bromo-7-methyl-benzothiophene-3-carbonitrile [ka]

[0126] Ethyl N-(4-bromo-3-cyano-7-methyl-benzothiophen-2-yl)carbamate (from Preparation 20) was used in a manner similar to that of Preparation 21, except that the reaction was heated at 100° C. for 2 days to give the title compound (1.9 g, 90%). ES / MS (m / z): 267.0 (M+H).

[0127] Preparation 29 tert-Butyl N-(4-bromo-3-cyano-7-methyl-benzothiophen-2-yl)carbamate [ka]

[0128] 2-Amino-4-bromo-7-methyl-benzothiophene-3-carbonitrile (from Preparation 21) was used in a similar manner to the method of Preparation 22 using THF as the reaction solvent to give the title compound (1.7 g, 64%). ES / MS (m / z): 367.0 (M+H).

[0129] Preparation 30 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-methyl-benzothiophene-2-yl]carbamate [ka]

[0130] A mixture of tert-butyl N-(4-bromo-3-cyano-7-methyl-benzothiophen-2-yl)carbamate (1.60 g, 4.36 mmol) and KOAc (1.07 g, 10.9 mmol) in toluene (60 mL) was heated in a reaction block at 175 °C to remove any HO into a Dean-Stark trap. The solution was cooled to 50 °C, treated with bis(neopentylglycolato)diboron (1.25 g, 5.53 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.153 g, 0.218 mmol), and heated to 80 °C overnight. The reaction mixture was diluted with EtOAc, stirred for 10 min, and filtered through diatomaceous earth. The filtrate was washed twice with saturated aqueous NaHCO3, followed by saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography, eluting with 10-40% (20% acetone in DCM) / hexane to give the product (1.02 g, 58.5%) as a white solid. ES / MS (m / z): 277.0 (M-tBu-CH2C(Me)2CH2+H). 11H NMR (400.13 MHz, DMSO-d6): δ 11.27 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 3.77 (s, 4H), 3.32 (s, 1H), 2.49 (s, 3H), 1.54 (s, 9H), 1.03 (s, 6H).

[0131]

Chem.

[0132] Scheme 1 shows the preparation of quinazoline compound (10). Using well-known conditions, commercially available 4-amino-2,3-difluoro-benzoic acid (1) may be chlorinated with a variety of suitable reagents, including but not limited to NCS, SO2Cl2, Cl2, and 1,3-dichloro-5,5-dimethylhydantoin, to provide chlorinated benzoic acid (2). Chlorinated benzoic acid (2) may be subjected to typical Sandmeyer conditions known to those skilled in the art to provide 4-bromo-5-chloro-2,3-difluoro-benzoic acid (3). 4-Bromo-5-chloro-2,3-difluoro-benzoic acid (3) may be treated with alkylating thiourea or a suitable salt thereof to provide arylsulfanylcarbonimidoyl (4). Subsequent cyclization of the arylsulfanylcarbonimidoyl (4) may be accomplished by heating in a suitable polar aprotic solvent to give the quinazoline (7), which one skilled in the art will recognize may alternatively be synthesized starting from commercially available 2-amino-4-bromo-3-fluoro-benzoic acid and chlorinated under the conditions previously described to provide 2-amino-4-bromo-5-chloro-3-fluoro-benzoic acid (5). 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid (5) may be cyclized to quinazoline (6) by forming the corresponding acid chloride followed by the addition of ammonium thiocyanate. 2-Thioxoquinazolin-4-one (6) may be converted to the corresponding alkylated quinazoline sulfide (7) under basic conditions and the addition of a suitable alkyl electrophile. A number of suitable protecting groups may be added to quinazoline (7) to provide protected quinazoline (10). 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid (5) may also be used to provide quinazoline-2,4-dione (8) en route to quinazoline (10) by addition of urea under heating. One skilled in the art will recognize that dione (8) may also be chlorinated by use of phosphoryl chloride or a similar chlorinating reagent. The chlorine adjacent to the nitrogen atom on the quinazoline may be selectively displaced to provide substituted quinazoline (10).

[0133] [ka]

[0134] Scheme 2 shows the preparation of benzothiophene-substituted quinazoline compounds (17). Thioethers (11) may be oxidized with mCPBA or other suitable oxidizing agents in DCM to provide sulfones (12). Nucleophilic aromatic substitution of the sulfone moiety (typically S) using strong non-nucleophilic bases in polar aprotic solvents such as THF and various heterocyclylalkyl alcohols can be used. N Ar) to give the substituted quinazoline (14). N Ar may be achieved by heating aryl chloride (13) with the aforementioned alcohol and a stoichiometric amount of KF in DMSO. Aryl coupling of bromo-quinazoline (14) with benzothiophene boronic acid esters may be achieved under Suzuki conditions using a base such as Cs2CO3 and various palladium(II) complexes with bis(2-(diphenylphosphino)phenyl) ether ligands well known to those skilled in the art to give bis-aryl compounds (15). Subsequent removal of the protecting group may be achieved by a method appropriate for the protecting group used, for example, BOC removal with TFA in DCM. The heterocyclic group on quinazoline (16) may be acylated under typical amide coupling reagents such as HATU, polar aprotic solvents such as DMF, and non-nucleophilic bases to give amides (17).

[0135] [ka]

[0136] Scheme 3 illustrates the preparation of 2,7-substituted quinazoline compounds (25). Chloro-quinazoline (18) may be dechlorinated by using a suitable palladium-ligand complex, such as bis(diphenylphosphino)ferrocene ligand, and a base, such as NaBHCN+N,N,N',N'-tetramethylethylenediamine, to form hydride-substituted quinazoline (19). Quinazoline (19) may be used convergently in two synthetic routes to gain access to different substitution points. Suzuki coupling of bromo-quinazoline (19) gives bis-aryl (20), which may be oxidized with a thioether moiety to produce sulfone (21). This may then be used as a S-aryl ester for the introduction of an ether moiety into quinazoline (24). N Alternatively, oxidation of the thioether (19) can be carried out directly to afford the S-alkylated heterocyclyl alcohol moiety. N Ar introduction may be permitted to give a variety of quinazolines (23). Suzuki aryl coupling then affords bis-aryl compounds (24), which represent the convergence of the two pathways, and may then be deprotected to produce substituted quinazolines (25).

[0137] [ka]

[0138] Scheme 4 illustrates the preparation of quinazoline compound (32). Nucleophilic displacement at the C-4 center of chloro-quinazoline (26) with an appropriate substituted sulfide gives thioether (27). Suzuki coupling of bromo-quinazoline (27) with substituted benzothiophene boronic ester gives substituted quinazoline compound (28), which may be displaced with an appropriate heterocyclic nucleophile to give further substituted quinazoline (31). Alternatively, 4,7-disubstituted quinazoline (31) may be constructed from either 4-chloro or 4-hydroxyquinazoline (29) by introducing the appropriate heterocycle to quinazoline (30) via nucleophilic displacement. Similar palladium-catalyzed Suzuki-Miyaura coupling conditions may be used to give protected bis-aryl (31). As detailed above, protected aminothiophene (31) may be deprotected under a variety of conditions well known to those skilled in the art.

[0139] [ka]

[0140] Scheme 5 illustrates the synthesis of compound (36). The aforementioned 4-chloroquinazoline (26) may be selectively coupled with an appropriate dicarboxylate using a suitable non-nucleophilic base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, or potassium bis(trimethylsilyl)amide to provide quaternary methyl acetate (33). One skilled in the art will recognize that the quinazoline ester (33) may be decarboxylated utilizing a suitable polar aprotic solvent, inorganic salt, and heat under a variety of conditions such as metal catalysis, photoredox catalysis, or Krapko conditions to provide the methine quinazoline (34). Palladium catalyzed Suzuki-Miyaura coupling conditions may be used on 7-bromoquinazoline (34) to affect aryl-aryl bond formation to produce substituted quinazoline (35). Additionally, protected aminothiophenes (35) may be deprotected under a variety of conditions well known to those skilled in the art, as detailed above.

[0141] [ka]

[0142] Scheme 6 shows the synthesis of compound 42. Commercially available 6-bromo-7-chloro-8-fluoro-quinoline (37) may be oxidized with AgF2 in a Chichibabin-type process to give 6-bromo-7-chloro-8-fluoro-quinoline (38). Those skilled in the art will recognize that addition of α-fluorinated quinoline (38) to a solution of N-methyl-L-prolinol and a suitable non-nucleophilic base (e.g., lithium bis(trimethylsilyl)amide, lithium diisopropylamide, or potassium bis(trimethylsilyl)amide) provides substituted quinoline (39). An alkyl group may be selectively substituted on 6-bromoquinoline (39) to provide alkylated quinoline (40) using typical palladium-catalyzed Suzuki-Miyaura coupling conditions. As previously mentioned, similar conditions may be further used on 7-chloroquinoline (40) to affect aryl-aryl bond formation to produce bis-aryl (41). Additionally, as detailed above, the protected aminothiophene (41) may be deprotected under a variety of conditions well known to one of skill in the art.

[0143] Preparation 31 4-Amino-5-chloro-2,3-difluorobenzoic acid [ka]

[0144] To a solution of 4-amino-2,3-difluoro-benzoic acid (33.3 g, 192 mmol) in ACN (400 mL) was charged NCS (34.5 g, 251 mmol, 1.30 equiv) in portions. The reaction was heated at 80° C. for 1.5 h. The flask was placed in an ice bath and once the temperature reached approximately 10° C., 1.2 L (3 vol) of H2O was added dropwise over approximately 1 h. The solid was filtered, rinsed with 500 mL of H2O, and left to dry under vacuum (Batch 1). The filtrate was further extracted with EtOAc (2×1 L), dried over anhydrous Na2SO4, filtered, and concentrated to a solid. The solid was slurried in H2O (1 L) for 2 h, then filtered and dried under vacuum (Batch 2). The batches were combined to give the product (25.9 g, 65%) as a tan solid. MS(ES) m / z=162 (M-CO2H). 1 H NMR (399.80MHz, DMSO-d6): δ7.88 (dd, J=2.2, 6.2Hz, 1H).

[0145] Preparation 32 4-Bromo-5-chloro-2,3-difluorobenzoic acid [ka] A suspension of ACN (200 mL) and CuBr2 (25.8 g, 116 mmol, 2.00 equiv) was placed in a heating mantle and the temperature controller was turned on to 78 °C. While the mixture was heated, tert-butyl nitrite (30 mL, 227 mmol, 3.9 equiv) was added dropwise over 10 min. The mixture was heated at 78 °C for 15 min, then 4-amino-5-chloro-2,3-difluoro-benzoic acid (12.00 g, 57.81 mmol) was added in portions. The mixture was heated at 78 °C for approximately 7 h. The mixture was concentrated, EtOAc (200 mL) was added, and it was washed with 1N HCl (2 x 100 mL), saturated aqueous NaHSO3 (100 mL), and saturated aqueous NaCl (100 mL). The organics were dried over anhydrous Na2SO4, which was then filtered, concentrated, and dried under house vacuum at room temperature to give the product (14 g, 89%) as a tan solid. MS (ES-) m / z=262 (M-CO2H). 1H NMR(399.80MHz,DMSO-d6):δ7.88(dd,J=2.2,6.2Hz,1H),

[0146] Preparation 33 4-Bromo-5-chloro-N-(ethylsulfanylcarbonimidoyl)-2,3-difluoro-benzamide [ka]

[0147] A suspension of 4-bromo-5-chloro-2,3-difluoro-benzoic acid (2.0 g, 6.1 mmol) in ACN (30 mL) was charged with S-ethylisothiourea hydrobromide (2.11 g, 11.2 mmol, 1.8 equiv), DIEA (2.6 mL, 15 mmol, 2.4 equiv), HATU (4.33 g, 11.2 mmol, 1.8 equiv) and stirred at room temperature for 15 min. The precipitate was filtered. The filtrate was treated dropwise with HO (120 mL) and stirred at room temperature for 15 min. The solid was filtered and left at 50° C. under house vacuum to give the product (1.86 g, 75%) as a light orange solid. MS (ES+) m / z=359 (M+1).

[0148] Preparation 34 7-Bromo-6-chloro-2-ethylsulfanyl-8-fluoro-3H-quinazolin-4-one [ka]

[0149] A solution of 4-bromo-5-chloro-N-(ethylsulfanylcarbonimidoyl)-2,3-difluoro-benzamide (8.6 g, 24 mmol) in NMP (80 mL) was heated at 100° C. for 6 h. The mixture was cooled to room temperature, treated dropwise with 240 mL of H2O, and stirred at room temperature for 2 h. The solid was filtered and dried under vacuum at 50° C. The solid was stirred with 40 mL of DCM for 0.5 h and filtered to give the product (5.22 g, 64%). MS (ES+) m / z=338 (M+1).

[0150] Preparation 35 7-Bromo-4,6-dichloro-2-ethylsulfanyl-8-fluoro-quinazoline [ka]

[0151] A suspension of 7-bromo-6-chloro-2-ethylsulfanyl-8-fluoro-3H-quinazolin-4-one (5.2 g, 15 mmol) in DCM (75 mL) was charged with (chloromethylene)dimethyliminium chloride (7.96 g, 31.1 mmol, 4.0 equiv) and stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of H2O, partitioned, and washed with saturated aqueous NaCl. The organics were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 10% to 60% DCM in hexanes to give the product (5.1 g, 93%) as a white solid. MS (ES+) m / z=338 (M+1).

[0152] Preparation 35a tert-Butyl 9-(7-bromo-6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate [ka]

[0153] 7-Bromo-4,6-dichloro-2-ethylsulfanyl-8-fluoro-quinazoline (0.34 g, 0.96 mmol) was placed in a vial with tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.25 g, 1.0 mmol, 1.1 equiv.) and DIPEA (0.33 mL, 1.9 mmol, 2 equiv.) in ACN (5 mL) and DMF (2 mL) and stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with H2O and saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to an oil. The oil was purified via silica gel chromatography eluting with a gradient from 100% hexanes to 30% EtOAc in hexanes to give the product (0.483 g, 92%) as a tan solid. MS(ES) m / z=547 / 549(M+1).

[0154] Preparation 36 tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate [ka]

[0155] 7,9-Diazabicyclo[3.3.1]nonane-7-carboxylate (0.480 g, 0.8761 mmol) was combined with tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (0.460 g, 1.14 mmol), Cs2CO3 (0.874 g, 2.6 mmol), and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (0.128 g, 0.17 mmol) in toluene (11 mL) in a 25 mL vial. The vial was capped and purged alternately with N2 / vacuum (2 times). The vial was placed in a heating block and heated at 120 °C for 2 h. The reaction was diluted with EtOAc, filtered through diatomaceous earth, and rinsed with EtOAc. The filtrate was concentrated and purified with a gradient from 100% hexanes to 40% EtOAc in hexanes to give the product (0.385 g, 58%) as an orange gummy solid. MS (ES) m / z=760 (M+1).

[0156] Preparation 37 tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate [ka]

[0157] tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.385 g, 0.51 mmol) and mCPBA (0.220 g, 1.27 mmol) were stirred in DCM (10 mL) at room temperature for 1 h. The reaction was diluted with DCM, washed with H2O and Na2S2O3, dried over anhydrous Na2SO4, filtered and concentrated to an oil. The oil was purified by silica gel chromatography eluting with a gradient from 100% hexane to 60% EtOAc in hexane to give the product (0.205 g, 32%). MS (ES) m / z=792 (M+1).

[0158] Preparation 38 tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate [ka]

[0159] Lithium bis(trimethylsilyl)amide (1 mol / L) in THF was added to a solution of N-methyl-L-prolinol (0.02 mL, 0.2 mmol) and stirred for 5 min. tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.060 g, 0.076 mmol) in THF (0.5 mL) was added and stirred at room temperature for 0.5 h. The mixture was diluted with EtOAc and concentrated to give the crude product (61 mg, quantitative) as an oil.

[0160] Example 1 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0161] tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.060 g, 0.074 mmol) was stirred in DCM (2 mL) and TFA (1 mL) at room temperature for 1 h. The mixture was concentrated and the residue was purified via silica gel chromatography eluting with a gradient from 100% DCM to 10% 2N NH3 in MeOH in DCM to give the product (0.024 g, 53%) as a white solid. MS (ES) m / z=612 (M+1).

[0162] The example compounds in Table 3 were prepared in a manner similar to that described in the Examples using the appropriate piperazine derivative at C4 and the appropriate alcohol at C2. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. [Table 3-1] [Table 3-2]

[0163] Preparation 39 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid [ka]

[0164] 2-Amino-4-bromo-3-fluoro-benzoic acid (200.0 g, 854 mmol) was added to DMF (850 mL) followed by NCS (114.7 g, 854 mmol) in four equal portions every 15 min. The mixture was stirred at room temperature for about 18 h. Another portion of NCS (23.8 g, 179 mmol) was added and the reaction was stirred at room temperature for an additional 72 h. The mixture was poured into HO (4 L), stirred, filtered and dried at 50 °C under house vacuum to give the product (214 g, 93%) as a beige solid. MS (ES) m / z = 267 (M-1).

[0165] preparation 40 7-Bromo-6-chloro-8-fluoro-2-thioxo-1H-quinazolin-4-one [ka]

[0166] 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid (213.7 g, 795.9 mmol) was added in portions to SOCl2 (500 mL) over 5-10 min. The flask was then fitted with an HCl trap and heated to reflux for 5 h. The homogeneous mixture was cooled to room temperature and stirred for 18 h. The mixture was concentrated and DCM (ca. 500 mL) was added and removed under reduced pressure twice. A separate 5 L flask equipped with an overhead stirrer and internal thermometer was charged with NHSCN (68 g, 871 mmol) and acetone (530 mL) and placed under a blanket of N2. A solution of the acid chloride in acetone (1060 mL) was added via addition funnel over 1 h at a rate to maintain the internal temperature below 55 °C. The reaction was stirred and cooled with stirring for 18 h. The mixture was concentrated to ca. 500 mL. The solid was collected by filtration, slurried, rinsed three times with acetone, and dried under vacuum for 18 hours to give the product (270 g, 90%) as a light brown solid. MS (ES) m / z=307 (M-1).

[0167] Preparation 41 7-Bromo-6-chloro-8-fluoro-2-methylsulfanyl-1H-quinazolin-4-one [ka]

[0168] To a flask containing 7-bromo-6-chloro-8-fluoro-2-thioxo-1H-quinazolin-4-one (106.6 g, 241 mmol) was added EtOH (1.2 L), NaOH (5 mol / L) in HO (51 mL, 255 mmol), followed by CHI (15.7 mL, 252 mmol) over 5 min. The reaction mixture was stirred at room temperature for 18 h. DCM (400 mL) and MeOH (200 mL) were introduced to aid in obtaining a homogenous solution. Further NaOH (5 mol / L) in HO (14.5 mL, 72.5 mmol) and CHI (4.5 mL, 72 mmol) were added and the reaction was stirred at room temperature for 18 h. The mixture was poured into DCM (3 L), partitioned, and the organic solution was concentrated to approximately 100-200 mL. The solid was filtered, rinsed with DCM, H2O, ACN, Et2O, and dried under vacuum at about 50 °C to give the product (18 g, 24%) as a tan solid. MS (ES) m / z = 321 (M-1).

[0169] Preparation 42 tert-Butyl-4-(7-bromo-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl)piperazine-1-carboxylate [ka]

[0170] A mixture of 7-bromo-6-chloro-8-fluoro-2-methylsulfanyl-1H-quinazolin-4-one (18.2 g, 56.3 mmol), POCl3 (13 mL, 138.1 mmol), and DIEA (10 mL, 57.3 mmol) in DCM (110 mL) was heated at 100° C. for 4 h. Heating was stopped and the reaction was left stirring at room temperature for 18 h. The mixture was concentrated in vacuo, azeotroped twice with DCM, and dried under house vacuum to give a dark brown solid (38.6 g, 56.4 mmol), which was dissolved in 1,4-dioxane (110 mL) and DIEA (30 mL, 172 mmol) and treated with tert-butyl piperazine-1-carboxylate (11 g, 57.88 mmol). The resulting mixture was stirred at room temperature under N2 for 1.5 h. The reaction mixture was then partitioned between EtOAc, saturated aqueous NaHCO3, and saturated aqueous NaCl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to a brown oil. The oil was purified via silica gel chromatography eluting with 100% hexanes to 20% EtOAc in hexanes to give the product (20.2 g, 73%) as a light tan solid. MS (ES) m / z=491 (M+1).

[0171] Preparation 43 tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl]piperazine-1-carboxylate [ka]

[0172] tert-Butyl 4-(7-bromo-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl)piperazine-1-carboxylate was prepared in the same manner as described in Preparation 36 to give the product (6.8 g, 52%) as a pale yellow foam. MS (ES) m / z=703 (M+1).

[0173] Preparation 44 tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-methylsulfonyl-quinazolin-4-yl]piperazine-1-carboxylate [ka]

[0174] tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl]piperazine-1-carboxylate was prepared in the same manner as described in Preparation 37 to obtain the product (5.6 g, 79%) as a white powder. MS (ES) m / z=735 (M+1).

[0175] Preparation 45 [(2S)-1-Allylpyrrolidin-2-yl]methanol [ka]

[0176] To a solution of L-prolinol (2.0 g, 19.2 mmol) in ACN (95 mL) was added K2CO3 (3.97 g, 28.8 mmol) and 3-bromobrop-1-ene (2.44 g, 20.1 mmol) at 0 °C. The resulting mixture was stirred and allowed to warm slowly to room temperature under N2 over 18 h. The reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated and the residue was purified via silica gel chromatography eluting with 2%-10% MeOH in DCM to give the product (1.9 g, 70%) as a pale yellow oil. MS (ES) m / z=142 (M+1).

[0177] Preparation 46 tert-Butyl 4-[2-[[(2S)-1-allylpyrrolidin-2-yl]methoxy]-7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate [ka]

[0178] A 5 mL microwave tube was charged with pre-dried powdered 4 Å molecular sieves (0.4 g) and Cs2CO3 (0.443 g, 1.36 mmol) and dried at 100° C. for 2 h. To the pre-dried tube was added a solution of tert-butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-methylsulfonyl-quinazolin-4-yl]piperazine-1-carboxylate (0.20 g, 0.27 mmol) and [(2S)-1-allylpyrrolidin-2-yl]methanol (0.154 g, 1.09 mmol) in DMSO (1.0 mL). The resulting mixture was stirred at 100° C. for 1 h. The mixture was diluted with EtOAc and filtered to remove solids. The organics were washed with H2O, saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 20% to 30% acetone in hexanes to give the product (0.18 g, 83%). MS (ES) m / z=796 (M+1).

[0179] Preparation 47 4-[2-[[(2S)-1-Allylpyrrolidin-2-yl]methoxy]-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0180] tert-Butyl 4-[2-[[(2S)-1-allylpyrrolidin-2-yl]methoxy]-7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazine-1-carboxylate was prepared in the same manner as described in Example 1 to obtain the product (0.078 g, 99%). MS (ES) m / z=596 (M+1).

[0181] Example 10 2-Amino-4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[[(2S)-1-propylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0182] A vial containing 4-[2-[[(2S)-1-allylpyrrolidin-2-yl]methoxy]-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile (38.4 mg, 0.0644 mmol) was placed in a glove box and a stir bar was added. (dippf)Rh(cod)BF4 (11 mg, 0.015 mmol) and MeOH (3 mL) were added. The vial was capped and removed from the glove box. The vial was placed in an autoclave. A needle was inserted into the cap and flushed with gas. The autoclave was sealed and purged with H2 three times. The reaction mixture was brought to a final pressure of 150 psi H2. After 18 h, the reaction was vented and the mixture was concentrated. The residue was dissolved in DCM and purified via silica gel chromatography eluting with a gradient of 100% EtOAc to 100% (5% Et3N / ACN) then 100% MeOH to give the product (0.015 g, 31%). MS (ES) m / z=598 (M+1).

[0183] Preparation 48 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid [ka]

[0184] 2-Amino-4-bromo-3-fluoro-benzoic acid (200 g, 854 mmol) and DMF (850 mL) were combined in a 2 L round bottom flask and NCS (136.3 g, 1.02 mol, 1.2 equiv) was charged in two approximately equal portions, 1 h apart, and stirred at room temperature for 18 h. The reaction mixture was poured into HO (4 L), stirred with a spatula, and the product was collected by filtration, rinsed with HO, and dried in a vacuum oven at 50-60 °C to give the product (216.3 g, 94%) as a beige solid. MS (ES) m / z=266 / 268 (M-1).

[0185] Preparation 49 7-Bromo-6-chloro-8-fluoro-1H-quinazoline-2,4-dione [ka]

[0186] In a 1 L round bottom flask equipped with a condenser, a mixture of 2-amino-4-bromo-5-chloro-3-fluoro-benzoic acid (50.0 g, 186.2 mmol) and urea (56.0 g, 932 mmol, 5 equiv.) was heated at 200° C. for 4 h. The reaction was allowed to cool to room temperature, at which point a brown solid formed in the flask. The material was scraped from the flask and larger pieces were ground with a mortar and pestle to give a brown solid. EtOAc and H2O were added and the mixture was stirred vigorously at 70° C. for 2 h. The mixture was filtered and rinsed with additional EtOAc to give a light brown solid. The wet solid was dried under house vacuum overnight to give the product (55.3 g, quantitative) as a light brown solid. MS (ES) m / z=291 / 293 (M-1).

[0187] preparation 50 7-Bromo-2,4,6-trichloro-8-fluoro-quinazoline [ka]

[0188] In a 500 mL round bottom flask equipped with a condenser, a mixture of 7-bromo-6-chloro-8-fluoro-1H-quinazoline-2,4-dione (23.9 g, 81.4 mmol), POCl3 (130 mL, 1381 mmol), and DIPEA (35 mL, 201 mmol, 2.5 equiv.) was heated at 105 °C for about 72 h. The mixture was concentrated in vacuo and azeotroped twice with toluene to give a dark brown oil. The oil was purified by silica gel chromatography eluting with 5% to 20% acetone in hexanes to give the product (14.6 g, 54%) as a light orange solid. MS (ES) m / z = 329 / 331 / 333 (M+1).

[0189] Preparation 51 tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)piperazine-1-carboxylate [ka]

[0190] tert-Butyl piperazine-1-carboxylate (7.0 g, 37 mmol, 1 equiv.) and DIEA (19 mL, 109 mmol, 3 equiv.) were added to a stirred mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (12.0 g, 36.3 mmol) in 1,4-dioxane (145 mL) and heated to 50° C. for 1 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with H2O and saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with a gradient from 100% hexanes to 30% EtOAc in hexanes to give the product (12.4 g, 71%) as an off-white solid. MS (ES) m / z=471 / 481 / 483 (M+1).

[0191] Preparation 52 tert-Butyl 4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate [ka]

[0192] tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)piperazine-1-carboxylate (3.0 g, 6.2 mmol) was combined with N-methyl-L-prolinol (2.9 g, 25 mmol, 4 eq.) and KF (2.2 g, 38 mmol, 6 eq.) in DMSO (20 mL, 280 mmol, 100% by weight) in a microwave and heated at 90° C. in a microwave for 2 h. The reaction solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with 100% DCM to 10% MeOH in DCM to give the product (1.4 g, 40%) as a tan foam. MS (ES) m / z=558 (M+1).

[0193] Preparation 53 tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate [ka]

[0194] To a vial containing tert-butyl 4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate (0.376 g, 0.672 mmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (0.353 g, 0.873 mmol, 2.5 equiv.), DPEPhosPdCl2 (0.096 g, 0.134 mmol, 0.2 equiv.), and Cs2CO3 (0.657 g, 2.02 mmol, 3 equiv.) was added toluene (8.4 mL). The flask was evacuated and backfilled with N2 (3 times) then placed in a heating block set at 125°C for 1.5 hours. The mixture was filtered through diatomaceous earth, rinsing with DCM and approximately 20 mL of 9:1 DCM / MeOH. The filtrate was concentrated and purified via silica gel chromatography, eluting with 100% DCM to 20% MeOH to give the product (0.224 g, 43%). MS (ES) m / z = 770 (M+1).

[0195] Preparation 54 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0196] To a solution of tert-butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate (0.098 g, 0.13 mmol) in DCM (2 mL) was added TFA (1 mL) and stirred at room temperature for 2 h. The reaction was concentrated and filtered through a 10 g SCX column, eluting with MeOH followed by 7N ammoniated MeOH. The filtrate was concentrated and the residue was purified via silica gel chromatography, eluting with 4% to 20% 7N NH3 in MeOH in DCM to give the product (0.045 g, 52%). MS (ES) m / z=570 (M+1).

[0197] Preparation 55 (Chiral Purification) tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate, isomer 2 [ka]

[0198] tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate (1.0 g, 175 mmol) was dissolved in MeOH (19 mL) and purified via SFC using a CHIRALPAK® AD-H (5×15 cm), 60 / 40 CO2 / IPA (with 0.5% DMEA) (flow rate=300 g / min, pressure=184 bar, 295 nm) to give the compound separated as isomer 1 (0.321 g, 56 mmol, ee>99%) and isomer 2 (0.505 g, 88 mmol, ee>99%).

[0199] Example 11 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile, isomer 2 [ka]

[0200] tert-Butyl 4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate (0.505 g, 0.66 mmol) was stirred in DCM (5 mL) and cooled to 0° C. TFA (2.5 mL) was added and the reaction was stirred for 2 h. The reaction solution was filtered through an SCX column (10 g), washed with 3 column volumes of MeOH, then eluted from the column with 3 column volumes of 2N NH3 in MeOH. The basic filtrate was concentrated to give the product (0.251 g, 67%) as a tan solid. MS (ES) m / z=570 (M+1).

[0201] Example 12 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0202] To a vial containing 2-amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (0.100 g, 0.17 mmol), HATU (0.204 g, 0.53 mmol), and DMF (2 mL) was added TFA (0.04 mL, 0.6 mmol) and DIEA (0.12 mL, 0.6 mmol). The reaction was stirred at room temperature for about 18 hours. The reaction solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via reverse phase chromatography (HPH Phenomenex Kinetix EVO 2.6u, 2.1 x 50 mm, 1.1 mL / min, 1.8 min, gradient 5 to 100% B, run time 2 min, Solvent A: 10 mM ammonium bicarbonate, Solvent B: ACN) to give the product (0.038 g, 33%) as a white solid. MS (ES) m / z = 666 (M+1).

[0203] Preparation 56 7-Bromo-6-chloro-2-ethylsulfanyl-8-fluoro-quinazoline [ka]

[0204] A solution of 7-bromo-4,6-dichloro-2-ethylsulfanyl-8-fluoro-quinazoline (19 g, 53.37 mmol) in THF (266 mL) was sparged with N2 for 2 min. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.2 g, 2.6 mmol), N,N,N',N'-tetramethylethylenediamine (9.6 mL, 64 mmol), and NaBH3CN (4.02 g, 64.0 mmol) were added and stirred at room temperature for 35 min. Saturated aqueous NH4Cl (300 mL) was added and the mixture was extracted with EtOAc (3 x 200 mL). The organics were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated. The residue (35 g) was dissolved in DCM (60 mL) and filtered through a plug of silica (200 g) eluted with DCM to give the product (16.2 g, 92%) as a pale yellow solid. MS (ES+) m / z=321 (M+1).

[0205] Preparation 57 tert-Butyl N-[4-(6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0206] A 1 L flask was charged with toluene (300 mL) and sparged with N2 for 60 minutes at 50° C. Then 7-bromo-6-chloro-2-ethylsulfanyl-8-fluoro-quinazoline (7.00 g, 21.8 mmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate (11.4 g, 28.2 mmol), and Cs2CO3 (21.3 g, 65.4 mmol) were added, followed by DPEPhosPdCl2 (3.11 g, 4.35 mmol). The mixture was then heated at 120° C. for 1.5 hours. The mixture was filtered through diatomaceous earth and rinsed with 1:1 EtOAc / MTBE (500 mL). The filtrate was washed with NaHCO3, H2O, saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 0-80% EtOAc / Hexanes to give the product (7.00 g, 60%) as a pale yellow solid. MS (ES+) m / z=533 (M+1).

[0207] Preparation 58 tert-Butyl N-[4-(6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0208] tert-Butyl N-[4-(6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (6.95 g, 13 mmol) and DCM (200 mL) were combined in a round bottom flask under nitrogen. mCPBA (8.40 g, 34.1 mmol) was added in one portion and stirred at room temperature for 1 h. 10% aqueous Na2S2O3 was added and the organic phase was washed with NaHCO3 solution. The isolated organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel chromatography eluting with 0-80% EtOAc / Hexanes to give the product (5.50 g, 75%) as a white solid. MS (ES+) m / z=565 (M+1).

[0209] Preparation 59 tert-Butyl N-[4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0210] A solution of N-methyl-L-prolinol (0.05 g, 0.4 mmol) in THF (1.5 mL) was charged with lithium bis(trimethylsilyl)amide (1 M in THF (0.6 mL, 0.6 mmol)) in one portion and stirred at room temperature for 5 min. Solid tert-butyl N-[4-(6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.150 g, 0.265 mmol) was added in one portion and stirred at room temperature for 0.5 h. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organics were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with 0-10% MeOH in DCM to give the product (0.086 g, 55%) as a yellow solid. MS(ES+) m / z=586(M+1).

[0211] Example 13 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0212] A solution of 2-amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (0.100 g, 0.171 mmol) in DCM (0.5 mL) was charged with TFA (0.7 mL) and stirred at room temperature for about 18 hours. The mixture was concentrated, DCM was added, and concentrated once more. The residue was purified via silica gel chromatography eluting with 10% 7N NH3 in MeOH in DCM to give the product (0.022 g, 27%) as a yellow solid. MS (ES+) m / z=486 (M+1).

[0213] Examples 14 and 15 2-Amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0214] The atropisomers of 2-amino-4-[6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (0.057 g, 0.12 mmol) were separated via SFC (CHIRALPAK® AD-H, 4.6×150 mm, 40% MeOH (0.2% IPAm) / CO2, 5 mL / min, 225 nm) to give the products (isomer 1, 0.012 g, ee>99%; isomer 2, 0.010 g, ee>99%) as white solids. Isomer 1: MS (ES+) m / z=486 (M+1); Isomer 2: MS (ES+) m / z=485.8 (M+1).

[0215] The example compounds in Table 4 were prepared in a manner similar to that described in Preparation 59 and deprotected in a manner similar to that described in Example 13. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. [Table 4-1] [Table 4-2]

[0216] Example 19 was prepared from Preparation 6 alcohol. Example 30 was prepared from Preparation 7 alcohol.

[0217] preparation 60 7-Bromo-6-chloro-2-ethylsulfonyl-8-fluoro-quinazoline [ka]

[0218] mCPBA (6.55 g, 38.1 mmol) was added to a solution of 7-bromo-6-chloro-2-ethylsulfanyl-8-fluoro-quinazoline (4.10 g, 12.7 mmol) in DCM (65.0 mL) at 0° C. After 0.5 h the ice bath was removed and the reaction was stirred at room temperature for approximately 18 h. The reaction was diluted with DCM and saturated aqueous NaHCO3, partitioned and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with saturated aqueous Na2SO4, saturated aqueous NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified via silica gel chromatography eluting with 100% DCM followed by a gradient of 0-10% EtOAc in DCM to give the product (1.87 g, 42%) as a white solid. MS (ES+) m / z=353 (M+1).

[0219] Preparation 61 7-Bromo-6-chloro-8-fluoro-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]quinazoline [ka]

[0220] Prepared in the same manner as described in Preparation 59 from 7-bromo-6-chloro-2-ethylsulfonyl-8-fluoro-quinazoline to give the crude product (1.0 g, 46%) as a brown solid. MS (ES+) m / z=374 (M+1).

[0221] Example 31 2-Amino-4-[6-chloro-8-fluoro-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-methyl-benzothiophene-3-carbonitrile [ka]

[0222] To a microwave vial was added tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-methyl-benzothiophene-2-yl]carbamate (0.310 g, 0.774 mmol), (2R)-2-[(7-bromo-6-chloro-8-fluoro-quinazolin-2-yl)oxymethyl]pyrrolidin-1-amine (0.25 g, 0.67 mmol), Cs2CO3 (0.60 g, 1.8 mmol), and toluene (5.00 mL). The mixture was degassed for 3-4 min by passing a stream of N2 through the mixture. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (DPEPhosPdCl2) (0.135 g, 0.185 mmol) was then added. The vial was capped and heated to 120 °C for 3 h. The mixture was diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with H2O, saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue (0.130 g, 0.223 mmol) was dissolved in DCM (2.20 mL) and treated with TFA (0.160 mL). The reaction was stirred at room temperature for approximately 18 h. The mixture was concentrated, dissolved in a minimal amount of DMSO, and purified by reverse phase chromatography, eluting with a gradient of 20-80% 10 mM ammonium bicarbonate with 5% MeOH in ACN. The appropriate fractions were combined, concentrated to a low volume, and extracted with EtOAc. The organics were dried over anhydrous Na2SO4 and concentrated to give the product (0.010 g, 9%) as a brown solid. MS (ES+) m / z=482 (M+1).

[0223] Preparation 62 7-Bromo-6-chloro-4-ethylsulfanyl-8-fluoro-quinazoline [ka]

[0224] To a solution of 7-bromo-4,6-dichloro-8-fluoro-quinazoline (12.31 g, 41.60 mmol, see U.S. Pat. No. 9,840,516 (B2), column 355) in DCM (125 mL) was added ethanethiol (6.0 mL, 83.0 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 (twice), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with DCM and further recrystallized from hexane and Et2O to give the product (11.41 g, 85%) as an off-white solid. MS (ES+) m / z=323 (M+1).

[0225] Preparation 63 tert-Butyl N-[4-(6-chloro-4-ethylsulfanyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0226] To a flask containing tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (8.491 g, 18.90 mmol) was added 7-bromo-6-chloro-4-ethylsulfanyl-8-fluoro-quinazoline (5.694 g, 17.35 mmol) and toluene (70 mL). N2 was bubbled through the solution with stirring and Cs2CO3 (11.31 g, 34.71 mmol) was added followed by dichlorobis(diphenylphosphinophenyl)etherpalladium(II) (3.74 g, 5.22 mmol). The reaction was heated at 110° C. overnight. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 0-75% acetone / hexanes to give the product (5.12 g, 53%) as a pale yellow solid: MS (ES+) m / z=533 (M+1).

[0227] Preparation 64 tert-Butyl 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0228] To a solution of tert-butyl N-[4-(6-chloro-4-ethylsulfanyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (100 mg, 0.188 mmol) in DMF (1.88 mL) was added mCPBA (130 mg, 0.75 mmol) and stirred at room temperature for 1 h. DMSO (0.27 mL, 3.75 mmol) was added and stirred at room temperature for 5 min. A 0.3 M solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DMF (2 mL, 0.60 mmol) and a 3 M solution of TEA in DMF (0.31 mL, 0.93 mmol) were added and the reaction was stirred at room temperature for 1 h. A 10 g C18 SPE cartridge was equilibrated with 40 mL MeOH and 40 mL H2O. The reaction mixture was poured onto the cartridge. The cartridge was eluted with 80 mL of HO, 60 mL of a 3:1 mixture of HO / MeOH, and 60 mL of a 1:1 mixture of DCM / MeOH to give the product (168 mg, 38% purity, 50% yield). MS (ES+) m / z=683 (M+1).

[0229] Preparation 65 tert-Butyl N-[4-(6-chloro-8-fluoro-4-hydroxy-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0230] To a solution of tert-butyl N-[4-(6-chloro-4-ethylsulfanyl-8-fluoro-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (3.50 g, 6.57 mmol) in acetone (75 mL) was added a solution of OXONE® (10.1 g, 16.4 mmol) in H2O (60 mL) in one portion. THF (75 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was diluted with H2O and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the product (3.28 g, 100% yield) as a white solid. MS (ES+) m / z=489 (M+1).

[0231] Preparation 66 tert-Butyl 9-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate [ka]

[0232] To a solution of tert-butyl N-[4-(6-chloro-8-fluoro-4-hydroxy-quinazolin-7-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (180 mg, 0.37 mmol) in ACN (10 mL) was added phosphonitrilic chloride trimer (128 mg, 0.37 mmol) and DIEA (0.32 mL, 1.84 mmol). After stirring at room temperature for 2 h, a 0.04 M solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate in ACN (9 mL, 0.36 mmol, 0.04 M) and DIEA (0.26 mL, 1.47 mmol) was added. After stirring at room temperature for 6 h, the crude was dissolved in a mixture of DCM and EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product (291 mg, 40% purity by LC-MS, 45% yield). MS (ES+) m / z=699 (M+1).

[0233] The compound of Preparation 67 in Table 5 was prepared in a manner similar to that described in Preparation 66 from 7-bromo-6-chloro-8-fluoroquinazolin-4-ol (see U.S. Pat. No. 9,840,516 (B2), see column 354 for 7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one). [Table 5]

[0234] Preparation 68 tert-Butyl (1S,4S)-5-(7-bromo-6-chloro-8-fluoro-quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [ka]

[0235] A mixture of 7-bromo-4,6-dichloro-8-fluoro-quinazoline (250 mg, 0.844 mmol, see U.S. Pat. No. 9,840,516 (B2), column 355), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (184 mg, 0.928 mmol), DIEA (0.44 mL, 2.5 mmol) in ACN (5.6 mL) was heated to 60° C. for 1 h. The reaction mixture was partially concentrated to approximately half of the original volume and the solid was collected via vacuum filtration and washed with minimal Et2O. The resulting material was dried overnight in a vacuum oven to give the product (284 mg, 74% yield) as a beige solid. MS (ES+) m / z=459 (M+1).

[0236] The compound of Preparation 69 in Table 6 was prepared in a manner similar to that described in Preparation 68. [Table 6]

[0237] Preparation 70 O1-tert-butyl O3-methyl 3-(7-bromo-6-chloro-8-fluoro-quinazolin-4-yl)azetidine-1,3-dicarboxylate [ka]

[0238] To a cooled solution of 7-bromo-4,6-dichloro-8-fluoro-quinazoline (1.06 g, 3.58 mmol) and O1-tert-butyl O3-methylazetidine-1,3-dicarboxylate (980 mg, 4.55 mmol) in THF (15 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (4 mL, 4 mmol, 1 mol / L) dropwise in a dry ice / acetone bath at -78 °C. After 10 min, the reaction was quenched by the addition of saturated aqueous NH4Cl and then extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 0-60% EtOAc / hexanes to give the product (810 mg, 43% yield) as an off-white solid. MS (ES+) m / z=474 (M+1).

[0239] Preparation 71 tert-Butyl 3-(7-bromo-6-chloro-8-fluoro-quinazolin-4-yl)azetidine-1-carboxylate [ka]

[0240] A microwave vessel was charged with O1-tert-butyl O3-methyl 3-(7-bromo-6-chloro-8-fluoro-quinazolin-4-yl)azetidine-1,3-dicarboxylate (400 mg, 0.7584 mmol), LiCl (340 mg, 8.02 mmol), and DMSO (2 mL). The vessel was then placed in a microwave reactor at 150 °C for 5 min. H2O was added to the reaction mixture, and the mixture was then extracted twice with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 0-60% EtOAc / hexanes to give the product (294 mg, 83% yield) as a pale yellow solid. MS (ES+) m / z=416 (M+1).

[0241] The compounds of Preparations 72 and 73 in Table 7 were prepared in a similar manner to that described in Preparations 70 and 71. The molecules were purified using different methods that would be apparent to one skilled in the art. [Table 7]

[0242] Compounds of Preparations 74-80 in Table 8 were prepared in a similar manner to that described in Preparation 63. The molecules were purified using different methods that would be apparent to one skilled in the art. [Table 8-1] [Table 8-2]

[0243] The example compounds in Table 9 were prepared in a manner similar to that described in Example 13. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. [Table 9-1] [Table 9-2]

[0244] Preparation 81 6-Bromo-7-chloro-2,8-difluoro-quinoline [ka]

[0245] In a glove box under N2 atmosphere in an oven-dried flask, a slurry of 6-bromo-7-chloro-8-fluoro-quinoline (4.31 g, 16.5 mmol) in anhydrous ACN (160 mL) was treated with AgF2 (7.54 g, 51.7 mmol). The resulting mixture was stirred overnight at ambient temperature in the glove box. The mixture was filtered through a pad of diatomaceous earth and the solid was rinsed with DCM. The filtrate was concentrated in vacuo to give an orange solid, which was stirred in 100 mL of DCM for several minutes and then filtered to remove the remaining solid. The filtrate was directly purified on silica (eluted with DCM) to give the product (2.64 g, 57%) as a white solid. GC / MS (m / z): 277.0 (M+).

[0246] Preparation 82 6-Bromo-7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline [ka]

[0247] Under an atmosphere of N2, a mixture of N-methyl-L-prolinol (2.4 mL, 20 mmol) and THF (120 mL) was treated dropwise via syringe with a solution of lithium bis(trimethylsilyl)amide (1.3 mol / L) in THF (16 mL, 21 mmol). The resulting mixture was stirred for 20 min. Solid 6-bromo-7-chloro-2,8-difluoro-quinoline (6.30 g, 17.0 mmol, 75% purity) was added in one portion and the mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with H2O and diluted with EtOAc. The layers were separated and the organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on silica (eluted with a gradient of 0-10% MeOH in EtOAc) to give the product (5.61 g, 88.5%). ES / MS (m / z): 373.0 (M+H).

[0248] Preparation 83 7-Chloro-8-fluoro-6-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline [ka]

[0249] A mixture of 6-bromo-7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline (0.45 g, 1.2 mmol), K2CO3 (0.47 g, 3.4 mmol), 1,4-dioxane (8 mL), and trimethylboroxine (0.20 mL, 1.4 mmol) in a microwave reactor was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (0.072 g, 0.060 mmol) was added. The resulting mixture was heated at 120 °C in a BIOTAGE INITIATOR® microwave reactor for 0.5 h, then it was filtered through a pad of diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified on silica (eluting with a gradient of 2.5% MeOH / DCM to 5% MeOH / DCM to 10% MeOH / DCM) to give the product (0.239 g, 64%). ES / MS (m / z): 309.2 (M+H).

[0250] Preparation 84 7-Chloro-6-cyclopropyl-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline [ka]

[0251] A mixture of 6-bromo-7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline (0.200 g, 0.535 mmol), cyclopropylboronic acid (0.092 mg, 1.07 mmol), tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.054 mmol), K3PO4 (0.239 g, 1.07 mmol), and 1,4-dioxane (5.35 mL) was heated at 90° C. overnight. The reaction mixture was cooled and filtered through a paper filter. The filtrate was concentrated in vacuum. A second batch was carried out in the same manner as described, starting from 50 mg of 6-bromo-7-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline. The residues from each reaction were dissolved in MeOH, combined and purified by SCX, rinsing first with MeOH, followed by elution with ammoniated methanol to give the product (196 mg, 87%). ES / MS (m / z): 335.0 (M+H).

[0252] Example 41 2-Amino-7-fluoro-4-[8-fluoro-6-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-quinolyl]benzothiophene-3-carbonitrile [ka]

[0253] KOtBu (0.067 g, 0.60 mmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate (0.213 g, 0.527 mmol), 7-chloro-8-fluoro-6-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline (0.116 g, 0.376 mmol) in THF (5 mL) was degassed with N2. SPhos Pd(crotyl)Cl (Pd-172; CAS number 1798781-99-3) (0.057 g, 0.09383 mmol) was added and the resulting mixture was heated at 70 °C overnight. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and H2O. The layers were separated. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica and eluted with a gradient of 2.5% to 5% MeOH in DCM. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h and then warmed at 40° C. for 1.5 h before being concentrated in vacuo. The residue was dissolved in MeOH and loaded onto a 10 g SCX cartridge, which was pre-washed with MeOH. The column was eluted with methanol followed by 2M ammonia in methanol. The ammoniated eluent was concentrated in vacuo. The residue was purified on silica (eluted with 2.5% MeOH:DCM to 5% MeOH:DCM to 10% MeOH:DCM to 10% 2M ammonia in MeOH:DCM) to give the product (27 mg, 15%) as a white solid. ES / MS(m / z):465.2(M+H).

[0254] Example 42 2-Amino-4-[6-cyclopropyl-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-quinolyl]-7-fluoro-benzothiophene-3-carbonitrile [ka]

[0255] Prepared from 7-chloro-6-cyclopropyl-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinoline in a manner similar to that of Example 41 using XPhos Pd(crotyl)Cl (Pd-170; CAS number 1798782-02-1) as catalyst to give the product (0.062 g, 22%). ES / MS (m / z): 491.2 (M+H).

[0256] Preparation 85 Methyl 2-amino-3-chloro-5,6-difluoro-benzoate [ka]

[0257] A solution of methyl 6-amino-2,3-difluoro-benzoate (63.3 g, 338 mmol) in acetonitrile (1.2 L) was treated with NCS (50 g, 374 mmol). The resulting mixture was heated at 45 °C overnight. The reaction was concentrated to half the volume and saturated aqueous NaHCO3 was added. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluted with a gradient of 10-25% EtOAc in hexanes) to give the product (49.5 g, 66%). 1 H NMR (399.80MHz, CDCl3): δ7.32 (dd, J=7.6, 9.4Hz, 1H), 6.00 (br s, 2H), 3.97 (s, 3H).

[0258] Preparation 86 Methyl 2-bromo-3-chloro-5,6-difluoro-benzoate [ka]

[0259] A mixture of CuBr2 (105 g, 470 mmol) and tert-butyl nitrite (78 mL, 590 mmol) in ACN (400 mL) was cooled in an ice-water bath and treated dropwise over 15 min with a solution of methyl 2-amino-3-chloro-5,6-difluoro-benzoate (91.2 g, 412 mmol) in ACN (400 mL). The resulting mixture was allowed to warm slowly to ambient temperature and stirred overnight. The reaction was concentrated to half the volume, diluted with DCM (2 L) and allowed to stand for 5 h. The mixture was filtered through a pad of diatomaceous earth and rinsed with DCM (1 L) followed by a mixture of 10% EtOAc / DCM until the filtrate was nearly colorless. The combined filtrate was washed twice with 10% citric acid (500 mL), twice with H2O (500 mL), and once with saturated aqueous EDTA (500 mL) before being concentrated in vacuo. The resulting solid was purified by flash silica gel chromatography (eluting with a gradient of 10-40% EtOAc in hexanes) to give the product (122 g, quantitative). 1 H NMR (399.80MHz, CDCl3): δ7.44 (dd, J=7.4, 9.4Hz, 1H), 4.02 (s, 3H).

[0260] Preparation 87 Methyl 5-chloro-2,3-difluoro-6-(methoxymethyl)benzoate [ka]

[0261] A mixture of methyl 2-bromo-3-chloro-5,6-difluoro-benzoate (25.0 g, 85.8 mmol) and potassium (methoxymethyl)trifluoroborate (19.5 g, 128 mmol) in dioxane (450 mL) was treated with a mixture of Cs2CO3 (84 g, 258 mmol) in HO (45 mL) and successively evacuated and backfilled with N2 five times. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dppf)Cl2 (6.27 g, 8.57 mmol) was added and the resulting mixture was degassed in vacuum and purged with N2 five more times before being heated at 100 °C overnight. Additional potassium (methoxymethyl)trifluoroborate (5.0 g, 32.9 mmol), Cs2CO3 (21 g, 64.5 mmol) in HO (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dppf)Cl2 (1.6 g, 2.2 mmol) were added and heating resumed for 12 h. The mixture was cooled to ambient temperature and diluted with EtOAc (1.5 L), HO (1 L), and saturated aqueous NaCl (1 L). The phases were separated and the aqueous layer was extracted with EtOAc (1 L). The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of 0-15% EtOAc in hexanes) to give the product (15 g, 70%) as a slightly colored oil. ES / MS (m / z): 251.2 (M+H).

[0262] Preparation 88 5-Chloro-2,3-difluoro-6-(methoxymethyl)benzoic acid [ka]

[0263] A solution of methyl 5-chloro-2,3-difluoro-6-(methoxymethyl)benzoate (10 g, 39.9 mmol) in THF (100 mL) and MeOH (65 mL) was treated with 5 M aqueous NaOH (24 mL, 120 mmol). The resulting mixture was stirred at ambient temperature overnight. Ice chips were added and the cold slush was treated dropwise with 5 N aqueous HCl to adjust the pH to about 1-2. The mixture was extracted with EtOAc (3×500 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The solid was dried in a vacuum oven at 55° C. for 2 h to give the product (9.49 g, 95.5%). ES / MS (m / z): 237.0 (M+H).

[0264] Preparation 89 5-Chloro-N-(ethylsulfanylcarbonimidoyl)-2,3-difluoro-6-(methoxymethyl)benzamide [ka]

[0265] A suspension of 5-chloro-2,3-difluoro-6-(methoxymethyl)benzoic acid (9.49 g, 40.1 mmol) and DIEA (28 mL, 161 mmol) in THF (350 mL) was cooled in an ice-water bath. S-Ethylisothiourea hydrobromide (12.0 g, 63.5 mmol) was added, followed by HATU (24.0 g, 61.9 mmol). The resulting mixture was allowed to warm slowly to ambient temperature as the ice bath melted. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The oily residue was purified by silica gel column chromatography (eluted with DCM) to give the product (12.9 g, 99%) as a clear, colorless oil. ES / MS (m / z): 323.2 (M+H).

[0266] Preparation 90 6-Chloro-2-ethylsulfanyl-8-fluoro-5-(methoxymethyl)quinazolin-4-ol [ka]

[0267] A solution of 5-chloro-N-(ethylsulfanylcarbonimidoyl)-2,3-difluoro-6-(methoxymethyl)benzamide (3.2 g, 9.4 mmol, 95% purity) in NMP (25 mL) was heated at 100° C. overnight. The reaction mixture was poured into chilled deionized water (600 mL). More water was added and the solid was collected by filtration. The solid was rinsed with additional HO (500 mL) and dried in a vacuum oven at 55° C. to give the product (2.84 g, 99%) as a light tan solid. ES / MS (m / z): 303.2 (M+H).

[0268] Preparation 91 6-Chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazolin-4-ol [ka]

[0269] 6-Chloro-2-ethylsulfanyl-8-fluoro-5-(methoxymethyl)-3H-quinazolin-4-one (3.50 g, 11.4 mmol) was placed in a dry 250 mL 3-neck round bottom flask equipped with a thermocouple and an addition funnel. The flask was sealed and flushed with N2. Anhydrous THF (60 mL) was added via cannula and the mixture was heated to 60° C. 2,2,6,6-Tetramethylpiperidinyl zinc chloride lithium chloride complex (1 M in THF, 35 mL, 35 mmol) was added dropwise to the reaction mixture over 5 min. After 2 h, the reaction mixture was treated dropwise with additional 2,2,6,6-tetramethylpiperidinyl zinc chloride-lithium chloride complex (1 M in THF, 11 mL, 11 mmol) and heating at 60° C. was continued overnight. Solid I2 (5.8 g, 23 mmol) was added in several small portions at such a rate as to keep the internal temperature below 70 °C. The reaction was heated for an additional 5 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (100 mL) and 1N aqueous HCl (100 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. DCM (100 mL) was added and the mixture was stirred for 10 min. The solid was collected by filtration and rinsed with additional DCM (20 mL) to give the product (2.96 g, 55.5%, 92% pure). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 25% EtOAc in hexanes) to give an additional batch of the product (0.910 g, 17%, 85% pure) as a white solid. ES / MS (m / z): 429.4 (M+H).

[0270] Preparation 92 4,6-Dichloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazoline [ka]

[0271] To a suspension of 6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazolin-4-ol (5.08 g, 11.9 mmol) in DCM (100 mL) was charged (chloromethylene)dimethyliminium chloride (3.03 g, 23.7 mmol) in one portion. The resulting mixture was stirred at ambient temperature for 2 h. Additional (chloromethylene)dimethyliminium chloride (0.30 g, 2.3 mmol) was added and stirred overnight. The reaction mixture was diluted with DCM and washed three times with H2O. The organic layer was dried over Na2SO4 and MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was dissolved in DCM and treated with activated charcoal (DARCO® 20-40 mesh). The mixture was stirred vigorously for 5 min. The clear solution was filtered through a plug of silica, eluting with DCM. The filtrate was concentrated in vacuo and further dried in a vacuum oven at 45° C. to give the product (4.4 g, 76%) as a slightly yellow solid. ES / MS (m / z): 447.2 (M+H).

[0272] Preparation 93 6-Chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazoline [ka]

[0273] A mixture of 4,6-dichloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazoline (1.5 g, 3.4 mmol) and p-toluenesulfonyl hydrazide (1.9 g, 10 mmol) in CHCl3 (70 mL, 874 mmol) was heated at 55° C. overnight in a sealed reaction vessel with a Teflon screw cap. The white suspension was evaporated to dryness using a stream of N2 to give 1.85 g of N'-[6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazolin-4-yl]-4-methyl-benzenesulfonohydrazide. To this solid was added a solution of Na2CO3 (3.28 g, 31.0 mmol) in H2O (83 mL). The mixture was heated at 120° C. in a sealed reaction vessel for 6.5 h. The reaction was filtered and the solid was rinsed with deionized water until the pH of the filtrate was approximately 7-8. The resulting tan solid was purified by silica gel chromatography (eluting with a gradient of 0-5% MeOH in DCM) to give the product (1.0 g, 72% overall yield) as a pale yellow solid. ES / MS (m / z): 412.6 (M+H).

[0274] Preparation 94 tert-Butyl N-[4-[6-chloro-2-ethylsulfanyl-8-fluoro-5-(methoxymethyl)quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0275] Prepared in a manner similar to the method of Preparation 36 from 6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazoline to give the product (1.03 g, 71.7%) as a tan solid. ES / MS (m / z): 491.2 (M+H).

[0276] Preparation 95 tert-Butyl N-[4-[6-chloro-2-ethylsulfonyl-8-fluoro-5-(methoxymethyl)quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0277] A mixture of tert-butyl N-[4-[6-chloro-2-ethylsulfanyl-8-fluoro-5-(methoxymethyl)quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.500 g, 0.87 mmol)) in DCM (20 mL) was treated with mCPBA (0.530 g, 2.36 mmol, 77%). The resulting mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was diluted with DCM and washed with 1 M saturated aqueous Na2S2O3 and saturated aqueous NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of 10-70% EtOAc in hexanes) to give the product (0.502 g, 95%) as a tan solid. ES / MS (m / z): 609.2 (M+H).

[0278] Preparation 96 tert-Butyl N-[4-[6-chloro-8-fluoro-5-(methoxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0279] A solution of lithium bis(trimethylsilyl)amide in THF (1.5 M, 1.2 mL, 1.8 mmol) was added to a solution of N-methyl-L-prolinol (0.22 mL, 1.8 mmol) in THF (8 mL). The resulting mixture was stirred for 5 min and treated with a solution of tert-butyl N-[4-[6-chloro-2-ethylsulfonyl-8-fluoro-5-(methoxymethyl)quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.502 g, 0.82 mmol) in THF (5 mL). Stirring was continued for 15 min at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluting with a gradient of 0-10% MeOH in DCM) to give the product (0.53 g, quantitative) as a yellow solid. ES / MS (m / z): 630.4 (M+H).

[0280] Example 43 2-Amino-4-[6-chloro-8-fluoro-5-(methoxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile, isomer 1 [ka]

[0281] A mixture of tert-butyl N-[4-[6-chloro-8-fluoro-5-(methoxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.200 g, 0.32 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) was heated in a sealed vessel at 120° C. for 1.5 h. The reaction mixture was cooled and concentrated under high vacuum. EtOAc was added and the mixture was concentrated (this process was repeated). The residue was purified by silica gel chromatography (eluting with a gradient of 0-10% MeOH in DCM) to give a mixture of atropisomers (105 mg). The mixture of atropisomers was separated by SFC using a CHIRALPAK® AS-H (21×250 cm), 80 / 20 CO2 / MeOH (with 0.2% isopropylamine) (flow rate=80 mL / min, UV detection wavelength=225 nM, column temperature 40° C.) to give the title compound as isomer 1 (0.032 g, 31%, ee>99%) as a solid. ES / MS (m / z): 530.4 (M+H).

[0282] Preparation 97 (6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazolin-5-yl)methanol [ka]

[0283] In a sealed reaction vessel, a solution of 6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-5-(methoxymethyl)quinazoline (0.293 g, 0.71 mmol) in DCM (20 mL) was cooled in an ice-water bath. A 1 M solution of BBr3 in DCM (1.4 mL, 1.4 mmol) was added. After stirring with cooling for 1.5 h, the reaction mixture was diluted with DCM and carefully quenched with saturated aqueous NaHCO3 until the aqueous layer was basic by pH. A yellow precipitate formed and the mixture was stirred vigorously for 5 min. DCM (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc and DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 337 mg of a ca. 9:1 mixture of 5-(bromomethyl)-6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazoline and (6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazolin-5-yl)methanol. The 9:1 mixture was suspended in 1,4-dioxane (30 mL) and H2O (30 mL). Cs2CO3 (2.0 g, 6.1 mmol) was added and the resulting mixture was heated at 50° C. overnight. The reaction was cooled to room temperature and diluted with EtOAc and saturated aqueous NaCl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined and dried over Na2SO4. The solution was treated with activated carbon, filtered, and concentrated in vacuo to give the product (0.253 g, 86% pure) as a tan solid. ES / MS(m / z):399.2(M+H).

[0284] Preparation 98 tert-Butyl-[(6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazolin-5-yl)methoxy]-dimethyl-silane [ka]

[0285] A suspension of (6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazolin-5-yl)methanol (0.373 g, 0.805 mmol, 86% purity) in DCM (20 mL) was cooled in an ice-water bath and treated with 2,6-lutidine (0.175 mL, 1.50 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonic acid (0.250 mL, 1.09 mmol). The cooling bath was removed and the mixture was allowed to stir at ambient temperature. After 1 h, additional 2,6-lutidine (0.175 mL, 1.50 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonic acid (0.250 mL, 1.09 mmol) were added and the resulting mixture was stirred for 20 min. The reaction mixture was cooled in an ice-water bath, quenched with saturated aqueous NH4Cl, and diluted with DCM and saturated aqueous NaCl. The phases were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with a gradient from 100% hexanes to 10% EtOAc in hexanes) to give the product (0.305 g, 70%) as a white solid. ES / MS (m / z): 513.4 (M+H).

[0286] Preparation 99 tert-Butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0287] Prepared in a manner similar to that of Preparation 36 from tert-butyl-[(6-chloro-2-ethylsulfanyl-8-fluoro-7-iodo-quinazolin-5-yl)methoxy]-dimethyl-silane to give the product (0.27 g, 64%). ES / MS (m / z): 677.3 (M+H).

[0288] preparation 100 tert-Butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0289] Prepared in a manner similar to that for the preparation of 95 from tert-butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-2-ethylsulfanyl-8-fluoro-quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate to give the product (0.28 g, quantitative) as a white solid. ES / MS (m / z): 709.0 (M+H).

[0290] Preparation 101 tert-Butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate [ka]

[0291] Prepared in a manner similar to that for the preparation of 96 from tert-butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-2-ethylsulfonyl-8-fluoro-quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate to give the product (0.26 g, 89%) as a yellow oil. ES / MS (m / z): 730.0 (M+H).

[0292] Example 44 2-Amino-4-[6-chloro-8-fluoro-5-(hydroxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile, isomer 1. [ka]

[0293] A mixture of tert-butyl N-[4-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.250 g, 0.342 mmol) in TFA (5 mL) was treated with H2O (0.5 mL). The resulting mixture was stirred at ambient temperature for 20 min. The solvent was removed in vacuo. The residue was treated with DCM, concentrated, and repeated. The residue was dissolved in DCM and saturated aqueous Na2CO3 to pH ∼8. The layers were separated and the aqueous layer was extracted three more times with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting white solid was purified by silica gel chromatography, eluting with a gradient of 2% to 10% (7N ammoniated MeOH) in DCM to give a mixture of atropisomers (0.134 g, 76%). The mixture of atropisomers (0.129 g) was separated by SFC (CHIRALPAK® IC, 21×250 mm; eluting with a mobile phase of 40% MeOH (with 0.5% DMEA) in 60% CO2; column temperature 40° C.; flow rate: 80 mL / min; UV detection wavelength: 225 nm) to give the title compound (0.046 g, >97% ee) as the first eluting enantiomer (isomer 1). ES / MS (m / z): 516.0 (M+H).

[0294] Biological assays The following assays demonstrate that the exemplified compounds are inhibitors of KRas G12D and inhibit the growth of certain tumors in vitro and / or in vivo.

[0295] PANC-1 Cell Active RAS GTPase ELISA (KRas G12D Mutation) The purpose of this assay is to measure the ability of test compounds to inhibit the activity of constitutive RAS GTPase in human PANC-1 (RRID: CVCL_0480) pancreatic ductal adenocarcinoma cells (supplier: ATCC number CRL-1469). The RAS GTPase ELISA kit (Active Motif catalog number 52097) contains a 96-well glutathione-coated capture plate and Glutathione-S-Transferase (GST) fused to the Raf-Ras Binding Domain (RBD) protein provided in the kit. Activated pan-RAS (GTP-bound) in cell extracts binds specifically to Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a developing substrate solution facilitates the chemiluminescent readout.

[0296] PANC-1 cells are plated at a concentration of 75,000 cells / well in 80 μL complete medium (DMEM, high glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37°C / 5% CO2. Approximately 24 hours later, 20 μL (1:3) of serially diluted (in complete medium) test compounds (highest concentration 1-50 μM) and 20 μL of serially diluted (in complete medium) controls (maximum signal wells: 0.5% DMSO and minimum signal wells: 10 μM reference positive control compound) are added to the cell plate and incubated for 2 hours at 37°C / 5% CO2. Complete lysis / binding buffer containing Protease Inhibitor cocktail (PIC) is prepared and stored on ice. One hour before the incubation of the cell plate is completed, GST-Raf-RBD is diluted in lysis / binding buffer and 50 μL of mixed buffer per well is added to the supplied milky white ELISA assay plate and incubated at 4 °C for a minimum of 1 hour with gentle rocking. After 2 hours, cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of lysis / binding buffer (AM11) supplied in the kit. After shaking the plate vigorously for 30-50 minutes at ambient temperature, the cell plate is centrifuged at 410 × g (approximately 1500 rpm) for 10 minutes. A wash buffer, diluted 1x with ultrapure HO and filtered through 0.2 μm, is prepared at ambient temperature during the centrifugation step and then used to wash the GST-Raf-RBD-coated assay plate (3 × 100 μL). Next, 50 μL of cell lysate is added to the GST-Raf-RBD-coated assay plate and incubated for 1 h at ambient temperature with gentle shaking. During this incubation period, 1x antibody binding buffer is prepared from thawed concentrate. The assay plate is washed with 1x wash buffer (3 x 100 μL) and then 50 μL of primary RAS antibody (supplied in the kit, no. 101678) diluted 1:500 in 1x antibody binding buffer is added. After 1 h of incubation at ambient temperature with gentle shaking, the assay plate is washed with 1x wash buffer (3 x 100 μL).Then, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL) (diluted 1:5000 in 1× antibody binding buffer) is added to each well of the assay plate and incubated for another hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4×100 μL), followed by the addition of 50 μL of mixed chemiluminescence working solution (a combination of reaction buffer and chemiluminescence substrate) at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0297] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. Maximum signal is the control wells with no inhibitor (DMSO). Minimum signal is the control wells containing enough reference inhibitor to completely inhibit activity. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter nonlinear logistic equation using Genedata Screener® version 17: y=(A+((BA) / (1+((x / C)^D)))), where y is the % inhibition, A is the minimum asymptote, B is the maximum asymptote, and C is the relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, where D is the Hill slope).

[0298] Compounds of formula I, II, III, or IV described herein and shown in Table 1 were evaluated in this assay substantially as described. The compounds exhibited the ability to inhibit constitutive RAS GTPase activity indicative of inhibition of the KRas G12D mutant enzyme. Approximately three-quarters of the example compounds in Table 1 herein had a relative IC of less than 500 nM in this assay. 50 Of these, the preferred Example compounds in Table 2 exhibited a relative IC of less than 100 nM in this assay.50 This data shows that compounds of formula I, II, III, or IV described herein can inhibit KRAS-GTP activity in this human pancreatic cancer cell culture, demonstrating the ability to inhibit the KRas G12D mutant.

[0299] MKN-45 cell activity RAS GTPase ELISA (KRas wild type) The purpose of this assay is to measure the ability of test compounds to inhibit constitutive RAS GTPase activity in human MKN-45 gastric adenocarcinoma cells (Supplier: JCRB, Supplier ID: JCRB 0254, Lot: 05222009). The RAS GTPase ELISA kit (Active Motif Cat. No. 52097) contains a 96-well glutathione-coated capture plate and glutathione-S-transferase (GST) fused to the Raf-Ras binding domain (RBD) protein provided in the kit. Activated pan-RAS (GTP bound) in cell extracts binds specifically to Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a developing substrate solution facilitates chemiluminescent readout.

[0300] MKN-45 cells are plated at a concentration of 75,000 cells / well in 80 μL complete medium (DMEM, high glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C / 5% CO2. Approximately 24 h later, 20 μL (1:3) of serially diluted (in complete medium) test compounds (highest concentration 1-10 μM) and 20 μL of serially diluted (in complete medium) controls (maximum signal wells: 0.1% DMSO and minimum signal wells: 10 μM reference positive control compound) are added to the cell plate and incubated for 2 h at 37 °C / 5% CO2. Complete lysis / binding buffer containing protease inhibitor cocktail (PIC) is prepared and stored on ice. One hour before the incubation of the cell plate is completed, GST-Raf-RBD is diluted in lysis / binding buffer and 50 μL of mixed buffer per well is added to the supplied milky white ELISA assay plate and incubated for a minimum of 1 hour at 4 °C with gentle rocking. After 2 hours, cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of lysis / binding buffer (AM11) supplied in the kit. After shaking the plate vigorously for 30-50 minutes at ambient temperature, the cell plate is centrifuged for 10 minutes at 410 × g (approximately 1500 rpm). During the centrifugation step, the wash buffer is diluted 1x with ultrapure H2O and then used to wash the GST-Raf-RBD-coated assay plate (3 × 100 μL). Next, 50 μL of cell lysate is added to the GST-Raf-RBD-coated assay plate and incubated for 1 hour at ambient temperature with gentle rocking. During this incubation period, 1x antibody binding buffer is prepared from thawed concentrate. The assay plate is washed with 1x wash buffer (3x100 μL) and then 50 μL of primary RAS antibody (supplied in the kit, no. 101678) diluted 1:500 in 1x antibody binding buffer is added. After 1 h of incubation at ambient temperature with gentle shaking, the assay plate is washed with 1x wash buffer (3x100 μL).Then, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL) (diluted 1:5000 in 1× antibody binding buffer) is added to each well of the assay plate and incubated for another hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4×100 μL), followed by the addition of 50 μL of mixed chemiluminescence working solution (a combination of reaction buffer and chemiluminescence substrate) at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0301] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. Maximum signal is the control wells with no inhibitor (DMSO). Minimum signal is the control wells containing enough reference inhibitor to completely inhibit activity. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter nonlinear logistic equation using Genedata Screener® version 17: y=(A+((BA) / (1+((x / C)^D)))), where y is the % inhibition, A is the minimum asymptote, B is the maximum asymptote, and C is the relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, where D is the Hill slope).

[0302] A subset of compounds of formula I, II, III, or IV described herein (Examples 3, 4, 7, 8, 15, 17, 21, 26, and 33) were evaluated in this assay substantially as described. All compounds tested in this assay were also tested and showed inhibitory activity in the KRas G12D mutant assay described above. Most of the compounds tested in this assay exhibited some ability to inhibit constitutive RAS GTPase activity (i.e., KRas wild-type inhibition). Compounds of Examples 3, 4, 7, and 33 showed significant (i.e., greater than 7-fold) selective inhibition preference for KRas G12D mutant over KRas wild-type, demonstrating the potential of compounds of formula I, II, III, or IV described herein as potent and selective inhibitors of KRas G12D mutant.

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, X is -O- or -S-; Y is -C(CN)- or -N-; Z is -C(H)- or -N-; R １ is H, azetidine, pyrrolidine, piperidine, or N-linked piperazine, and the azetidine, pyrrolidine, piperidine, or N-linked piperazine is C １－４ Alkyl or C ２－４ Optionally substituted with heteroalkyl, １－４ Alkyl, C ２－４ Heteroalkyl is optionally substituted by halogen or oxo, and said azetidine, pyrrolidine, piperidine, or N-linked piperazine is １－４ Alkyl or C ２－４ The azetidine, pyrrolidine, piperidine, or N-linked piperazine is optionally bridged by a heteroalkyl, １－４ Alkyl or C ２－４ optionally fused with a heteroalkyl to form a bicyclic ring; R ２ is H, —O—CH ２ -R ７ or -O-CH(CH ３ )-R ７ and R ７ is azetidine, pyrrolidine, or tetrahydrofuran, wherein the azetidine, pyrrolidine, or tetrahydrofuran is one or more of halogen, hydroxyl, C １－４ Alkyl, or C １－４ alkenyl, １－４ The alkyl is optionally substituted with one or more halogens or hydroxyls, and the azetidine, pyrrolidine, or tetrahydrofuran is １－４ optionally fused with an alkyl to form a bicyclic ring; R ２ is H, then R １ is not H, R ３ and R ５ are each independently H, a halogen, or —C ０－３ Alkyl-cyclopropyl, R ８ -C optionally substituted 1 to 3 times with １－６ Alkyl, or R ８ -OC optionally substituted 1 to 3 times １－６ is alkyl, R ４ａ , R ４ｂ , and R ４ｃ are each independently H, halogen, or R ８ -C optionally substituted 1 to 3 times with １－６ is alkyl, R ６ is H, -CH ２ OH, -CH ２ -O-CH ３ and R ８ are each independently halogen, oxo, hydroxy, -C １－４ Alkyl, or -O-C １－４ a compound, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein X is -S-.

3. 3. The compound according to claim 1 or 2, wherein Y is -C(CN)-, or a pharma- ceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein Z is -N-.

5. R １ The compound according to any one of claims 1 to 4, wherein is H, or a pharma- ceutically acceptable salt thereof.

6. R １ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is azetidine, pyrrolidine, piperidine, or N-linked piperazine.

7. R １ 7. The compound of claim 6, or a pharma- ceutically acceptable salt thereof, wherein: is an N-linked piperazine.

8. R １ but, 【Chemistry 2】 The compound according to claim 6, or a pharma- ceutically acceptable salt thereof.

9. R １ but, 【Chemistry 3】 The compound according to claim 6, or a pharma- ceutically acceptable salt thereof.

10. R ２ But -O-CH ２ -R ７ or -O-CH(CH ３ )-R ７ 10. The compound according to any one of claims 1 to 9, wherein:

11. R ２ But -O-CH ２ -R ７ 10. The compound according to any one of claims 1 to 9, wherein:

12. R ７ 12. The compound of claim 10 or 11, or a pharma- ceutically acceptable salt thereof, wherein is pyrrolidine.

13. R ２ but, 【Chemistry 4】 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

14. R ２ but, 【Chemistry 5】 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

15. R ３ and R ５ each independently represents a halogen, —C ０－３ Alkyl-cyclopropyl, R ８ -C optionally substituted 1 to 3 times with １－６ Alkyl, or R ８ -OC optionally substituted 1 to 3 times １－６ The compound according to any one of claims 1 to 14, which is alkyl.

16. R ３ The compound according to any one of claims 1 to 15, wherein is F. 、 or a pharma- ceutically acceptable salt thereof.

17. R ４ｃ is F or -CH ３ 17. The compound according to any one of claims 1 to 16, wherein:

18. R ５ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is Cl.

19. X is S, Y is -C(CN)-, and R ３ is F and R ４ａ is H, and R ４ｂ is H, and R ４ｃ is F and R ５ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

20. 【Chemical 6】 The compound according to claim 1, selected from or a pharma- ceutically acceptable salt thereof.

21. [Chemical 7] 21. The compound of claim 20,

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

23. 23. A method of treating a patient with cancer, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of claim 22, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

24. 22. A method of treating a patient with cancer, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

25. 26. The method of claim 24 or 25, wherein the cancer is non-small cell lung cancer and one or more cells express a KRas G12D mutant protein.

26. 26. The method of claim 24 or 25, wherein the cancer is colorectal cancer and one or more cells express a KRas G12D mutant protein.

27. 26. The method of claim 24 or 25, wherein the cancer is pancreatic cancer and one or more cells express a KRas G12D mutant protein.

28. 26. The method of claim 24 or 25, wherein the patient has a cancer that is determined to have one or more cells that express the KRas G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

29. 22. A method of treating a patient having a cancer with a KRas G12D mutation, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof.

30. 30. The method of any one of claims 24-29, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharma- ceutically acceptable salt thereof.

31. 22. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, for use in therapy.

32. 22. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

33. 33. The compound for use according to claim 32, or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

34. 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in simultaneous, separate or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CD4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharma- ceutically acceptable salt thereof.