WO2024041573A1

WO2024041573A1 - Fused multi-heterocyclic compounds as kras g12d modulators and uses thereof

Info

Publication number: WO2024041573A1
Application number: PCT/CN2023/114491
Authority: WO
Inventors: Yong He; Lanqi Jia; Wenting Wu; Shangfeng LI; Jun Lu; Yugui Gu; Xiaojie LU
Original assignee: Zai Lab Shanghai Co Ltd
Current assignee: Zai Lab Shanghai Co Ltd
Priority date: 2022-08-25
Filing date: 2023-08-23
Publication date: 2024-02-29
Anticipated expiration: 2025-02-25

Abstract

This application discloses compounds of formula (I), which can be inhibitors of KRAS G12D or other KRAS mutants, and their uses.

Description

FUSED MULTI-HETEROCYCLIC COMPOUNDS AS KRAS G12D MODULATORS AND USES THEREOF

FIELD

This application relates to KRAS G12D modulators, their preparation and uses thereof.

BACKGROUND

Rat sarcoma (RAS) , encoded by the proto-oncogenes HRAS, NRAS and KRAS, is a GTP-binding protein that is in an activated state when binding with GTP, and is in an inactive state when binding with GDP. RAS is distributed on the inner surface of the cell membrane and is activated when it binds to GTP and inactivated when it binds to GDP. The upstream of RAS is receptor tyrosine kinase (RTK) , which regulates downstream signaling pathways such as PI3K and RAF after activation, thereby regulating cell growth, survival, migration and differentiation functions. Since RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.

Among RAS family members, oncogenic mutations are most commonly found in KRAS (85%) , and aberrant expression of KRAS accounts for up to 20%of all cancers, with G12D mutations accounting for 25%of pancreatic cancer (PDAC) , colon cancer (CRC) 13.3%, rectal cancer (RC) 10.1%, non-small cell lung cancer (NSCLC) 4.1%.

Although there is a high clinical need, so far there is no drug that directly targets the KRAS G12D mutation on the market. There are two main difficulties in the development of KRAS G12D inhibitors. On the one hand, the RAS protein has a smooth structure and there is no obvious pocket on the surface for small molecules to bind to; on the other hand, the affinity of KRAS protein for GTP is as high as picomolar level and endogenous GTP levels are high. Thus, it is difficult for small-molecule drugs to block the binding of the two. At present, no targeted drug for KRAS G12D mutation has entered the clinical research stage, and there is a large unmet clinical need.

SUMMARY

Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

Q¹, Q², and Q³ are independently selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN;

R¹ is selected from L-5-12 membered heterocyclyl and L-C_3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyl and C_3-8 cycloalkyl is optionally substituted with one or more W;

L is selected from -CH₂-, -CH (CH₃) -, CH₂-CH₂-, and a bond;

R² and R⁴ are independently selected from H, C_1-6 alkyl optionally substituted with one or more W, C_3-6 cycloalkyl optionally substituted with one or more W, and 4-8 membered heterocyclyl optionally substituted with one or more W; or R² and R⁴, together with the atoms to which they are attached, form a 4-12 membered heterocyclyl or a 9-12 membered fused bi-cyclic heteroaryl, each of which is optionally substituted with one or more W;

R³ is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;

X is selected from O, S and NR⁵;

Y is selected from a bond and -O-;

Z is selected from (CR⁶R⁷) _n;

n is 1 or 2;

R⁵, R⁶, and R⁷ are independently selected from H and C_1-6 alkyl; and

W is independently selected from OH, CN, halo, C_2-4 alkenyl, C_2-4 alkynyl, -NR⁸R⁹, =NR⁸, oxo, -OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) OR¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, phenyl, C_3-8 cycloalkyl, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, S (O) ₂-C_3-8 cycloalkyl, C_1-6 alkylidene, and C_1-6 alkyl, wherein each of the 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, phenyl, C_3-8 cycloalkyl, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, S (O) ₂-C_3-8 cycloalkyl, C_1-6 alkylidene, and C_1-6 alkyl is optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, -OC (O) NR⁸R⁹, and oxo;

R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl; and

R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.

In some embodiments, Q¹ is N, one of Q² and Q³ is N, the other is not. In some embodiments, Q¹ is N, Q² is N, and Q³ is not N. In some embodiments, Q¹ is N, Q² is N, and Q³ is C-H or C-F. In some embodiments, Q¹ is N, Q² is selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is not N. In some embodiments, Q¹ is N, Q² is selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is C-H or C-F. In some embodiments, Q¹ is N, Q² is selected from CH, C- CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is C-H or C-F.

In some embodiments, R³ is phenyl or naphthyl optionally substituted with one or more W. In some embodiments, R³ is pyridinyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W. In some embodiments, R³ is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W. In some embodiments, R³ is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more groups selected from F, Cl, methyl, ethyl, ethenyl, ethynyl, CF₃, cyclopropyl, iso-propyl, -NH₂, -CN, and OH.

In some embodiments, R³ is selected from

In some embodiments, Y is O.

In some embodiments, X is O.

In some embodiments, Z is CH_2, CH (CH₃) , or CH₂CH₂.

In some embodiments, R¹ is selected from -L-fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen, and -L-4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen, each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen and 4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen is optionally substituted with one or more W.

In some embodiments, each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen and 4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen is optionally substituted with one or more group selected from F, C_1-6 alkoxy, OH, C_1-3 alkylidene optionally substituted with 1-5 F, and C_1- ₃ alkyl optionally substituted with -OC (O) NR⁸R⁹ or –NR⁸R⁹, with R⁸ and R⁹ independently being selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C_1-6 alkyl. In some embodiments, R⁸ and R⁹ are methyl or R⁸ and R⁹, together with the nitrogen to which they are attached, form a morpholine.

In some embodiments, R¹ is L-C_3-8 cycloalkyl optionally substituted with one or more W. In some embodiments, R¹ is L-C_3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -OC (O) NR⁸R⁹ or –NR⁸R⁹, with R⁸ and R⁹ independently being selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C_1-6 alkyl. In some embodiments, R¹ is L-C_3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -O (CO) N (CH₃) ₂, -O (CO) -morpholine, -N (CH₃) ₂, or morpholine.

In some embodiments, R¹ is

In some embodiments, L is a bond, CH₂ or CH (CH₃) .

In some embodiments, R² is selected from H, 4-8 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, C_3-6 cycloalkyl optionally substituted with one or more substituent selected from OH, -NR⁸R⁹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, and oxo, and C_1-6 alkyl optionally substituted with one or more substituent selected from OH, -NR⁸R⁹, -NR¹⁰C (O) R¹¹, -S (O) ₂-C_1-6 alkyl, and 4 or 5 membered heterocyclyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.

In some embodiments, R² is selected from H, methyl, ethyl, - (CH₂) ₂OH, - (CH₂) ₃OH, - (CH₂) ₂NH₂, - (CH₂) ₂NHC (O) CH₃,

In some embodiments, R⁴ is selected from H, C_1-6 alkyl optionally substituted with one or more group selected from OH and NH₂, and 4-6 membered heterocyclyl optionally substituted with one or more group selected from methyl and ethyl.

In some embodiments, R⁴ is selected from H, methyl, ethyl, -CH (CH₃) ₂, -CH (OH) CH₃, -C (OH) (CH₃) _2, -CH₂NH₂, -CHCH₃NH₂, -C (CH₃) ₂NH₂,

In some embodiments, R² is a C_1-6 alkyl optionally substituted with one or more W. In some embodiments, R² is a C_1-6 alkyl optionally substituted with one or more substituent selected from halo, CN, OH, oxo, =NR⁸, -NR⁸R⁹, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) OR¹¹, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, -S (O) ₂-C_3-8 cycloalkyl, C_3-8 cycloalkyl, 5 or 6 membered heteroaryl, and 4 or 5 membered heterocyclyl, wherein the C_1-6 alkox, C_3-8 cycloalkyl, S (O) ₂-C_3-8 cycloalkyl , 5 or 6 membered heteroaryl and 4 or 5 membered heterocyclyl are optionally and independently substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.

In some embodiments, R² is selected from methyl, ethyl, isopropyl, -C (O) CH₃, - (CH₂) ₂OH, - (CH₂) ₂OCH₃, -CH₂CN, -CH₂CH₂SO₂CH₃, -CH₂C (O) N (CH₃) ₂, -CH₂CH₂C (O) N (CH₃) _2, -CH₂CH₂OC (O) N (CH₃) _2, -CH₂CH₂N (CH₃) C (O) OCH_3, -CH₂CH₂NHC (O) OCH_3, -CH₂C (O) N (CH₃) (CH₂CH₃) , -CH₂CH₂N (CH₃) _2, -CH (CH₃) CH₂NHCH₃, -CH₂CH₂OC (O) CH₃, - (CH₂) ₃OH, - (CH₂) ₂NH_2, - (CH₂) ₂F, -CH₂CHF₂, -CH₂CF₃, , - (CH₂) ₂NHC (O) CH₃, -CH₂C (O) NH₂, - (CH₂) ₂C (O) NH₂, -C (NH) NH₂, -C (NH) CH₃, -CH (CH₃) CH₂NHCH₃, -CH (CH₂CH₃) CH₂NHCH₃, -CH (CH₂OH) CH₂NHCH₃, -CH (CH₂OH) CH₂OH,

In some embodiments, R² is a 4-8 membered heterocyclyl optionally substituted with one or more W. In some embodiments, R² is a 4-8 membered heterocyclyl optionally substituted with one or more substituent selected from oxo, methyl and ethyl, each of the methyl and ethyl is optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl.

In some embodiments, R² is selected from

In some embodiments, R² is a C_3-6 cycloalkyl optionally substituted with one or more W. In some embodiments, R² is a C_3-6 cycloalkyl optionally substituted with one or more substituent selected from F, Cl, OH, CN, -NR⁸R⁹, and C_1-6 alkyl optionally substituted with one or more group selected from F, CL, OH, C_1-6 alkoxy, -NR⁸R⁹, -OC (O) NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1- ₆ alkyl.

In some embodiments, R² is selected from cyclopropanyl, cyclobutanyl,

In some embodiments, R⁴ is a C_1-6 alkyl optionally substituted with one or more W. R⁴ is a C_1-6 alkyl optionally substituted with one or more group selected from halo, oxo, OH and -NR⁸R⁹, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl.

In some embodiments, R⁴ is selected from H, methyl, ethyl, -CH (CH₃) ₂, -CH₂OH, -CH₂CH₂OH, -CH (OH) CH₃, -C (OH) (CH₃) _2, -CH₂NH₂, -CHCH₃NH₂, -C (CH₃) ₂NH₂, -C (O) NH₂, and CF₃.

In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a 4-9 membered heterocyclyl which contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R⁴ is attached. In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a 4-7 membered monocyclic heterocyclyl optionally substituted with one or more W. In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a 8-12 membered fused, bridged, or spiro bicyclic heterocyclyl optionally substituted with one or more W. In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a heterocyclyl selected from each of which is optionally substituted with one or more group selected from OH, F, Cl, CN, NH₂, oxo, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.

In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a 4-10 membered heterocyclyl selected from

In some embodiments, R² and R⁴, together with the atoms to which they are attached, form a 9-12 membered fused bi-cyclic heteroaryl, which is optionally substituted with one or more W. In some embodiments, the 9-12 membered fused bi-cyclic heteroaryl has one ring as being aromatic and the other non-aromatic. In some embodiments, the 9-12 membered fused bi-cyclic heteroaryl has the ring containing N attached to R⁴ as being non-aromatic and the other aromatic. In some embodiments, R² and R⁴, together with the atoms to which they are attached, formwhich is optionally substituted with one or more group selected from OH, F, Cl, CN, NH₂, oxo, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.

In some embodiments, R² and R⁴, together with the atoms to which they are attached, form

In some embodiments, R² and R⁴, together with the atoms to which they are attached, form which is optionally substituted with two groups selected from C_1-6 alkyl optionally substituted with 1-5 F or Cl, OH, F, Cl, CN, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ are independently selected from H and C_1-6 alkyl.

In some embodiments, when (1) Q¹ is N, Q² and Q³ are independently selected from CH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, and C-CN, and (2) R² and R⁴, together with the atoms to which they are attached, form a 5-9 membered heterocyclyl optionally substituted with one or more W, then the 5-9 membered heterocyclyl contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R⁴ is attached.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof as disclosed herein is selected from

, or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

Also provided is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a pharmaceutically acceptable excipient.

Also provided is a method of inhibiting KRAS activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition as disclosed herein.

Also provided is a method of inhibiting KRAS activity comprising contacting KRAS with the compound or a pharmaceutically acceptable salt thereof disclosed herein or the composition disclosed herein to inhibit the activity of the KRAS.

In some embodiments, the KRAS is wild type or KRAS mutant selected from KRAS G12C, G12D, G12V G12S, G12R, G12A, G13D, G13C, G13A, and G13V.

In some embodiments, the KRAS is KRAS G12D.

Also provided is a method of treating a disease or disorder associated with KRAS mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a composition as disclosed herein.

In some embodiments, the disease or disorder is cancer.

Also provided is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition disclosed herein, wherein the cancer comprises cancer cells having KRAS mutation.

In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12R, KRAS G12A, KRAS G13D, KRAS G13C, KRAS G13A, and KRAS G13V.

In some embodiments, the KRAS mutation is KRAS G12D.

In some embodiments, the disease or disorder associated with KRAS mutation is cancer. In some embodiments, the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, lung cancer, small intestine cancer, sarcoma, leukemia, melanoma, lymphoma, cholangiocarcinoma, appendiceal cancer, multiple myeloma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, glioblastoma, and renal cancer.

In some embodiments, the method further comprises administering to the subject in need thereof an additional known anti-cancer agent.

DETAILED DESCRIPTION

I. Definitions

The substituents as disclosed herein intend to result in a chemical structure that is stable. Any substitution pattern that will render a compound known to be chemically unstable to a skilled artisan is not contemplated herein.

Notwithstanding the title, nothing in this application indicates that the compounds as disclosed herein can be only used as KRAS G12D modulators. The clinical success of compounds inhibiting KRAS mutant G12C (KRAS G12 C) , such as sotorasib and adagrasib has encouraged efforts in developing inhibitors for all KRAS mutants. Inhibitors for multiple KRAS mutants, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12R, KRAS G12A, KRAS G13D, KRAS G13C, KRAS G13A, and/or KRAS G13V, as well as for wild type KRAS are desired to address broad patient populations. As indicated in this application, the compounds disclosed herein can also be modulators of other KRAS mutants, including, for example, KRAS G12C, G12V, and G12S, as well as modulators of amplified WT KRAS.

A dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent. For example, -CONH₂ is attached through the carbon atom.

The term "alkyl" herein refers to a straight or branched hydrocarbon chain containing 1-14 carbons. The symbol of C subscripted with a number range that precedes the term “alkyl” stands for the number of carbons in the alkyl. For example, C_1-5 alkyl represents an alkyl containing 1, 2, 3, 4, or 5 carbon atoms. Examples of C_1-5 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and pentyl.

The term “alkylidene” here refers to a divalent group derived from a straight or branched hydrocarbon chain containing 1-14 carbons by removal of two hydrogen atoms from the same carbon atom so that the hydrocarbon chain attaches to an atom through a double bond formed by the same carbon and the atom. C_1-6 alkylidene can be represented by the formulawherein R_a and R_b are selected from H and C_1-5 alkyl provided that the carbon atoms from R₁ and R₂ are at most 5 in total.

The term “alkenyl” herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon double bond. The group may be in either the cis or trans configuration about the double bond. The symbol of C subscripted with a number range that precedes the term “alkenyl” stands for the number of carbons in the alkenyl. For example, C_2-8 alkenyl represents an alkenyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary alkenyl includes, but are not limited to, ethylenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl) , prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1, 3-dien-1-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon double bond.

The term “alkynyl” herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon triple bond. The symbol of C subscripted with a number range that precedes the term “alkynyl” stands for the number of carbons in the alkynyl. For example, C_2-8 alkynyl represents an alkynyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary alkynyl includes, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon triple bond.

The term “alkoxyl” or “alkoxy” herein refers to -O-alkyl. The symbol of C subscripted with a number range that precedes the term “alkoxy” stands for the number of carbons in the alkoxy. For example, C_1-5 alkoxy represents an alkoxy containing 1, 2, 3, 4, or 5 carbon atoms. Examples of C_1-5 alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, butoxy, and pentoxy.

The term “aryl” refers to a 6-10 ring membered monocyclic aromatic hydrocarbon ring, such as phenyl. Aryl also refers to a 8-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic and does not comprise a heteroatom selected from O, S, and N as ring atom, the remaining cyclic (s) or ring (s) may be saturated, partially saturated, or aromatic, provided (1) when the remaining cyclic (s) or ring (s) is aromatic, it does not comprise a heteroatom selected from O, S, and N as ring atom, and (2) when the remaining cyclic (s) or ring (s) is not aromatic, it may or may not comprise a heteroatom selected from O, S, and N as ring atom. The point of attachment can be any ring atom. For example, are aryls.

The term "cycloalkyl" herein refers to a 3-14 ring membered saturated or partially unsaturated mono-cyclic, or spiro, fused, or bridged bi-, or multi-cyclic hydrocarbon group only having carbon atom as the ring atom. The symbol of C subscripted with a number range that precedes the term “cycloalkyl” stands for the carbon ring numbers in the cycloalkyl. For example, C_3-5 cycloalkyl represents a cycloalkyl containing 3, 4, or 5 carbon ring atoms, i.e., cyclopropyl, cyclobutyl, or cyclopentyl. The ring may be saturated or have one or more double bonds (i.e. partially unsaturated) , but not fully conjugated. When cycloalkyl is spiro, fused, or bridged bi-, or multi-cyclic, none of the cycles or rings is aromatic.

The term "heteroaryl" refers to 5-14 ring membered, such as 5 or 6 ring membered, mono-cyclic aromatic ring containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Heteroaryl also refers to 7-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S as ring atoms, the remaining cyclic (s) or ring (s) (1) may or may not contain heteroatoms selected from N, O, and S and (2) may be saturated, partially saturated, or aromatic. The point of the attachment can be any ring atom. For example, are heteroaryls.

Further exemplary heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.

The term “heterocyclyl" herein refers to a 5 to 14 ring membered, saturated or partially unsaturated mono-cyclic ring, or fused, spiro, or bridged bicyclic or multicyclic ring, containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. The point of the attachment can be any ring atom. When heterocyclyl is spiro, fused, or bridged bi-, or multi-cyclic, none of the cycles or rings is aromatic.

Exemplary heterocyclyl includes but are not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3-oxa-9-azaspiro [5.5] undecanyl, 7-oxa-2-azaspiro [3.5] nonanyl, and 2-oxa-7-azaspiro [3.5] nonanyl, azepanyl, 1, 2, 5-triazepanyl, 6, 7, 8, 9-tetrahydro-1H, 5H- [1, 2, 4] triazolo [1, 2-a] [1, 2, 5] triazepinyl, diazepanyl, 1, 2, 5-oxadiazepanyl.

“Halo” refers to F. Cl, Br or I.

“Oxo” refers to = (O) .

“Pharmaceutically acceptable salt” refers to a salt form of a compound (e.g., a drug) having at least one group capable of salt formation that causes no significant adverse toxicological effects to the subject. Pharmaceutically acceptable salts include, for example, salts prepared by reaction with an inorganic acid, organic acid, or a base depending on the nature of the compound (e.g., drug) . The inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, and the like; the organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid and the like. The base that can form a salt with an acid drug can be an amine containing compound or inorganic base such as sodium hydroxide, sodium carbonate, and the like. Suitable pharmaceutically acceptable salt forms can be found in, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002; P.H. Stahl and C.G. Wermuth, Eds.

The terms “treating” , “treatment” , or “treat” (of) a disease refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease. The terms also refer to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.

A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

The term “subject” as used herein refers to animal (such as mammal) or human.

Compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, their solvates, optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. Where compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound. Moreover, compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein also include compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein certain atoms in formula (I) are replaced with their corresponding isotopes, such as certain H is replaced by D (deuterium) .

II. Compounds and uses thereof

Compounds disclosed herein (the term “compound (s) disclosed herein” includes pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted administration modes for agents in the form of a pharmaceutical composition that serve similar utilities. Therapeutically effective amount of the compounds disclosed herein may range from 0.01 to 500 mg per kg subject body weight, which can be administered in single or multiple doses per day. For oral administration, the pharmaceutical compositions can be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the compound disclosed herein, such as, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 mg of the compound disclosed herein.

In addition to oral administration, the compound disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.

Thus, also provided is a pharmaceutical composition comprising the compound disclosed herein and a pharmaceutically acceptable excipient. When prepared for unit dosage form, the pharmaceutical compositions can comprise from 1 mg to 1000 mg of the compound disclosed herein.

Exemplary solid pharmaceutical excipient includes starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e g, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid excipients, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000) .

Further provided is a method of inhibiting KRAS G12D activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound described herein.

Further provided is a method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of the compound described herein.

The disease or disorder associated with KRAS G12D mutation can be cancer. The cancer includes but not limited to carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.

The compound disclosed herein may be administered in combination with other anti-cancer agents, or in combination with radiation therapy or surgery. Other anti-cancer agents can be Paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitor (such as niraparib, Olaparib) , anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, mTOR inhibitor, IGF1R inhibitor, HADC inhibitor, EGFR inhibitor, for example, anti-EGFR antibody (such as panitumumab) , HIF-1 inhibitor, VEGF/VEGFR inhibitors (such as sorafenib, bevacizumab) .

EXAMPLES

The compounds and processes of the present disclosure will be better understood in connection with the following examples, which are intended as an illustration only and not limiting the scope of the disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations, and/or method of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

Example 1: Intermediate Synthesis.

Synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1)

Step 1: Synthesis of 2, 6-dichloro-3-fluoropyridin-4-amine (Intermediate 1-1) .

To a solution of 2, 6-dichloropyridin-4-amine (50 g, 307 mmol) in methanol (500 mL) and water (100 mL) was added Selectfluor (130 g, 367 mmol) at room temperature. After stirring at ～45 ℃ for 16 hours, the reaction mixture was concentrated. The residue was diluted with ethyl acetate (500 mL) , washed with water (500 mLx3) , brine, dried over sodium sulfate, and concentrated to afford Intermediate 1-1 (50 g, 90%yield) as a white solid. LC-MS: m/z = 181.0 [M+H] ⁺.

Step 2: Synthesis of tert-butyl (tert-butoxycarbonyl) (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (Intermediate 1-2) .

To a solution of Intermediate 1-1 (50 g, 277.79 mmol) in tetrahydrofuran (500 mL) were added 4-dimethylaminopyridine (1.7 g, 13.89 mmol) and di-tert-butyl dicarbonate (150 g, 694.38 mmol) portion-wise at room temperature. The mixture was stirred at 60 ℃ for 4 hours and then concentrated under vacuum. The crude product was triturated with methanol (200 mL) to give Intermediate 1-2 (50 g, 47.5%yield) as a white solid. LC-MS: m/z = 381.0 [M+H] ⁺.

Step 3: Synthesis of tert-butyl 4- ( (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinate (Intermediate 1-3) .

To a solution of diisopropylamine (22.3 g, 219 mmol) in anhydrous tetrahydrofuran (180 mL) was added n-butyllithium (2.7 M, 81 mL, 218.7 mmol) dropwise at -78 ℃ under nitrogen. The mixture was stirred for another hour at the same temperature. To the above lithium solution was added a solution of Intermediate 1-2 (30 g, 78.9 mmol) in tetrahydrofuran (150 mL) dropwise at -78 ℃ under nitrogen. After stirring for one hour, the reaction mixture was carefully quenched with acetic acid and diluted with ethyl acetate (1500 mL) . The resulting mixture was washed with water (500 mLx3) , brine (500 mL) , dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give Intermediate 1-3 (15 g, 50%yield) as a white solid. LC-MS: m/z = 381.0 [M+H] ⁺.

Step 4: Synthesis of 4-amino-2, 6-dichloro-5-fluoronicotinic acid hydrochloride (Intermediate 1-4) .

To Intermediate 1-3 (10 g, 26.25 mmol) was added 4M HCl in 1, 4-dioxane solution (100 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to afford Intermediate 1-4 (5.5 g, 93%yield) as a white solid. LC-MS: m/z = 224.9 [M+H] ⁺.

Step 5: Synthesis of 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1-5) .

To a solution of Intermediate 1-4 (5 g, 22.32 mmol) in thionyl chloride (150 mL) was added N, N-dimethylformamide (2 drops) . The reaction mixture was stirred at 90 ℃ for 3 hours and then concentrated. To the residue were added tetrahydrofuran (10 mL) and ammonia thiocyanate (5.10 g, 66.96 mmol) . The resulting mixture was stirred at room temperature for 2 hours and then diluted with ethyl acetate (600 mL) . The mixture was washed with water (200 mL) , brine, dried over sodium sulfate, and concentrated to afford Intermediate 1-5 (5.5 g, 94.8%yield) as a yellow solid.

Step 6: Synthesis of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) .

To a solution of Intermediate 1-5 (5.4 g, 20.3 mmol) in methanol (400 mL) and water (400 mL) was added iodomethane (5.76 g, 40.6 mmol) followed by sodium hydroxide (1.62 g, 40.6 mmol) . The reaction was stirred at room temperature for 2 hours. The resulting mixture was then diluted with water (400 mL) and adjusted the pH to ～7 with 2 M hydrochloric acid. The resulting precipitate was collected by filtration, and the filter cake was washed with water (100 mL) and oven dried to afford Intermediate 1 (3.8 g, 67.1%yield) as a yellow solid. LC-MS: m/z = 279.9 [M+H] ⁺.

Synthesis of 4, 5, 7-trichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidine (Intermediate 2) .

To a solution of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 1) (1.0 g, 3.57 mmol) in phosphorus oxychloride (8 mL) was added N, N-diisopropylethylamine (2.3 g, 17.85 mmol) at 25 ℃. The mixture was heated at 130 ℃ for 4 hours. The mixture was cooled to room temperature and concentrated. The crude was diluted with ethyl acetate (200 mL) , washed with cold water (200 mLx2) , cold brine (100 mL) , dried over Na₂SO₄, and concentrated at 25 ℃ to afford Intermediate 2 (1.2 g, crude) as a brown solid, which was used in the next step without further purification.

Synthesis of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol (Intermediate 3) .

Step 1: Synthesis of 7-bromo-6-chloro-5, 8-difluoro-2-mercaptoquinazolin-4-ol (Intermediate 3-1)

A mixture of 2-amino-4-bromo-5-chloro-3, 6-difluorobenzoic acid (10 g, 35.09 mmol) in SOCl₂ (50 mL) was stirred at 80 ℃ for 1 h. The reaction was concentrated under vacuum and the residue was dissolved with acetone (25 mL) . The solution was then added dropwise to a mixture of NH₄SCN (2.9 g, 38.15 mmol) in acetone (25 mL) at rt. After stirred at rt for 2 hrs, the mixture was poured into water (150 mL) and filtered. The filter cake was washed with water (25mL x2) . The filtrate was extracted with EtOAc (75 mL x2) . The organic phase and the cake were combined and concentrated under vacuum. The residue was slurried with petroleum ether/EtOAc (1/1) and filtered to afford Intermediate 3-1 (7 g, 61.2%) as a yellow solid. LC-MS: m/z = 326.8 [M+H] ⁺.

Step 2: Synthesis of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol (Intermediate 3)

To a stirred mixture of Intermediate 3-1 (7 g, crude) , NaOH solution (1.05 g, 26.25 mmol in 7 mL of water) and MeOH (70 mL) was added MeI (3.64 g, 25.6 mmol) at rt. The resulting mixture was stirred at rt for 2 hrs. The reaction was poured into water (400 mL) and adjusted to pH to 6 by HCl (2M) . The filter cake was washed with water (60 mL x2) . The filtrate was extracted with DCM (90 mL x2) . The organic phase and the cake were combined and concentrated under vacuum. The residue was triturated with MeOH (140 mL) and filtered to afford Intermediate 3 (5 g, 68.3%yield) as a yellow solid. LC-MS: m/z = 341.0 [M+H] ⁺.

Example 2: Compound Synthesis:

Compound 1: Synthesis of 5-ethynyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 1)

Step 1: Synthesis of (S) - (1- (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-2-yl) methanol (Compound 1-1) .

To a solution of Intermediate 1 (3.0 g, 10.7 mmol) in acetonitrile (90 mL) at room temperature were added potassium phosphate tribasic (5.68 g, 26.78 mmol) , phosphonitrilic chloride trimer (HCCP) (3.72 g, 10.71 mmol) and the reaction was stirred at room temperature for 1 hour. Then, (S) -piperidin-2-ylmethanol (1.36 g, 11.78 mmol) was added, and the reaction mixture was stirred for another hour before it was diluted with ethyl acetate (600 mL) and water (200 mL) . The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-100%) to afford Compound 1-1 (1.2 g, 29.7%yield) as a yellow solid. LC-MS: m/z = 376.8 [M+H] ⁺.

Step 2: Synthesis of (S) -2-chloro-1-fluoro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 1-2)

To a solution of Compound 1-1 (1.2 g, 3.18 mmol) in tetrahydrofuran (12 mL) at room temperature was added NaH (60%in mineral oil, 636.11 mg, 15.90 mmol) . The reaction was stirred at room temperature for 1 hour and then at 45 ℃ for 16 hours. The resulting mixture was diluted with ethyl acetate (300 mL) , washed with water (100 mL) , brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 1-2 (280 mg, 25.8%yield) as a yellow solid. LC-MS: m/z = 340.9 [M+H] ⁺.

Step 3: Synthesis of (S) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 1-3) .

To a solution of Compound 1-2 (270 mg, 0.792 mmol) in dioxane (6 mL) and water (1.5 mL) were added 3-a (629.42 mg, 1.27 mmol) , cataCXium-A-Pd-G3 [CAS: 1651823-59-4] (115.4 mg, 0.158 mmol) and potassium phosphate tribasic (504.5 mg, 2.38 mmol) . The reaction was stirred at 95 ℃ for 3 hours. The resulting mixture was diluted with ethyl acetate (300 mL) , washed with water (100 mL) , brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 1-3 (270 mg, 49.3%yield) as a yellow solid. LC-MS: m/z = 690.2 [M+H] ⁺.

Step 4: Synthesis of (5aS) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 1-4)

To a solution of Compound 1-3 (260 mg, 0.376 mmol) in dichloromethane (5 mL) at 0 ℃ was add m-CPBA (91.7 mg, 0.45 mmol) , and the reaction was stirred at 0 ℃ for 30 min. The resulting mixture was diluted with ethyl acetate (300 mL) , washed with water (100 mL) , brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-100%) to afford Compound 1-4 (175 mg, 65.8%yield) as a yellow solid. LC-MS: m/z = 707.3 [M+H] ⁺.

Step 5: Synthesis of (S) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 1-5) .

To a solution of 4-a (74.32 mg, 0.466 mmol) in tetrahydrofuran (2 mL) at 0 ℃ was added NaH (60%in mineral oil, 28.0 mg, 0.7 mmol) , and the reaction was stirred at 0 ℃ for 30 min. Then Compound 1-4 (165 mg, 0.233 mmol) was added, and the reaction was stirred at 0 ℃ for another 30 min. The resulting mixture was diluted with ethyl acetate (300 mL) , washed with water (100 mL) , with brine, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (eluting with methanol in dichloromethane 0-10%) to afford Compound 1-5 (80 mg, 42.7%yield) as a yellow solid. LC-MS: m/z = 802.4 [M+H] ⁺.

Step 6: Synthesis of (S) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 1-6) .

To a solution of Compound 1-5 (75 mg, 0.093 mmol) in N, N-dimethylformamide (2 mL) was added cesium fluoride (142.05 mg, 0.935 mmol) , and the reaction was stirred at 60 ℃ for 1 hour. The resulting mixture was diluted with ethyl acetate (300 mL) , washed with water (100 mL) , brine, dried over sodium sulfate, and concentrated to afford Compound 1-6 (48 mg, 79.3%yield) as a yellow solid. LC-MS: m/z = 646.2 [M+H] ⁺.

Step 7: Synthesis of 5-ethynyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 1)

To a solution of Compound 1-6 (45 mg, 0.069 mmol) in methanol (1 mL) was added HCl (4M in dioxane, 1 mL) , and the reaction was stirred at 25 ℃ for 1 hour. The resulting mixture was concentrated and adjusted to pH = ～ 8 with addition of ammonia in methanol solution. The precipitated NH₄Cl salt was removed by filtration. The filtrate was concentrated and purified by prep-HPLC (MeCN/water/NH₄HCO₃) to afford Compound 1 (6.65 mg, 15.9%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H) , 8.00-7.91 (m, 1H) , 7.45 (t, J = 8.8 Hz, 1H) , 7.36 (s, 1H) , 7.14 (d, J = 13.2 Hz, 1H) , 5.28 (d, J = 54.8 Hz, 1H) , 5.13-5.03 (m, 1H) , 4.52-4.30 (m, 2H) , 4.20-3.80 (m, 4H) , 3.20-2.90 (m, 4H) , 2.84 (s, 1H) , 2.13-1.90 (m, 3H) , 1.89-1.66 (m, 8H) , 1.59 (s, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -110.7, -145.2, -172.1; LC-MS: m/z = 602.3 [M+H] ⁺.

Compound 2: Synthesis of 5-ethynyl-6-fluoro-4- ( (R) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 2)

Compound 2 was synthesized by following procedures similar for the synthesis of Compound 1 described above. ¹H NMR (400 MHz, DMSO) δ 10.13 (s, 1H) , 8.00 –7.91 (m, 1H) , 7.45 (t, J = 9.2 Hz, 1H) , 7.37 (d, J = 2.4 Hz, 1H) , 7.17-7.12 (m, 1H) , 5.32 (d, J = 55.2 Hz, 1H) , 5.22-5.08 (m, 1H) , 4.56-4.38 (m, 2H) , 4.25-3.87 (m, 4H) , 3.25-2.95 (m, 4H) , 2.84 (s, 1H) , 2.30-1.99 (m, 3H) , 1.97-1.65 (m, 8H) , 1.59 (s, 1H) .; ¹⁹F NMR (376 MHz, DMSO) δ -71.1, -110.7, -145.2; LC-MS: m/z = 602.2 [M+H] ⁺.

Compound 3: Synthesis of (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 3)

Compound 3 was synthesized by following procedures similar for the synthesis of Compound 1 described above. ¹H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, J = 8.9, 6.3 Hz, 1H) , 8.17 (dd, J = 8.0, 1.6 Hz, 1H) , 7.69-7.58 (m, 3H) , 5.28 (d, J = 54.2 Hz, 1H) , 5.14 (d, J = 21.8 Hz, 1H) , 4.53-4.38 (m, 2H) , 4.16 (d, J = 17.0 Hz, 1H) , 4.13-4.07 (m, 1H) , 4.00-3.96 (m, 1H) , 3.94 (s, 1H) , 3.09 (d, J = 9.0 Hz, 2H) , 3.02 (d, J = 7.4 Hz, 2H) , 2.84 (t, J = 7.4 Hz, 1H) , 2.10 (dd, J = 24.6, 8.8 Hz, 2H) , 1.96-1.69 (m, 8H) , 1.69-1.47 (m, 2H) ; 19F NMR (376 MHz, DMSO-d6) δ -105.7 (s) , -145.1 (s) , -145.5 (s) , -172.1 (s) , -172.2 (s) ; LC-MS: m/z = 586.3 [M+H] ⁺.

Compound 4: Synthesis of (R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 4)

Compound 4 was synthesized by following procedures similar for the synthesis of Compound 1 described above. ¹H NMR (400 MHz, DMSO) δ 8.26 –8.15 (m, 2H) , 7.71 –7.54 (m, 3H) , 5.28 (d, J = 54.0 Hz, 1H) , 5.21 –5.02 (m, 1H) , 4.60 –4.36 (m, 2H) , 4.20 –3.80 (m, 4H) , 3.13–3.07 (m, 2H) , 3.02 (s, 2H) , 2.95 –2.75 (m, 1H) , 2.20 –1.95 (m, 2H) , 2.01 –1.69 (m, 8H) , 1.66-1.40 (m, 2H) . ¹⁹F NMR (376 MHz, DMSO-d6) δ -105.7 (s) , -145.1 (s) , -145.4 (s) , -172.1 (s) , -172.2 (s) ; LC-MS: m/z = 585.8 [M+H] ⁺.

Compound 5: Synthesis of 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 5)

Step 1: Synthesis of 2- ( (2- ( (tert-butyldimethylsilyl) oxy) ethyl) (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) amino) ethan-1-ol (Compound 5-1) .

To a solution of Intermediate 2 (1.2 g, crude) in dichloromethane (8 mL) at -60 ℃ under N₂ atmosphere were added N, N-diisopropylethylamine (2.3 g, 17.85 mmol) and 2- ( (2- ( (tert-butyldimethylsilyl) oxy) ethyl) amino) ethan-1-ol (1.2 g, 5.36 mmol) , The mixture was stirred at -60 ℃ for 10 minutes. The mixture was then concentrated, and the residue was purified by silica gel chromatography (EtOAc/petroleum ether = 20%to 50%) to afford Compound 5-1 (1.3 g, 76%yield) as a yellow oil. LC-MS: m/z = 479.1 [M-H] ^-.

Step 2: Synthesis of 10- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -5-chloro-4-fluoro-2- (methylthio) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 5-2) .

A mixture of Compound 5-1 (500 mg, 1.04 mmol) , triethylenediamine (116 mg, 1.04 mmol) and cesium carbonate (1.0 g, 3.12 mmol) in N, N-dimethylformamide (5 mL) and THF (5 mL) was stirred at 50 ℃ for 3 hrs. The mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) , washed with water (200 mL x2) , 0.5 M HCl (100 mL) and brine (100 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated to afford Compound 5-2 (430 mg, yield: 93%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.54-4.53 (m, 2H) , 3.96-3.82 (m, 6H) , 2.51-2.49 (m, 3H) , 0.81 (s, 9H) , 0.00 (s, 6H) .

Step 3-6: Synthesis of 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 5) .

Following similar procedures described in Step 3-6 of Compound 1 synthesis, Compound 5-2 was converted to Compound 5 as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.14 (m, 2H) , 7.67 (t, J = 7.6 Hz, 1H) , 7.64-7.57 (m, 2H) , 5.52-5.28 (m, 1H) , 4.90 (t, J = 5.2 Hz, 1H) , 4.61-4.50 (m, 2H) , 4.47-3.68 (m, 10H) , 3.54-3.34 (m, 2H) , 3.12-2.90 (m, 1H) , 2.40-2.06 (m, 3H) , 2.05-1.83 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.75, -146.67, -172.43; LC-MS: m/z = 576.3 [M+H] ⁺.

Compound 6: Synthesis of 2- (5- (8-ethyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 6) .

Compound 6 was prepared from Compound 5 following the standard hydrogenation procedure. ¹H NMR (400 MHz, DMSO-d₆) δ 8.14-8.08 (m, 1H) , 8.01 (dd, J = 9.2, 6.4 Hz, 1H) , 7.56 (t, J = 7.2 Hz, 1H) , 7.53-7.42 (m, 2H) , 5.57-5.35 (m, 1H) , 4.91 (t, J = 5.2 Hz, 1H) , 4.66-4.51 (m, 2H) , 4.50-4.20 (m, 2H) , 4.10-3.92 (m, 4H) , 3.81-3.70 (m, 2H) , 3.69-3.36 (m, 3H) , 3.21-2.99 (m, 1H) , 2.42-1.85 (m, 8H) , 0.84 (t, J = 7.2 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -114.56, -145.76, -172.59; LC-MS: m/z = 580.3 [M+H] ⁺.

The following compounds were synthesized following similar procedures as described above.

Compound 7: 2- ( (R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 7)

¹H NMR (400 MHz, DMSO-d₆) : δ 8.23-8.16 (m, 2H) , 7.70-7.57 (m, 3H) , 5.44-5.30 (m, 1H) , 4.93 (t, J = 4.8, 1H) , 4.60-4.52 (m, 1H) , 4.44-4.40 (m, 1H) , 4.28-4.08 (m, 5H) , 3.88-3.36 (m, 5H) , 3.24-3.14 (m, 1H) , 3.00 (s, 1H) , 2.30-1.84 (m, 6H) , 1.29 (d, J = 6.4, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.75, -146.08, -172.35; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 8: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 7, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 8)

¹H NMR (400 MHz, DMSO-d₆) δ 8.29-8.11 (m, 2H) , 7.76-7.52 (m, 3H) , 5.47-5.33 (m, 1H) , 5.22-5.07 (m, 1H) , 4.70-4.54 (m, 2H) , 4.44-4.09 (m, 4H) , 3.61-3.39 (m, 6H) , 3.19-2.95 (m, 4H) , 2.35-2.10 (m, 3H) , 2.06-1.81 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.54, -144.48, -172.34; LC-MS: m/z = 587.3 [M+H] ⁺.

Compound 9: 2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 9)

¹H NMR (400 MHz, CD₃OD) δ 8.11-8.06 (m, 2H) , 7.70-7.58 (m, 2H) , 7.46-7.39 (m, 1H) , 5.45-5.29 (m, 1H) , 4.67-4.60 (m, 1H) , 4.55-4.48 (m, 1H) , 4.44-4.29 (m, 4H) , 4.08-3.92 (m, 2H) , 3.80-3.70 (m, 1H) , 3.57-3.35 (m, 4H) , 3.18-3.11 (m, 1H) , 2.48-2.30 (m, 2H) , 2.24-2.18 (m, 1H) , 2.13-2.05 (m, 2H) , 2.01-1.92 (m, 1H) , 1.43-1.38 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -102.90, -142.89, -169.88; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 10: 2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 10)

¹H NMR (400 MHz, DMSO-d6) δ 8.23-8.16 (m, 2H) , 7.70-7.56 (m, 3H) , 5.41-5.28 (m, 1H) , 4.92-4.87 (m, 1H) , 4.74-4.66 (m, 1H) , 4.27-4.09 (m, 3H) , 4.06-3.75 (m, 6H) , 3.26-3.08 (m, 3H) , 2.94 (s, 1H) , 2.26-1.79 (m, 6H) , 1.41 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.80, -147.04, -172.28; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 11: 2- ( (R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 11)

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.16 (m, 2H) , 7.69-7.56 (m, 3H) , 5.40-5.26 (m, 1H) , 4.92-4.88 (m, 1H) , 4.74-4.65 (m, 1H) , 4.24-3.73 (m, 9H) , 3.26-3.10 (m, 3H) , 2.91 (s, 1H) , 2.20-1.78 (m, 6H) , 1.41 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.80, -147.05, -172.27; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 12: (R) -1- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-2-ol (Compound 12)

¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.14 (m, 2H) , 7.69-7.58 (m, 3H) , 5.54 (d, J = 53.6 Hz, 1H) , 4.98 (s, 1H) , 4.58 (s, 4H) , 4.22-3.94 (m, 5H) , 3.86-3.59 (m, 3H) , 3.57-3.39 (m, 1H) , 3.28-3.17 (m, 1H) , 2.63-2.53 (m, 1H) , 2.43 (s, 1H) , 2.31-1.93 (m, 4H) , 1.16 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.71, -146.61, -172.65; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 13: 1- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) -2-methylpropan-2-ol (Compound 13)

¹H NMR (400 MHz, DMSO-d₆) : δ 8.22-8.16 (m, 2H) , 7.69-7.57 (m, 3H) , 5.34-5.20 (m, 1H) , 4.83 (s, 1H) , 4.58 (s, 2H) , 4.21-3.98 (m, 6H) , 3.74 (d, J = 13.6, 1H) , 3.09-3.07 (m, 2H) , 3.01 (s, 1H) , 2.85-2.80 (m, 1H) , 2.10 (s, 1H) , 2.03 (s, 1H) , 1.97 (s, 1H) , 1.86-1.72 (m, 3H) , 1.18 (d, J = 10.4 , 6H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.8, -147.0, -172.0; LC-MS: m/z = 604.3 [M+H] ⁺.

Compound 14: 3- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 14)

¹H NMR (400 MHz, DMSO-d₆) δ 8.24-8.15 (m, 2H) , 7.70-7.56 (m, 3H) , 5.37 (d, J = 52.0 Hz, 1H) , 4.63 (t, J = 5.2 Hz, 1H) , 4.59-4.48 (m, 2H) , 4.14 (s, 3H) , 4.06-3.89 (m, 3H) , 3.87-3.76 (m, 1H) , 3.56-3.49 (m, 2H) , 3.29-2.77 (s, 4H) , 2.33-1.83 (m, 8H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.78, -146.57, -172.30; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 15: (R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 7, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 15)

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.14 (m, 2H) , 7.70-7.56 (m, 3H) , 5.39-5.20 (m, 1H) , 5.14-5.02 (m, 1H) , 4.64-4.46 (m, 2H) , 4.21-3.97 (m, 4H) , 3.26-3.19 (m, 3H) , 3.18-3.01 (m, 4H) , 2.98-2.81 (m, 2H) , 2.02-1.93 (m, 3H) , 1.89-1.75 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.63, -144.75, -172.15; LC-MS: m/z = 587.3 [M+H] ⁺.

Compound 16: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (R) -pyrrolidin-3-yl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 16)

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.16 (m, 2H) , 7.69-7.58 (m, 3H) , 5.77-5.68 (m, 1H) , 5.35-5.22 (m, 1H) , 4.62-4.48 (m, 2H) , 4.21-4.00 (m, 4H) , 3.93-3.83 (m, 1H) , 3.51-3.40 (m, 2H) , 3.24-3.03 (m, 5H) , 2.88-2.78 (m, 1H) , 3.34-3.22 (m, 1H) , 2.18-1.98 (m, 4H) , 1.90-1.74 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.75, -146.61, -172.01; LC-MS: m/z = 601.3 [M+H] ⁺.

Compound 17: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (S) -pyrrolidin-3-yl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 17)

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.15 (m, 2H) , 7.71-7.57 (m, 3H) , 5.71 (s, 1H) , 5.49-5.28 (m, 1H) , 4.63-4.50 (m, 2H) , 4.45-4.19 (m, 2H) , 4.14 (s, 1H) , 4.12-4.00 (m, 1H) , 3.97-3.86 (m, 1H) , 3.60-3.44 (m, 3H) , 3.25-3.17 (m, 3H) , 3.10-2.88 (m, 2H) , 2.35-2.11 (m, 5H) , 2.03-1.85 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.69, -146.44, -172.24; LC-MS: m/z = 601.3 [M+H] ⁺.

Compound 18: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 18)

LC-MS: m/z = 532.2 [M+H] ⁺ .

Compound 19: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 19)

¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.13 (m, 2H) , 7.77-7.53 (m, 3H) , 5.30 (d, J = 53.6 Hz, 1H) , 4.63-4.45 (m, 2H) , 4.30-4.13 (m, 2H) , 4.11-3.85 (m, 3H) , 3.36 (s, 3H) , 3.27-2.97 (m, 3H) , 2.93-2.79 (m, 1H) , 2.25-1.95 (m, 3H) , 1.95-1.71 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.81, -146.40, -172.15; LC-MS: m/z = 546.3 [M+H] ⁺.

Compound 20: 10-ethyl-5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 20)

¹H NMR (400 MHz, CD₃OD) δ 8.11-8.06 (m, 2H) , 7.64-7.62 (m, 2H) , 7.43 (t, J = 9.2 Hz, 1H) , 5.48-5.35 (m, 1H) , 4.62-4.60 (m, 2H) , 4.49-4.43 (m, 2H) , 4.10-3.90 (m, 4H) , 3.73-3.44 (m, 4H) , 3.27-3.16 (m, 1H) , 2.55-2.11 (m, 5H) , 2.07-1.97 (m, 1H) , 1.35 (t, J = 7.2 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.87, -147.15, -173.92; LC-MS: m/z = 560.3 [M+H] ⁺.

Compound 21 and 22: 2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol and 2- ( (R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-9-yl) propan-2-ol (Compound 21 and 22)

Compound 21: ¹H NMR (400 MHz, CD₃OD) δ 8.14-8.05 (m, 2H) , 7.72-7.59 (m, 2H) , 7.50-7.38 (m, 1H) , 5.42-5.32 (m, 1H) , 5.30-5.23 (m, 1H) , 4.80-4.64 (m, 1H) , 4.63-4.46 (m, 1H) , 4.38-4.23 (m, 2H) , 3.68-3.40 (m, 2H) , 3.38-3.31 (m, 2H) , 3.17-3.01 (m, 1H) , 2.45-2.13 (m, 4H) , 2.09-1.84 (m, 3H) , 1.19-1.08 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -108.51, -149.66, -175.28; LC-MS: m/z = 574.4 [M+H] ⁺.

Compound 22: ¹H NMR (400 MHz, CD₃OD) δ 8.17-8.05 (m, 2H) , 7.72-7.59 (m, 2H) , 7.50-7.38 (m, 1H) , 5.56-5.43 (m, 1H) , 5.38-5.19 (m, 1H) , 4.80-4.70 (m, 1H) , 4.63-4.22 (m, 3H) , 4.01-3.68 (m, 3H) , 3.66-3.50 (m, 1H) , 3.41-3.33 (m, 1H) , 2.71-2.45 (m, 2H) , 2.38-2.20 (m, 3H) , 2.18-1.98 (m, 2H) , 1.21-1.07 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.95, -148.44, -174.08; LC-MS: m/z = 574.4 [M+H] ⁺.

Compound 23: 2- ( (R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-9-yl) propan-2-ol (Compound 23)

¹H NMR (400 MHz, DMSO-d₆) : δ 8.65-8.56 (m, 1H) , 8.26-8.19 (m, 2H) , 7.72-7.58 (m, 3H) , 5.34-5.15 (m, 3H) , 4.87-4.79 (m, 1H) , 4.15-4.03 (m, 3H) , 3.51 (s, 1H) , 3.08 (s, 3H) , 2.82 (s, 1H) , 2.03-1.96 (m, 3H) , 1.77 (s, 3H) , 1.35-1.26 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.3, -147.1, -172.1; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 24: tert-butyl (2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethyl) carbamate (Compound 24)

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.12 (m, 2H) , 7.67 (t, J = 7.6 Hz, 1H) , 7.61-7.57 (m, 2H) , 5.35-5.21 (m, 1H) , 4.61-4.51 (m, 2H) , 4.19-3.83 (m, 8H) , 3.17-2.99 (m, 6H) , 2.87-2.78 (m, 1H) , 2.18-2.12 (m, 1H) , 2.08-1.97 (m, 2H) , 1.89-1.72 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.80, -146.69, -171.97 ; LC-MS: m/z = 575.3 [M+H] ⁺.

Compound 25: N- (2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethyl) acetamide (Compound 25)

¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H) , 8.25-8.16 (m, 2H) , 7.69-7.58 (m, 3H) , 5.60-5.46 (m, 1H) , 4.72-4.46 (m, 4H) , 4.23 (s, 1H) , 4.12-3.82 (m, 5H) , 3.79-3.59 (m, 2H) , 3.54-3.45 (m, 1H) , 3.41-3.37 (m, 1H) , 3.27-3.18 (m, 1H) , 2.45-2.37 (m, 1H) , 2.35-2.24 (m, 1H) , 2.20-1.95 (m, 4H) , 1.77 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.68, -146.73, -172.72; LC-MS: m/z = 617.4 [M+H] ⁺.

Compound 26: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( ( (R) -pyrrolidin-2-yl) methyl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 26)

¹H NMR (400 MHz, CD₃OD) δ 8.18-8.09 (m, 2H) , 7.74-7.61 (m, 2H) , 7.49-7.42 (m, 1H) , 5.55-5.41 (m, 1H) , 4.74-4.62 (m, 3H) , 4.59-4.41 (m, 1H) , 4.15-4.14 (m, 1H) , 4.10-3.94 (m, 2H) , 3.86-3.63 (m, 4H) , 3.55-3.48 (m, 1H) , 3.42-3.33 (m, 2H) , 2.60-2.17 (m, 8H) , 2.14-1.88 (m, 4H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -102.84, -143.03, -170.45; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 27: 2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 27)

Step 1: Synthesis of (S) - (1- (7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-yl) piperidin-2-yl) methanol (Compound 27-1)

A mixture of 7-bromo-6-chloro-5, 8-difluoro-2- (methylthio) quinazolin-4-ol Intermediate 3 (0.9 g, 2.65 mmol) , phosphonitrilic chloride trimer (915 mg, 2.65 mmol) and potassium phosphate tribasic (1.41 g, 6.64 mmol) in acetonitrile (30 mL) was stirred at room temperature for 1 hour. (S) -piperidin-2-ylmethanol (0.33 g, 2.87 mmol) was then added and the mixture was stirred for another 16 hours at rt. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-70%) to afford Compound 27-1 (0.6 g, 52.2%yield) as a yellow solid. LC-MS: m/z = 437.7&439.6 [M+H] ⁺.

Step 2: Synthesis of (S) -2-bromo-3-chloro-1-fluoro-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 27-2)

To a solution of Compound 27-1 (0.6 g, 1.37 mmol) in tetrahydrofuran (10 mL) was added NaH (60%mineral oil, 300 mg, 7.5 mmol) at room temperature. The mixture was stirred at 50 ℃ for 16 hours before poured into saturated. aq. NH₄Cl (50 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-15%) to afford Compound 27-2 (220 mg, 38.5%yield) as an off-white solid. LC-MS: m/z = 417.9&419.8 [M+H] ⁺.

Step 3: Synthesis of (5aS) -2-bromo-3-chloro-1-fluoro-12- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (compound 27-3)

To a solution of Compound 27-3 (190 mg, 0.456 mmol) in dichloromethane (20 mL) at 0℃ was added m-CPBA (122 mg, 0.567 mmol) . The resulting mixture was stirred at 0℃ for 30 min before diluted with water (100 mL) , extracted with ethyl acetate (100 mL x3) . The combined organic layers were washed with brine (100 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-100%) to afford Compound 27-3 (150 mg, yield: 76.2%) as a yellow solid. LC-MS: m/z = 434.0&436.0 [M+H] ⁺.

Step 4: Synthesis of (S) -2-bromo-3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 27-4) .

To a solution of compound 27-3 (150 mg, 0.347 mmol) in tetrahydrofuran (15 mL) was added t-BuONa (167 mg, 1.735 mmol) . After stirring at room temperature for 5 min, ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (275 mg, 1.35 mmol) was added and the final mixture was stirred at room temperature for additional 4 hours. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0-10%methanol in dichloromethane) to afford Compound 27-4 (110 mg, 60.11%yield) as a yellow solid. LC-MS: m/z = 529.0 [M+H] ⁺.

Step 5: Synthesis of tert-butyl (4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 27-5)

A mixture of Compound 27-4 (100 mg, 0.189 mmol) , tert-butyl (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl) -7-fluorobenzo [b] thiophen-2-yl) carbamate (115 mg, 0.284 mmol) , cesium carbonate (186 mg, 0.260 mmol) , and DPEPhosPdCl₂ (27 mg, 0.05 mmol) in toluene (20 mL) was stirred at 110 ℃for 2 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (50 mL x3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0-10%methanol in dichloromethane) to afford Compound 27-5 (45 mg, 32.1%yield) as a yellow solid. LC-MS: m/z = 741.2 [M+H] ⁺.

Step 6: Synthesis of 2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 27)

To a solution of Compound 27-5 (45 mg, 0.061 mmol) in dichloromethane (2.0 mL) was added TFA (0.7 mL) , and the resulting mixture was stirred at 25 ℃ for 45 min. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (MeCN/water /FA) to afford Compound 27 (15 mg, 38.5%yield) as a white solid. ¹H NMR (400 MHz, DMSO) δ 8.16-8.00 (m, 2H) , 7.40-6.95 (m, 2H) , 5.57 (d, J = 54.4 Hz, 1H) , 5.21-4.93 (m, 1H) , 4.71-4.30 (m, 4H) , 4.08-3.74 (m, 4H) , 3.15-2.94 (m, 2H) , 2.26-1.44 (m, 12H) ; ¹⁹F NMR (376 MHz, DMSO) δ -73.6 (s) , -116.5 (s) , -130.4 (s) ; LC-MS: m/z = 640.7 [M+H] ⁺.

Compound 28 and Compound 29: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 28) and (S) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 29)

Compound 28 and Compound 29 were obtained by SFC separation of Compound 27 on a column. Compound 28 was the first fraction and Compound 29 was the second fraction eluting from the column.

Compound 28: ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 2H) , 7.25 –7.19 (m, 1H) , 7.16 –7.09 (m, 1H) , 5.46 –5.16 (m, 1H) , 5.12 –4.92 (m, 1H) , 4.58 –4.47 (m, 2H) , 4.04 –4.18 (m, 1H) , 4.03 –3.88 (m, 2H) , 3.18 –2.92 (m, 4H) , 2.91–2.75 (m, 1H) , 2.25 –1.95 (m, 4H) , 1.94 –1.75 (m, 6H) , 1.62 –1.48 (m, 2H) ; ¹⁹F NMR (376 MHz, DMSO-d₆) δ -116.6 (s) , -130.3 (d, J = 16.8 Hz) , -172.1 (s) ; LC-MS: m/z = 640.7 [M+H] ⁺.

Compound 29: ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 2H) , 7.25 –7.19 (m, 1H) , 7.17 –7.08 (m, 1H) , 5.44 –5.16 (m, 1H) , 5.06 –4.93 (m, 1H) , 4.45 –4.37 (m, 2H) , 4.04 –4.18 (m, 1H) , 4.03 –3.88 (m, 2H) , 3.18 –2.92 (m, 4H) , 2.91–2.76 (m, 1H) , 2.25 –1.96 (m, 4H) , 1.94 –1.74 (m, 6H) , 1.62 –1.48 (m, 2H) ; ¹⁹F NMR (376 MHz, DMSO-d₆) δ -116.6 (s) , -130.3 (d, J = 6.4 Hz) , -172.2 (s) ; LC-MS: m/z = 640.7 [M+H] ⁺.

Compound 30: 2-amino-4- (8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 30)

¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 2H) , 7.21 (dd, J = 8.4, 5.2 Hz, 1H) , 7.13 (t, J = 8.4 Hz, 1H) , 5.42-5.18 (m, 1H) , 4.91 (t, J = 5.2 Hz, 1H) , 4.66-4.46 (m, 2H) , 4.25-3.88 (m, 6H) , 3.82-3.69 (m, 2H) , 3.25-2.99 (m, 3H) , 2.96-2.83 (m, 1H) , 2.20-1.74 (m, 6H) ; ¹⁹FNMR (377 MHz, DMSO-d₆) δ -116.95, -147.34, -173.88; LC-MSm/z=616.3 [M+H] ⁺.

Compound 31: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 31)

Step 1: Synthesis of tert-butyl (S) - ( (1- (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-2-yl) methyl) carbamate (Compound 31-1)

To a solution of Intermediate 1 (2.0 g, 7.1 mmol) in acetonitrile (60 mL) was added phosphonitrilic chloride trimer (2.5 g, 7.1 mmol) and potassium phosphate tribasic (3.8 g, 17.9 mmol) . After stirring at room temperature for 1 hour, tert-butyl (S) - (piperidin-2-ylmethyl) carbamate (1.7 g, 7.9 mmol) was added and the mixture was stirred for 16 hours. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-30%) to afford Compound 31-1 (1 g, 29.2%yield) as a yellow solid. LC-MS: m/z = 476.2 [M+H] ⁺.

Step 2: Synthesis of tert-butyl (S) -2-chloro-1-fluoro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene-4-carboxylate (Compound 31-2)

To a solution of Compound 31-1 (1 g, 2.1 mmol) in tetrahydrofuran (20 mL) was added NaH (60%mineral oil, 340 mg, 8.4 mmol) at room temperature. The reaction was stirred at 50 ℃ for 16 hours. The mixture was then poured into sat. aq. NH₄Cl (50 mL) and extracted with ethyl acetate (50 mL x3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-15%) to afford Compound 31-2 (500 mg, 63.0%yield) as an off-white solid. LC-MS: m/z = 440.2 [M+H] ⁺.

Step 3: Synthesis of tert-butyl (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene-4-carboxylate (Compound 31-3)

To a solution of Compound 31-2 (130 mg, 0.295 mmol) in dioxane (4 mL) and water (1 mL) were added ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (240.68 mg, 0.531 mmol) , cataCXium-A-Pd-G3 [CAS: 1651823-59-4] (43.04 mg, 0.059 mmol) , and potassium phosphate tribasic (188.17 mg, 0.886 mmol) . The mixture was stirred at 95 ℃ for 3 hours. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 31-3 (110 mg, 51.0%yield) as a yellow solid. LC-MS: m/z = 730.5 [M+H] ⁺.

Step 4: Synthesis of tert-butyl (5aS) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene-4-carboxylate (Compound 31-4)

To a solution of Compound 31-3 (100 mg, 0.136 mmol) in dichloromethane (3 mL) at 0 ℃ was added m-CPBA (33.37 mg, 0.164 mmol) , and the mixture was stirred at 0 ℃ for 30 min. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-100%) to afford Compound 31-4 (60 mg, 80.4%yield) as a yellow solid. LC-MS: m/z = 746.4 [M+H] ⁺.

Step 5: Synthesis of tert-butyl (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene-4-carboxylate (Compound 31-5)

To a solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (22.98 mg, 0.144 mmol) (4-a) in tetrahydrofuran (2.0 mL) at 0 ℃ was added NaH (60%mineral oil, 8.66 mg, 0.216 mmol) , and the mixture was stirred at 0 ℃ for 30 min. Compound 31-4 (55 mg, 0.072 mmol) was added and the mixture was stirred at 0 ℃ for another 30 min. The reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 0-10%MeOH in dichloromethane) to afford Compound 31-5 (35 mg, 57.7%yield) as a yellow solid. LC-MS: m/z = 841.5 [M+H] ⁺.

Step 6: Synthesis of tert-butyl (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene-4-carboxylate (Compound 31-6)

To a solution of Compound 31-5 (33 mg, 0.044 mmol) in N, N-dimethylformamide (2.0 mL) was added cesium fluoride (67.65 mg, 0.445 mmol) . The resulting mixture was stirred at 60 ℃ for 1 hour before diluted with ethyl acetate (100 mL) and water (100 mL) . The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford Compound 31-6 (25 mg, 36.5%yield) as a yellow solid. LC-MS: m/z = 685.3 [M+H] ⁺.

Step 7: Synthesis of (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 31)

To a solution of Compound 31-6 (23 mg, 0.033 mmol) in acetonitrile (2 mL) was added HCl (4M in dioxane) (0.4 mL) , and the mixture was stirred at 25 ℃ for 3 hours. The reaction mixture was concentrated and adjusted to pH = ～ 8 by addition of ammonia in methanol solution. The precipitated NH₄Cl salt was removed by filtration. The filtrate was concentrated and purified by prep-HPLC (MeCN/water/NH₄HCO₃) to afford Compound 31 (4.95 mg, 25.2%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.19-8.09 (m, 2H) , 7.66-7.51 (m, 3H) , 7.23 (d, J = 17.8 Hz, 1H) , 5.28 (d, J = 54.6 Hz, 1H) , 4.95 (s, 1H) , 4.11 (d, J = 10.4 Hz, 1H) , 4.02 (s, 1H) , 3.95 (d, J = 34.0 Hz, 1H) , 3.76 (s, 1H) , 3.41 (d, J = 32.8 Hz, 2H) , 3.04 (dd, J = 28.4, 13.4 Hz, 4H) , 2.85 (t, J = 7.8 Hz, 1H) , 2.20-1.98 (m, 3H) , 1.91-1.66 (m, 8H) , 1.52 (s, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -106.0 (d, J = 13.4 Hz) , -153.1 (s) , -153.5 (s) , -172.0 (s) , -172.1 (s) ; LC-MS: m/z =585.2 [M+H] ⁺.

Compound 32: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32)

Step 1: Synthesis of (S) - (1- (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-2-yl) methanamine (Compound 32-1)

To a solution of Compound 31-1 (3 g, 6.30 mmol) in acetonitrile (10 mL) was added HCl (4M in dioxane, 6 mL) , and the mixture was stirred at 25 ℃ for 3 hours. The reaction solution was concentrated in vacuum to provide the crude Compound 32-1 which was directly used in the next step. LC-MS: m/z = 376.0 [M+H] ⁺.

Step 2: Synthesis of (S) -2-chloro-1-fluoro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32-2)

A mixture of Compound 32-1 (2.2 g, 5.85 mmol) and Hunig’s base (3.78 g, 29.23 mmol) in N, N-dimethylformamide (30 mL) was stirred at 80 ℃ for 3 hours before diluted with ethyl acetate (300 mL) and water (300 mL) . The organic layer was separated, washed with brine (100 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-40%) to afford Compound 32-2 (410 mg, 20.6%yield) as a yellow solid. LC-MS: m/z = 340.0 [M+H] ⁺.

Step 3: Synthesis of (S) -2-chloro-1-fluoro-4-methyl-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32-3)

To a solution of Compound 32-2 (410 mg, 1.21 mmol) in N, N-dimethylformamide (100 mL) at 0 ℃ was added NaH (60%mineral oil, 144.8 mg, 3.62 mmol) . After stirring at 0 ℃ for 30 min, iodomethane (342.51 mg, 2.41 mmol) was added. The reaction mixture was warmed to 25 ℃ and stirred for another 1 hour before diluted with ethyl acetate (300 mL) and water (300 mL) . The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-30%) to afford Compound 32-3 (300 mg, 70.3%yield) as a yellow solid. LC-MS: m/z = 354.0 [M+H] ⁺.

Step 4: Synthesis of (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -4-methyl-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32-4)

A mixture of Compound 32-3 (290 mg, 0.819 mmol) , ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (556.27 mg, 1.23 mmol) , cataCXium-A-Pd-G3 [CAS: 1651823-59-4] (119.38 mg, 0.163 mmol) and potassium phosphate tribasic (521.90 mg, 2.46 mmol) in dioxane (6 mL) and water (1.5 mL) was stirred at 95 ℃ for 3 hours before diluted with ethyl acetate (200 mL) and water (200 mL) . The organic layer was separated, washed with brine (100 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 32-4 (270 mg, 51.2%yield) as a yellow solid. LC-MS: m/z = 644.3 [M+H] ⁺.

Step 5: Synthesis of (5aS) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -4-methyl-11- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32-5)

To a solution of Compound 32-4 (260 mg, 0.403 mmol) in dichloromethane (5 mL) at 0 ℃ was add m-CPBA (90.17 mg, 0.444 mmol) . The mixture was stirred at 0 ℃ for 30 min. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL) . The organic layer was separated, washed with brine (100 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-100%) to afford Compound 32-5 (210 mg, 78.8%yield) as a yellow solid. LC-MS: m/z = 660.3 [M+H] ⁺.

Step 6: Synthesis of (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32-6)

To a solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (96.50 mg, 0.606 mmol) in tetrahydrofuran (3 mL) at 0 ℃ was added NaH (60%mineral oil, 36.36 mg, 0.909 mmol) . After stirring at 0℃ for 30 min, Compound 32-5 (200 mg, 0.303 mmol) was added, and the mixture was stirred at 0 ℃ for another 30 min. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) . The organic layer was separated, washed with brine (100 mL) , dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with methanol in dichloromethane 0-10%) to afford Compound 32-6 (180 mg, 78.7%yield) as a yellow solid. LC-MS: m/z = 755.4 [M+H] ⁺.

Step 7: Synthesis of (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4H-3, 4, 9a, 10, 12-pentaazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 32)

A mixture of compound 32-6 (120 mg, 0.158 mmol) and cesium fluoride (241.43 mg, 1.59 mmol) in N, N-dimethylformamide (2 mL) was stirred at 60 ℃ for 1 hour before diluted with ethyl acetate (100 mL) and water (100 mL) . The separated organic layer was concentrated. The residue was purified by prep-HPLC (MeCN /water /NH₄HCO₃) to afford Compound 32 (14.15 mg, 14.9%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.23-8.11 (m, 2H) , 7.62 (ddd, J = 26.4, 12.1, 6.0 Hz, 3H) , 5.28 (d, J = 55.2 Hz, 1H) , 4.21 (d, J = 28.6 Hz, 1H) , 4.10 (dt, J = 27.0, 13.6 Hz, 2H) , 3.97 (dd, J = 10.4, 6.0 Hz, 1H) , 3.71 (dd, J = 25.6, 13.2 Hz, 1H) , 3.57 (dd, J = 19.6, 12.4 Hz, 2H) , 3.30 (d, J = 7.0 Hz, 3H) , 3.09 (d, J = 10.4 Hz, 2H) , 3.01 (s, 1H) , 2.83 (s, 1H) , 2.77-2.65 (m, 1H) , 2.08 (d, J = 32.0 Hz, 2H) , 1.85 (s, 2H) , 1.77 (d, J = 9.0 Hz, 2H) , 1.53 (d, J = 11.0 Hz, 2H) , 0.99 (d, J = 6.0 Hz, 4H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -105.8, -152.4, -172.1; LC-MS: m/z = 599.4 [M+H] ⁺.

Compounds 33-256 were prepared using synthetic methods described above unless otherwise specified.

Compound 33: (5aS) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 33)

¹H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2H) , 7.25-7.17 (m, 1H) , 7.09-7.01 (m, 1H) , 5.56 (d, J = 51.2 Hz, 1H) , 5.08 (d, J = 12.4 Hz, 1H) , 4.51-4.47 (m, 2H) , 3.95-3.76 (m, 4H) , 3.08-3.01 m, 1H) , 2.48-2.41 (m, 4H) , 2.33-2.09 (m, 4H) , 2.09-1.83 (m, 4H) , 1.82-1.50 (m, 4H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -112.4, -130.1, -173.1; LC-MS: m/z = 617.4 [M+H] ⁺.

Compound 34 and Compound 35: (S) -4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [d] thiazol-2-amine (Compound 34) and (S) -4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [d] thiazol-2-amine (Compound 35)

Compound 34: ¹H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2H) , 7.25-7.17 (m, 1H) , 7.09-7.01 (m, 1H) , 5.56 (d, J = 51.2 Hz, 1H) , 5.08 (d, J = 12.4 Hz, 1H) , 4.51-4.47 (m, 2H) , 3.95-3.76 (m, 4H) , 3.08-3.01 m, 1H) , 2.48-2.41 (m, 4H) , 2.33-2.09 (m, 4H) , 2.09-1.83 (m, 4H) , 1.82-1.50 (m, 4H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -112.4, -130.1, -173.1; LC-MS: m/z = 617.4 [M+H] ⁺.

Compound 35: ¹H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 2H) , 7.23 -7.14 (m, 1H) , 7.06 (m, 1H) , 5.55 (d, J = 53.2 Hz, 1H) , 5.09 (d, J = 11.6 Hz, 1H) , 4.52-4.45 (m, 2H) , 3.96-3.72 (m, 4H) , 3.09-3.00 (m, 1H) , 2.48-2.41 (m, 4H) , 2.36-2.08 (m, 4H) , 2.06-1.83 (m, 3H) , 1.81-1.40 (m, 4H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -112.5, -129.8, -173.0; LC-MS: m/z = 617.4 [M+H] ⁺.

Compound 36: (S) -8- (8-ethynyl-7-fluoronaphthalen-1-yl) -7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 3, 11, 11a-tetrahydro-1H-10-oxa-3a, 4, 6, 9-tetraazanaphtho [1, 8-ef] azulene (Compound 36)

¹H NMR (400 MHz, DMSO-d6) δ 8.33-7.99 (m, 2H) , 7.80-7, 31 (m, 3H) , 5.40-5.17 (m, 1H) , 4.72-4.61 (m, 1H) , 4.17 (m, 4H) , 3.81 (m, 2H) , 3.03 (m, 4H) , 2.22 (m, 2H) , 2.12-1.64 (m, 10H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -105.6, -146.2, -146.7; LC-MS: m/z = 572.1 [M+H] ⁺.

Compound 37: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( ( (S) -pyrrolidin-2-yl) methyl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 37)

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.08 (m, 2H) , 7.67-7.62 (m, 2H) , 7.46-7.44 (m, 1H) , 5.55-5.41 (m, 1H) , 4.77-4.46 (m, 5H) , 4.15-4.14 (m, 2H) , 4.08-3.61 (m, 6H) , 3.55-3.46 (m, 1H) , 3.42-3.33 (m, 2H) , 2.52-2.30 (m, 3H) , 2.27-2.02 (m, 6H) , 1.95-1.85 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.78, -146.84, -170.40; LC-MS: m/z=615.3 [M+H] ⁺

Compound 38: (1- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopropyl) methanol (Compound 38)

¹HNMR (400 MHz, DMSO-d₆) δ 8.23-8.16 (m, 2H) , 7.68-7.58 (m, 3H) , 5.41-5.22 (m, 1H) , 4.98-4.95 (m, 1H) , 4.50 (s, 2H) , 4.30-3.94 (m, 6H) , 3.25-2.78 (m, 5H) , 2.30-1.95 (m, 4H) , 1.95-1.73 (m, 2H) , 1.10-0.94 (m, 4H) ; ¹⁹FNMR (377 MHz, DMSO-d₆) δ -73.41, -105.79, -146.94.; LC-MS: m/z=602.3 [M+H] ⁺.

Compound 39: (S) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 39)

¹H NMR (400 MHz, DMSO-d₆) δ 8.22-8.14 (m, 2H) , 7.67-7.54 (m, 3H) , 5.59 (s, 1H) , 5.54-5.38 (m, 1H) , 4.63-4.55 (m, 1H) , 4.51-4.35 (m, 3H) , 4.25 (d, J = 14.0Hz, 1H) , 3.97-3.91 (m, 1H) , 3.83-3.76 (m, 2H) , 3.73-3.47 (m, 4H) , 3.39-3.35 (m, 1H) , 3.20-3.14 (m, 1H) , 2.47-2.41 (m, 1H) , 2.36-2.30 (m, 1H) , 2.26-1.86 (m, 4H) , 1.46 (t, J = 6.8, 3H) ; ¹⁹FNMR (377 MHz, DMSO-d₆) δ -105.77, -146.82, -172.34.

Compound 40: (1S, 2S) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopentan-1-ol (Compound 40)

¹HNMR (400 MHz, CD₃OD) δ 8.10-8.06 (m, 2H) , 7.64-7.62 (m, 2H) , 7.42 (t, J = 8.0 Hz, 1H) , 5.51-5.45 (m, 1H) , 5.41-5.28 (m, 1H) , 4.74-4.52 (m, 2H) , 4.39-4.33 (m, 3H) , 4.07-3.80 (m, 2H) , 3.61 (d, J = 8.0 Hz, 1H) , 3.51-3.34 (m, 3H) , 3.14-3.06 (m, 1H) , 2.43-2.28 (m, 2H) , 2.23-1.80 (m, 8H) , 1.78-1.66 (m, 2H) ; ¹⁹FNMR (377 MHz, CD₃OD) δ -105.70, -146.50, -172.53; LC-MS: m/z=615.3 [M+H] ⁺.

Compound 41: (1R, 3s) -3- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclobutan-1-ol (Compound 41)

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.16 (m, 2H) , 7.69-7.58 (m, 3H) , 5.43-5.29 (m, 1H) , 5.23-5.22 (m, 1H) , 4.74-4.66 (m, 1H) , 4.61-4.50 (m, 2H) , 4.37-3.85 (m, 5H) , 3.21-2.83 (m, 2H) , 2.72-2.63 (m, 2H) , 2.45-1.66 (m, 10H) ; ¹⁹FNMR (377 MHz, DMSO-d₆) δ -105.81, -146.72, -172.35; LC-MS: m/z=602.3 [M+H] ⁺.

Compound 42: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (R) -1-methylpyrrolidin-3-yl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 42)

¹HNMR (400 MHz, DMSO-d₆) δ 8.28-8.14 (m, 2H) , 7.75-7.57 (m, 3H) , 5.90-5.76 (m, 1H) , 5.53-5.39 (m, 1H) , 4.71-4.29 (m, 4H) , 4.21-4.07 (m, 2H) , 4.05-3.93 (m, 1H) , 3.69-3.48 (m, 4H) , 3.19-2.98 (m, 4H) , 2.89-2.66 (m, 3H) , 2.44-2.18 (m, 4H) , 2.13-1.89 (m, 4H) ; ¹⁹FNMR (377 MHz, DMSO-d₆) δ -105.70, -146.50, -172.53; LC-MS: m/z=615.3 [M+H] ⁺.

Compound 43: 2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13-tetraazanaphtho [1, 8-ab] heptalene (Compound 43)

¹H NMR (400 MHz, DMSO-d₆) δ 8.29 –8.12 (m, 2H) , 7.71 –7.56 (m, 3H) , 5.41 –5.15 (m, 1H) , 4.98 –4.80 (m, 1H) , 4.62 –4.36 (m, 2H) , 4.37–4.63 (m, 4H) , 3.13 –2.82 (m, 4H) , 2.20–1.95 (m, 5H) , 1.92–1.71 (m, 6H) , 1.69 –1.51 (m, 4H) ; ¹⁹F NMR (376 MHz, DMSO-d₆) δ -105.8 (d, J = 50.0 Hz) , -145.9 (s) , -172.1 (s) ; LC-MS: m/z = 600.1 [M+H] ⁺.

Compound 44: 2- ( (S) -9-ethyl-5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) ethan-1-ol (Compound 44)

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.09 (m, 2H) , 7.. 70-7.59 (m, 2H) , 7.47-7.41 (m, 1H) , 5.60-5.47 (m, 1H) , 4.81-4.80 (m, 1H) , 4.80-4.65 (m, 1H) , 4.59-4.47 (m, 3H) , 4.14-4.02 (m, 2H) , 4.00-3.75 (m, 4H) , 3.72-3.64 (m, 1H) , 3.58-3.48 (m, 1H) , 3.45-3.39 (m, 1H) , 2.71-2.54 (m, 2H) , 2.41-2.27 (m, 3H) , 2.19-2.07 (m, 1H) , 1.90–1.70 (m, 2H) , 1.13-1.08 (m, 3H) ; ¹⁹FNMR (377 MHz, CD₃OD) δ -106.74, -147.37, -174.16; LC-MS: m/z=604.3 [M+H] ⁺.

Compound 45 and Compound 46: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13-tetraazanaphtho [1, 8-ab] heptalene (Compound 45) and (R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13-tetraazanaphtho [1, 8-ab] heptalene (Compound 46)

Compound 45 and Compound 46 were obtained by SFC separation of Compound 43 on a column. Compound 45 was the first fraction and Compound 46 was the second fraction eluting from the column.

Compound 45: ¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H) , 8.27-8.12 (m, 2H) , 7.72-7.57 (m, 3H) , 5.55 (d, J = 54.4 Hz, 1H) , 4.99-4.85 (m, 1H) , 4.66-4.38 (m, 4H) , 4.27-3.54 (m, 6H) , 2.60-2.52 (m, 2H) , 2.31-1.16 (m, 13H) . ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.66, -146.45, -173.06. LC-MS: m/z = 600.5 [M+H] ⁺.

Compound 46: ¹H NMR (400 MHz, DMSO-d6) δ 8.23-8.16 (m, 2H) , 7.68-7.58 (m, 3H) , 5.28 (d, J =55.2 Hz, 1H) , 4.95-4.84 (m, 1H) , 4.61-4.39 (m, 2H) , 4.18-3.87 (m, 4H) , 3.26-3.19 (m, 1H) , 3.10-3.02 (m, 3H) , 2.87-2.79 (m, 1H) , 2.15-1.18 (m, 14H) . ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.77, -146.34, -172.12. LC-MS: m/z = 600.5 [M+H] ⁺.

Compound 47: 5-ethynyl-6-fluoro-4- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 12, 13-hexahydro-7, 11-dioxa-1, 3, 6, 13a-tetraazanaphtho [1, 8-ab] heptalen-5-yl) naphthalen-2-ol (Compound 47)

¹H NMR (400 MHz, CD₃OD) δ 7.85-7.82 (m, 1H) , 7.37-7.17 (m, 3H) , 5.47-5.33 (m, 1H) , 5.22-5.18 (m, 1H) , 4.75-4.65 (m, 1H) , 4.59-4.53 (m, 1H) , 4.45-4.37 (m, 2H) , 4.34-4.29 (m, 1H) , 4.02-3.89 (m, 3H) , 3.74-3.39 (m, 6H) , 3.23-3.17 (m, 1H) , 2.53-2.35 (m, 2H) , 2.28-2.22 (m, 1H) , 2.16-1.97 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -111.53, -145.94, -173.85; LC-MS: m/z = 618.3 [M+H] ⁺.

Compound 48: 5-ethynyl-6-fluoro-4- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8a, 9, 12, 13-tetrahydro-8H, 11H-7, 10-dioxa-1, 3, 6, 13a-tetraazanaphtho [1, 8-ab] heptalen-5-yl) naphthalen-2-ol (Compound 48)

¹H NMR (400 MHz, CD₃OD) δ 7.85-7.82 (m, 1H) , 7.33-7.16 (m, 3H) , 5.42-5.19 (m, 2H) , 4.75-4.70 (m, 1H) , 4.59-4.55 (m, 1H) , 4.41-4.31 (m, 3H) , 4.21-4.12 (m, 1H) , 4.02-3.93 (m, 1H) , 3.84-3.78 (m, 1H) , 3.69-3.35 (m, 6H) , 3.13-3.07 (m, 1H) , 2.46-2.28 (m, 2H) , 2.23-2.17 (m, 2H) , 2.09-2.02 (m, 2H) , 1.97-1.90 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -111.57, -145.63, -173.74; LC-MS: m/z = 618.2 [M+H] ⁺.

Compound 49: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49)

Step 1: Synthesis of tert-butyl (S) -4- (2-hydroxyethyl) -2, 2-dimethyloxazolidine-3-carboxylate (Compound 49-2)

To a solution of Compound 49-1 (10 g, 48.7 mmol) in anhydrous dichloromethane (100 mL) was added 2, 2-dimethoxypropane (25 g, 240 mmol) and catalytic amount of (1R) - (-) -10 camphor sulfonic acid (1.13 g, 4.87 mmol) , and the reaction mixture was stirred at 65℃ for 3 hours. Then, 10%citric acid (aq. ) (100 mL) was added and the reaction was stirred overnight. The reaction mixture was diluted with DCM (300 mL) , washed with brine (200 mL x3) , dried over Na₂SO₄ and concentrated to dryness. The residue was purified using silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 49-2 (4 g, 33.6%yield) as an off-white solid. LC-MS: m/z = 246.1 [M+H] ⁺.

Step 2: Synthesis of tert-butyl (S) -2, 2-dimethyl-4- (2- ( (methylsulfonyl) oxy) ethyl) oxazolidine-3-carboxylate (Compound 49-3)

To a solution of Compound 49-2 (2 g, 8.13 mmol) in DCM (50 mL) was added Hunig’s base (7 mL, 69 mmol) and MsCl (1.12g, 9.82 mmol) at 0 ℃, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (100 mL) , washed with brine (50 mL x3) , dried over Na₂SO₄, and concentrated to afford Compound 49-3 (1.8 g, 69.2%yield) as a yellow oil, which was directly used in the next step without further purification. LC-MS: m/z = 324.1 [M+H] ⁺. Step 3: Synthesis of tert-butyl (S) -4- (2- (5-formyl-3-methyl-1H-pyrazol-1-yl) ethyl) -2, 2-dimethyloxazolidine-3-carboxylate (Compound 49-4)

To a 50-mL round-bottomed flask, equipped with magnetic stirring was added a solution of Compound 49-3 (5.0 g, 15.5 mmol) in DMF (100 mL) followed by 3-methyl-1H-pyrazole-5-carbaldehyde (1.87 g, 17.05 mmol) and Cs₂CO₃ (10.1 g, 31.0 mmol) at room temperature. The mixture was stirred at 30℃ for 15 hours before diluting with EtOAc (100 mL) , washed with H₂O (50 mL x3) , dried over Na₂SO₄ and concentrated to dryness. The residue was purified by combi-flash (eluting with ethyl acetate in petroleum ether 0-25%) to afford Compound 49-4 (1.5 g, 28.6%yield) as a white solid. LC-MS: m/z = 338.2 [M+H] ⁺.

Step 4: Synthesis of (S) - (2-methyl-7, 8-dihydro-6H-pyrazolo [1, 5-a] [1, 4] diazepin-6-yl) methanol (Compound 49-5)

To a solution of Compound 49-4 (1.5 g, 4.45 mmol) in DCM (10 mL) was added TFA (4.88 g, 42.83 mmol, 3.3 mL) at 0℃, and the reaction was stirred at 20℃ for 2 hours. The reaction mixture was concentrated to afford Compound 49-5 (700 mg, 87.8%yield) , which was directly used in the next step without further purification. LC-MS: m/z = 180.2 [M+H] ⁺.

Step 5: Synthesis of (S) - (2-methyl-5, 6, 7, 8-tetrahydro-4H-pyrazolo [1, 5-a] [1, 4] diazepin-6-yl) methanol (Compound 49-6)

To a solution of Compound 49-5 (1.5 g, 8.37 mmol) in MeOH (20 mL) was added NaBH₃CN (1.05 g, 16.74 mmol) and the reaction was stirred at 20 ℃ for 15 hours. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC (HCO₂H) to afford Compound 49-6 (500 mg, 32.9%yield) as a white solid. LC-MS: m/z = 182.0 [M+H] ⁺.

Step 6: Synthesis of (S) -7-chloro-8-fluoro-5- ( (2-methyl-5, 6, 7, 8-tetrahydro-4H-pyrazolo [1, 5-a] [1, 4] diazepin-6-yl) methoxy) -2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Compound 49-7)

To a solution of Compound 49-6 (142.34 mg, 785.42 μmol) in THF (5 mL) at 0℃ was added NaH (114.23 mg, 2.86 mmol, 60%purity) and the mixture was stirred at 0℃ for 1 hour Before a solution of Intermediate 1 (200 mg, 714.02 μmol) in THF (0.5 mL) was added. The reaction was stirred at 15℃ for another 2 hours before quenched with Sat. aqueous NH₄Cl (20 mL) . It was extracted with ethyl acetate (20 mL x3) and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by combi-flash (eluting with methanol in DCM 0-10%) to afford Compound 49-7 (120 mg, 39.56%yield) as a white solid. LC-MS: m/z = 424.9 [M+H] ⁺.

Step 7: Synthesis of (S) -2-chloro-1-fluoro-9-methyl-13- (methylthio) -5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49-8)

To a solution of Compound 49-7 (120 mg, 282.43 μmol) in DCM (3 mL) at 0℃ was added 3- [chloro- (2-oxooxazolidin-3-yl) phosphoryl] oxazolidin-2-one (359.49 mg, 1.41 mmol) and Hunig’s base (360.96 mg, 2.82 mmol) , and the mixture was stirred at 15℃ for 2 hours. The reaction mixture was diluted with Sat. aqueous NH₄Cl (20 mL) and extracted with ethyl acetate (20 mL x3) . The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by Prep-TLC (eluting with methanol in DCM 0-10%) to afford Compound 49-8 (100 mg, 87.0%yield) as a white solid. LC-MS: m/z = 406.9 [M+H] ⁺.

Step 8: Synthesis of (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -9-methyl-13- (methylthio) -5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49-9)

To a solution of Compound 49-8 (20 mg, 49.16 μmol) and 3-b (44.48 mg, 98.31 μmol) in dioxane (0.8 mL) and H₂O (0.2 mL) were added APd G3 (7.16 mg, 9.83 μmol) and K₃PO₄ (31.26 mg, 147.47 μmol) , and the mixture (argon protected) was stirred at 120℃ for 1 hour under microwave irradiation. The reaction mixture was extracted with the mixed solvents of DCM/MeOH (v/v, 10/1, 10 mL x3) . The combined organic layers were dried and concentrated. The residue was purified by Prep-TLC (DCM/MeOH=10/1) to afford Compound 49-9 (20 mg, 57.1%yield) as a white solid. LC-MS: m/z = 697.1 [M+H] ⁺.

Step 9: Synthesis of (5aS) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -9-methyl-13- (methylsulfinyl) -5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49-10)

To a solution of Compound 49-9 (30 mg, 43.05 μmol) in DCM (0.5 mL) was added 3-chloroperoxybenzoic acid (7.43 mg, 43.05 μmol) and the reaction was stirred at 0℃ for 0.5 hour. The reaction solution was washed with Sat. aq. Na₂SO₃ (5 mL x3) , dried over Na₂SO₄, and concentrated to afford Compound 49-10, which was directly used in the next step without further purification. LC-MS: m/z = 713.2 [M+H] ⁺.

Step 10: Synthesis of (S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49-11)

To a solution of 4-a (33.50 mg, 210.40 μmol) in toluene (1 mL) was added sodium tert-butoxide (20.22 mg, 210.40 μmol) . The reaction was stirred at 0℃ for 10 min before addition of Compound 49-10 (30 mg, 42.08 μmol) . The mixture was stirred at 25℃ for another 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x3) . The organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluting with MeOH in DCM 0-5%) to afford Compound 49-11 (20 mg, 58.8%yield) as a white solid. LC-MS: m/z = 808.4 [M+H] ⁺.

Step 11: Synthesis of (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene (Compound 49)

A mixture of Compound 49-11 (15 mg, 18.20 μmol) and CsF (27.65 mg, 182.03 μmol) in DMF (0.9 mL) mixture was stirred at 75 ℃ for 1 hour. The reaction mixture was directly purified by Prep-HPLC (HCOOH) to afford Compound 49 (1.74 mg, 14.7%yield) . ¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 0.42 formate) , 8.14-7.98 (m, 2H) , 7.70-7.53 (m, 2H) , 7.42 (td, J = 9.2, 5.6 Hz, 1H) , 6.27-6.05 (m, 2H) , 5.39 (d, J = 54.0 Hz, 1H) , 4.76 (dd, J = 8.4, 4.4 Hz, 1H) , 4.58 (d, J = 13.2 Hz, 2H) , 4.52 (d, J = 4.8 Hz, 2H) , 4.48-4.38 (m, 4H) , 3.55-3.36 (m, 3H) , 3.16 (s, 1H) , 2.49-2.27 (m, 3H) , 2.27-2.20 (m, 1H) , 2.17 (d, J = 9.6 Hz, 3H) , 2.11 (s, 3H) , 2.01 (d, J = 19.6 Hz, 1H) ; ¹⁹F NMR (376 MHz, CD₃OD) δ -106.84, -145.49, -173.74; LC-MS: m/z = 652.2 [M+H] ⁺.

Compound 50: (S) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -N, N-dimethyl-5, 5a, 6, 7-tetrahydro-11H-4-oxa-3, 7a, 8, 11a, 12, 14-hexaazacyclopenta [i] naphtho [1, 8-ab] heptalene-9-carboxamide (Compound 50)

Compound 50 was synthesized by following the procedures of Compound 49 described above. ¹H NMR (400 MHz, CD₃OD) δ 8.02-7.91 (m, 2H) , 7.57-7.42 (m, 2H) , 7.31 (td, J = 8.8, 7.2 Hz, 1H) , 6.63 (d, J = 7.6 Hz, 1H) , 6.19 (t, J = 15.6 Hz, 1H) , 5.23 (d, J = 54.0 Hz, 1H) , 4.73-4.53 (m, 4H) , 4.53-4.45 (m, 1H) , 4.39 (dd, J = 15.2, 7.2 Hz, 2H) , 4.26 (d, J = 1.6 Hz, 2H) , 3.49 (s, 1H) , 3.22 (d, J = 5.2 Hz, 3H) , 3.21 (d, J = 1.6 Hz, 2H) , 2.97 (t, J = 7.2 Hz, 4H) , 2.33-2.14 (m, 3H) , 2.12-1.88 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.8, -145.4, -173.6; LC-MS: m/z = 709.0 [M+H] ⁺.

Compound 51: 2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 6a, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13-tetraazabenzo [4, 5] cycloocta [1, 2, 3-de] naphthalene (Compound 51)

¹H NMR (400 MHz, DMSO-d6) δ 8.25-8.15 (m, 2H) , 7.73-7.53 (m, 3H) , 5.62-5.44 (m, 1H) , 5.22-5.11 (m, 1H) , 4.63-4.40 (m, 3H) , 4.17-3.97 (m, 3H) , 3.71 (br, 3H) , 3.26-3.08 (m, 2H) , 2.47-2.38 (m, 2H) , 2.32-2.22 (m, 1H) , 2.20-2.07 (m, 2H) , 2.05-1.89 (m, 3H) , 1.88-1.81 (m, 1H) , 1.75-1.62 (m, 3H) , 1.55-1.44 (m, 1H) , 1.34-1.25 (m, 1H) ; 19F NMR (377 MHz, DMSO-d6) δ -105.56, -149.08, -172.79; LC-MS: m/z =600.3 [M+H] ⁺.

Compound 52: (5aR, 6R) -rel-2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-6-ol (Compound 52)

¹H NMR (400 MHz, DMSO-d6) δ 8.24-8.15 (m, 2H) , 7.68-7.54 (m, 3H) , 5.28 (d, J = 53.2 Hz, 1H) , 4.91 (d, J = 4.0 Hz, 2H) , 4.60 (d, J = 12.8 Hz, 1H) , 4.46 (d, J = 9.2 Hz, 1H) , 4.07 (d, J = 6.4 Hz, 3H) , 3.95 (s, 1H) , 3.10 (s, 2H) , 3.02 (s, 1H) , 2.84 (s, 1H) , 2.14 (s, 1H) , 2.02 (s, 1H) , 1.79 (d, J = 12.0 Hz, 4H) , 1.57 (d, J = 12.8 Hz, 1H) , 0.85 (s, 4H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -105.75, 145.22, -172.12; LC-MS: m/z = 602.0 [M+H] ⁺.

Compound 53: (5aS, 8R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-8-amine (Compound 53)

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 0.78H, formate) , 8.09 (dd, J = 8.4, 5.2 Hz, 2H) , 7.61 (dd, J =14.0, 6.4 Hz, 2H) , 7.43 (t, J = 8.8 Hz, 1H) , 5.48 (s, 1H) , 5.34 (d, J = 53.2 Hz, 1H) , 4.57 (dt, J = 13.6, 10.8 Hz, 2H) , 4.33 (ddd, J = 30.8, 10.8, 6.0 Hz, 2H) , 3.97 (s, 1H) , 3.55 (d, J = 7.6 Hz, 1H) , 3.48-3.34 (m, 2H) , 3.20-3.06 (m, 2H) , 2.96 (t, J = 11.6 Hz, 1H) , 2.45-2.15 (m, 4H) , 2.04 (d, J = 12.0 Hz, 3H) , 1.97-1.64 (m, 3H) , 1.29 (s, 1H) ; ¹⁹F NMR (376 MHz, CD₃OD) δ -106.87, -145.18, -173.87; LC-MS: m/z = 601.1 [M+H] ⁺.

Compound 54: (5aS, 7R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-7-ol (Compound 54)

¹H NMR (400 MHz, CDCl₃) δ 7.94-7.86 (m, 2H) , 7.65-7.52 (m, 2H) , 7.29-7.26 (m, 1H) , 5.38-5.25 (m, 2H) , 4.52-4.45 (m, 1H) , 4.42-4.36 (m, 1H) , 4.36-4.31 (m, 2H) , 4.09-4.02 (m, 1H) , 3.89-3.76 (m, 1H) , 3.45-3.34 (m, 1H) , 3.35-3.13 (m, 2H) , 3.05-2.93 (m, 3H) , 2.34-2.27 (m, 2H) , 2.23-2.15 (m, 3H) , 1.83-1.52 (m, 5H) ; ¹⁹F NMR (377 MHz, CDCl₃) δ -105.02, -142.89, -172.92; LC-MS: m/z = 602.3 [M+H] ⁺.

Compound 55: (5aS, 7R) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-7-ol (Compound 55)

¹H NMR (400 MHz, CD₃OD) δ 7.87-7.80 (m, 1H) , 7.36-7.27 (m, 2H) , 7.22 (d, J = 16.4 Hz, 1H) , 5.47-5.28 (m, 2H) , 4.63-4.48 (m, 2H) , 4.46-4.38 (m, 1H) , 4.38-4.29 (m, 1H) , 4.09-3.94 (m, 2H) , 3.59-3.36 (m, 4H) , 3.20-3.04 (m, 2H) , 2.49-2.28 (m, 2H) , 2.26-2.17 (m, 2H) , 2.13-2.04 (m, 3H) , 2.01-1.89 (m, 1H) , 1.73-1.60 (m, 1H) , 1.56-1.45 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -111.64, -145.40, -173.84; LC-MS:m/z = 618.2 [M+H] ⁺.

Compound 56: (2aR, 5aR, 13aS) -rel-10- (8-ethynyl-7-fluoronaphthalen-1-yl) -9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 2a, 3, 4, 5, 5a, 13, 13a-octahydro-1H-12-oxa-3, 5b, 6, 8, 11-pentaazaindeno [4', 5': 4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 56)

¹H NMR (400 MHz, CD₃OD) δ 8.11-8.08 (m, 2H) , 7.66-7.58 (m, 2H) , 7.46-7.41 (m, 1H) , 5.63-5.53 (m, 1H) , 5.46-5.33 (m, 1H) , 4.63-4.60 (m, 1H) , 4.53-4.34 (m, 3H) , 4.09-3.96 (m, 2H) , 3.70-3.42 (m, 4H) , 3.24-3.15 (m, 2H) , 2.94-2.86 (m, 1H) , 2.46-1.95 (m, 11H) , 1.60 (s, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.87, -147.11, -173.97; LC-MS: m/z = 627.3 [M+H] ⁺.

Compound 57: (2R, 11aS) -8- (8-ethynyl-7-fluoronaphthalen-1-yl) -7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 3, 11, 11a-tetrahydro-1H-10-oxa-3a, 4, 6, 9-tetraazanaphtho [1, 8-ef] azulen-2-ol (Compound 57)

¹H NMR (400 MHz, DMSO-d6) δ 8.19-8.09 (m, 2H) , 7.66-7.51 (m, 3H) , 7.23 (d, J = 17.6 Hz, 1H) , 5.28 (d, J = 54.8 Hz, 1H) , 4.95 (s, 1H) , 4.11 (d, J = 10.4 Hz, 1H) , 4.02 (s, 1H) , 3.95 (d, J = 34.0 Hz, 1H) , 3.76 (s, 1H) , 3.41 (d, J = 32.8 Hz, 2H) , 3.04 (dd, J = 28.4, 13.2 Hz, 4H) , 2.85 (t, J = 7.6 Hz, 1H) , 2.20-1.98 (m, 3H) , 1.91-1.66 (m, 8H) , 1.52 (s, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -106.01, -153.11, -172.13. LC-MS:m/z = 588.2 [M+H] ⁺.

Compound 58: (5aS, 6aR, 7aR) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-9- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 6a, 7, 7a-hexahydro-4-oxa-3, 7b, 8, 10-tetraazacyclopropa [a] naphtho [1, 8-gh] azulene (Compound 58)

¹H NMR (400 MHz, DMSO-d6) δ 8.24-8.13 (m, 2H) , 7.70-7.53 (m, 3H) , 5.44-5.19 (m, 1H) , 4.64-4.54 (m, 2H) , 4.23-4.10 (m, 3H) , 4.06-3.85 (m, 2H) , 5.30-3.27 (m, 1H) , 3.17-2.98 (m, 3H) , 2.92-2.73 (m, 1H) , 2.30-2.11 (m, 1H) , 2.03-1.94 (m, 3H) , 1.85-1.75 (m, 2H) , 1.70-1.41 (m, 2H) , 0.98-0.89 (m, 2H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.82, -145.91, -172.20; LC-MS: m/z = 584.4 [M+H] ⁺.

Compound 59: 8- (8-ethynyl-7-fluoronaphthalen-1-yl) -7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 3, 11, 11a-tetrahydro-1H-10-oxa-3a, 4, 6, 9-tetraaza-1, 3-methanonaphtho [1, 8-ef] azulene (Compound 59)

¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.15 (m, 2H) , 7.73-7.55 (m, 3H) , 5.52 (d, J = 53.6, 1H) , 5.44-5.36 (m, 1H) , 4.92-4.75 (m, 1H) , 4.53 (s, 2H) , 4.43-4.31 (m, 1H) , 4.31-4.08 (m, 2H) , 3.69 (s, 3H) , 3.22 (s, 1H) , 3.05 (s, 1H) , 2.43-1.97 (m, 8H) , 1.77-1.59 (m, 2H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.72, -146.86, -172.56; LC-MS: m/z = 584.3 [M+H] ⁺.

Compound 60: ( (2R, 10aS) -rel-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6-fluoro-4- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 10, 10a-tetrahydro-9-oxa-2a, 3, 5, 8-tetraazacyclobuta [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) methanol (Compound 60)

¹H NMR (400 MHz, DMSO-d6) δ 8.27-8.12 (m, 2H) , 7.72-7.53 (m, 3H) , 5.34-5.12 (m, 2H) , 4.80-4.70 (m, 2H) , 4.67-4.23 (m, 3H) , 4.19-3.92 (m, 3H) , 3.71-3.50 (m, 1H) , 3.10-3.01 (m, 3H) , 2.86-2.82 (m, 1H) , 2.59-2.54 (m, 1H) , 2.33-2.25 (m, 1H) , 2.16-1.91 (m, 3H) , 1.90-1.66 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.80, -147.02, -172.05; LC-MS: m/z = 588.5 [M+H] ⁺.

Compound 61 and Compound 62: ( (2S, 10aR) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6-fluoro-4- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 10, 10a-tetrahydro-9-oxa-2a, 3, 5, 8-tetraazacyclobuta [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) methanol (Compound 61) and ( (2R, 10aS) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -6-fluoro-4- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 10, 10a-tetrahydro-9-oxa-2a, 3, 5, 8-tetraazacyclobuta [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) methanol (Compound 62)

Compound 61 and Compound 62 were obtained by SFC separation of Compound 60 on a column. Compound 61 was the first fraction and Compound 62 was the second fraction eluting from the column.

Compound 61: ¹H NMR (400 MHz, DMSO-d6) δ 8.24-8.13 (m, 2H) , 7.70-7.54 (m, 3H) , 5.27 (d, J =55.4 Hz, 2H) , 4.78-4.72 (m, 2H) , 4.65-4.29 (m, 3H) , 4.19-3.93 (m, 3H) , 3.66-3.55 (m, 1H) , 3.09-3.01 (m, 3H) , 2.85-2.82 (m, 1H) , 2.61-2.52 (m, 1H) , 2.35-2.21 (m, 1H) , 2.12-1.94 (m, 3H) , 1.85-1.76 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.73, -146.76, -172.05; LC-MS: m/z = 588.5 [M+H] ⁺.

Compound 62: ¹H NMR (400 MHz, DMSO-d6) δ 8.24-8.14 (m, 3H) , 7.71-7.50 (m, 3H) , 5.38-5.04 (m, 2H) , 4.78-4.72 (m, 2H) , 4.64-4.57 (m, 1H) , 4.53-4.26 (m, 2H) , 4.18-3.92 (m, 3H) , 3.65-3.55 (m, 1H) , 3.17-3.01 (m, 3H) , 2.89-2.82 (m, 1H) , 2.60-2.52 (m, 1H) , 2.35-2.24 (m, 1H) , 2.13-1.97 (m, 3H) , 1.91- 1.69 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.77, -146.53, -172.10; LC-MS: m/z = 588.4 [M+H] ⁺.

Compound 63: 5-ethynyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-amine (Compound 63)

Step 1: Synthesis of 6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-ol (Compound 63-1)

To a solution of Compound 1-5 (230 mg, 0.28 mmol) in acetonitrile (6 mL) was added HCl/dioxane (3 mL, 4M) at 25 ℃. The resulting mixture was stirred at 25℃ for 2 hours. The reaction mixture was adjusted to pH = 8-9 with saturated aqueous sodium carbonate solution (50 mL) and extracted with DCM (50 mL x2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/10) to afford Compound 63-1 (185 mg, 85%yield) as a yellow solid. LC-MS: m/z = 758.4 [M+H] ⁺.

Step 2: Synthesis of 6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl trifluoromethanesulfonate (Compound 63-2)

To a solution of Compound 63-1 (165 mg, 0.21 mmol) in DCM (20 mL) at -60 ℃ under N₂ atmosphere was added Hunig’s base (87 mg, 0.67 mmol) and trifluoromethanesulfonic anhydride (96 mg, 0.34 mmol) . The mixture was stirred at -60 ℃ for 10 minutes. The mixture was diluted with DCM (100 mL) , washed with water (50 mL x3) and brine (100 mL) . The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/12) to afford Compound 63-2 (170 mg, 88%yield) as a yellow solid. LC-MS: m/z = 445.8 [M/2+H] ⁺.

Step 3: Synthesis of N- (6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl) -1, 1-diphenylmethanimine (Compound 63-3)

A mixture of Compound 63-2 (160 mg, 0.18 mmol) , diphenylmethanimine (72 mg, 0.39 mmol) , cesium carbonate (194 mg, 0.59 mmol) , 4, 5-bis (triphenylphosphines) -9, 9-dimethylxanthene (23 mg, 0.04 mmol) and tris (dibenzylideneacetone) dipalladium (18 mg, 0.02 mmol) in toluene (12 mL) was stirred at 100 ℃ for 2 hours under N₂ atmosphere. The mixture was diluted with ethyl acetate (150 mL) and washed with water (100 mL) and brine (100 mL) , successively. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/12) to afford Compound 63-3 (102 mg, 62%yield) as a yellow oil. LC-MS: m/z = 461.4 [M/2+H] ⁺.

Step 4: Synthesis of 6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-amine (Compound 63-4)

To a solution of Compound 63-3 (96 mg, 0.11 mmol) in acetonitrile (6 mL) was added HCl/dioxane (2 mL, 4M) at 25 ℃. The resulting solution was stirred at 25℃ for 2 hours. The reaction mixture was adjusted to pH = 8-9 with saturated aqueous sodium carbonate solution and extracted with DCM (50 mL x2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/10) to afford Compound 63-4 (31 mg, 39%yield) as a yellow solid. LC-MS: m/z = 379.3 [M/2+H] ⁺.

Step 5: Synthesis of 5-ethynyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-amine (Compound 63)

To a solution of Compound 63-4 (31 mg, 0.04 mmol) in N, N-dimethylformamide (5 mL) at 25℃ was added cesium fluoride (187 mg, 1.23 mmol) , and the mixture was stirred for 1 hour at the same temperature. The mixture was diluted with ethyl acetate (100 mL) , washed with water (100 mL x3) and brine (100 mL) , dried over Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/10) to afford Compound 63 (9 mg, 37%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (dd, J = 6.0, 9.2 Hz, 1H) , 7.33 (t, J = 9.2 Hz, 1H) , 7.03-6.98 (m, 2H) , 5.67-5.55 (m, 2H) , 5.39-5.25 (m, 1H) , 5.19-5.11 (m, 1H) , 4.52-4.38 (m, 2H) , 4.23-3.88 (m, 4H) , 3.27-3.00 (m, 4H) , 2.95-2.83 (m, 1H) , 2.24-2.01 (m, 3H) , 1.95-1.69 (m, 7H) , 1.63-1.44 (m, 2H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -113.35, -145.40, -172.31; LC-MS: m/z = 601.3 [M+H] ⁺.

Compound 64: Synthesis of 5-ethyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 64) .

Compound 64 was prepared from Compound 1 following the standard hydrogenation procedure. ¹H NMR (400 MHz, CD₃OD) δ 7.70-7.61 (m, 1H) , 7.33-7.19 (m, 2H) , 7.12-6.98 (m, 1H) , 5.42 (m, 2H) , 4.59-4.36 (m, 4H) , 4.05-3.92 (m, 1H) , 3.69-3.47 (m, 3H) , 3.26-3.19 (m, 1H) , 3.18-3.08 (m, 1H) , 2.59-2.21 (m, 5H) , 2.20-2.09 (m, 2H) , 2.07-1.91 (m, 2H) , 1.96-1.75 (m, 4H) , 1.69-1.56 (m, 1H) , 0.91-0.80 (m, 3H); ¹⁹F NMR (377 MHz, CD₃OD) δ -121.07, -144.94, 173.90; LC-MS: m/z = 606.3 [M+H] ⁺.

Compound 65: 5-ethynyl-6-fluoro-4- ( (S) -1, 8, 8-trifluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 65)

¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H) , 7.88-7.85 (m, 1H) , 7.35-7.31 (m, 2H) , 7.27-7.19 (m, 1H) , 5.68-5.59 (m, 1H) , 5.52-5.39 (m, 1H) , 4.71-4.62 (m, 2H) , 4.56-4.45 (m, 2H) , 4.11-4.10 (m, 1H) , 3.72-3.48 (m, 5H) , 3.29-3.22 (m, 1H) , 2.56-2.04 (m, 10H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -101.25, -106.94, -111.53, -145.27, -173.96. LC-MS: m/z = 638.2 [M+H] ⁺.

Compound 66: 5-ethynyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 8, 9-tetrahydro-5H-4, 7-dioxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 66)

¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (d, J = 2.4 Hz, 1H) , 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.47 (t, J = 9.2 Hz, 1H) , 7.39 (d, J = 2.4 Hz, 1H) , 7.18 (d, J = 2.4 Hz, 1H) , 5.46 (d, J = 52.4 Hz, 1H) , 5.01 (t, J = 14.0 Hz, 1H) , 4.61-4.27 (m, 3H) , 4.21-3.96 (m, 4H) , 3.73-3.41 (m, 5H) , 3.34-2.91 (m, 3H) , 2.41-1.92 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -110.65, -144.75, -172.56; LC-MS: m/z = 604.3 [M+H] ⁺.

Compound 67: 5-ethyl-6-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 8, 9-tetrahydro-5H-4, 7-dioxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) naphthalen-2-ol (Compound 67)

Compound 67 was prepared from Compound 66 following the standard hydrogenation procedure. ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H) , 7.75 (dd, J = 8.8, 6.0 Hz, 1H) , 7.38-7.32 (m, 2H) , 7.03 (s, 1H) , 5.38 (d, J = 53.6 Hz, 1H) , 4.99 (d, J = 13.2 Hz, 1H) , 4.58-4.47 (m, 2H) , 4.37-4.08 (m, 3H) , 4.09-3.98 (m, 2H) , 3.66-3.45 (m, 3H) , 3.32-3.20 (m, 3H) , 2.98 (s, 1H) , 2.39-2.09 (m, 5H) , 2.00-1.81 (m, 3H) , 0.80 (q, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -119.47, -144.04, -172.36; LC-MS: m/z = 608.3 [M+H] ⁺.

Compound 68: 4- (10-ethyl-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8H,10H-7-oxa-1, 3, 6, 10-tetraazaspiro [cyclohepta [de] naphthalene-9, 1'-cyclopropan] -1 (10a) , 2, 3a, 4, 6-pentaen-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 68)

¹H NMR (400 MHz, CD₃OD) δ 7.84 (dd, J = 9.2, 5.6 Hz, 1H) , 7.33-7.31 (m, 2H) , 7.22 (d, J = 2.4 Hz, 1H) , 5.36 (d, J = 52.8 Hz, 1H) , 4.69-4.65 (m, 1H) , 4.42-4.30 (m, 3H) , 4.15-4.10 (m, 1H) , 3.94-3.88 (m, 1H) , 3.50 (d, J = 3.6 Hz, 1H) , 3.48-3.36 (m, 3H) , 3.16-3.09 (m, 1H) , 2.46-1.92 (m, 7H) , 1.53-1.45 (m, 1H) , 1.33 (t, J = 7.2 Hz, 5H) , 1.22-1.61 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -111.76, -148.96, -173.83; LC-MS: m/z = 602.3 [M+H] ⁺.

Compound 69: ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-9-yl) methanamine (Compound 69)

LC-MS: m/z = 575.3 [M+H] ⁺.

Compound 70: ( (S) -10-ethyl-5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-9-yl) methanol (Compound 70)

¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.14 (m, 2H) , 7.80-7.55 (m, 3H) , 5.48 (d, J = 52.8 Hz, 1H) , 5.24 (d, J = 5.6 Hz, 1H) , 4.86-4.70 (m, 1H) , 4.68-3.94 (m, 6H) , 3.79-3.40 (m, 6H) , 3.14 (br, 1H) , 2.46-1.81 (m, 6H) , 1.35-1.27 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.74, -146.77, -172.54; LC-MS: m/z =590.3 [M+H] ⁺.

Compound 71: 1- ( (R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-9-yl) ethan-1-ol (Compound 71)

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.14 (m, 2H) , 7.71-7.56 (m, 3H) , 5.59-5.28 (m, 1H) , 5.20-4.99 (m, 1H) , 4.93-4.64 (m, 1H) , 4.48-3.94 (m, 4H) , 3.91-3.76 (m, 1H) , 3.70-3.37 (m, 7H) , 3.16-2.90 (m, 1H) , 2.44-2.10 (m, 3H) , 2.05-1.78 (m, 3H) , 1.28-1.15 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.66, -147.15, -172.50; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 72: (R) -2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 72)

Step 1: Synthesis of (S) -1- ( (tert-butyldimethylsilyl) oxy) propan-2-ol (Compound 72-1)

To a solution of (S) -propane-1, 2-diol (CAS: 4254-15-3, 5.0 g, 65.7 mmol) in dichloromethane (30 mL) at 25 ℃ was added imidazole (5.4 g, 78.8 mmol) and tert-butyldimethylsilyl chloride (9.9 g, 65.7 mmol) . The mixture was stirred at 25 ℃ for 2 hours. The mixture was diluted with dichloromethane (50 mL) , washed with water (20 mL x2) and brine (20 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to afford Compound 72-1 (9.5 g, 76.0%yield) as an off-yellow oil.

Step 2: Synthesis of (S) -1- ( (tert-butyldimethylsilyl) oxy) propan-2-yl methanesulfonate (Compound 72-2)

To a solution of Compound 72-1 (3.0 g, 15.7 mmol) and DIPEA (4.1 g, 31.5 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (2.7 g, 23.64 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes before diluted with dichloromethane (50 mL) . It was washed with water (20 mL x2) and brine (20 mL) . The separated organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 72-2 (4.2 g, 100%yield) as a yellow oil.

Step 3: Synthesis of (S) -2- ( ( (R) -1- ( (tert-butyldimethylsilyl) oxy) propan-2-yl) amino) propan-1-ol (Compound 72-3)

A mixture of Compound 72-2 (4.2 g, 15.76 mmol) and (S) -2-aminopropan-1-ol (CAS: 2749-11-3, 10 mL) was stirred at 80 ℃ for 16 hours. The reaction mixture was cooled and diluted with brine (50 mL) , extracted with ethyl acetate (20 mL x3) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to afford Compound 72-3 (3.8 g, 97.4%yield) as an off-yellow oil. LC-MS: m/z = 248.3 [M+H] ⁺.

Step 4 ～ Step 9: From the synthesis of 5- ( (S) -2- ( ( (R) -1- ( (tert-butyldimethylsilyl) oxy) propan-2-yl) amino) propoxy) -7-chloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (Compound 72-4) to the synthesis of (R) -2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 72)

These steps followed the procedures described in the synthesis of Compound 1. ¹H NMR (400 MHz, CD₃OD) δ 8.11-8.06 (m, 2H) , 7.70-7.59 (m, 2H) , 7.46-7.40 (m, 1H) , 5.80-5.48 (m, 1H) , 5.46-5.30 (m, 1H) , 4.69-4.63 (m, 1H) , 4.48-4.29 (m, 4H) , 3.99-3.87 (m, 1H) , 3.79-3.74 (m, 1H) , 3.63-3.36 (m, 4H) , 3.20-3.12 (m, 1H) , 2.50-2.30 (m, 2H) , 2.26-2.20 (m, 1H) , 2.14-2.06 (m, 2H) , 2.01-1.92 (m, 1H) , 1.40-1.31 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -108.43, -149.02, -175.42; LC-MS: m/z = 604.3 [M+H] ⁺.

Compound 73: (R) -2- ( (S) -5- (8-ethyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 73)

Compound 73 was prepared from Compound 72 following the standard hydrogenation procedure. ¹H NMR (400 MHz, CD₃OD) δ 8.06-8.01 (m, 1H) , 7.93-7.88 (m, 1H) , 7.57-7.42 (m, 2H) , 7.38-7.32 (m, 1H) , 5.59 (br, 1H) , 5.45-5.29 (m, 1H) , 4.69-4.63 (m, 1H) , 4.45-4.36 (m, 3H) , 4.31-4.27 (m, 1H) , 3.99-3.88 (m, 1H) , 3.79-3.73 (m, 1H) , 3.53-3.35 (m, 3H) , 3.16-3.09 (m, 1H) , 2.68-2.43 (m, 2H) , 2.41-2.29 (m, 2H) , 2.24-2.18 (m, 1H) , 2.12-2.04 (m, 2H) , 2.01-1.93 (m, 1H) , 1.38-1.32 (m, 6H) , 0.93-0.86 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -116.29, -146.63, -173.81; LC-MS: m/z = 608.4 [M+H] ⁺.

Compound 74: (S) -2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta- [de] naphthalen-10-yl) propan-1-ol (Compound 74)

Compound 74 was synthesized following the procedures described in the synthesis of Compound 72. ¹H NMR (400 MHz, CD₃OD) : δ 8.12-8.08 (m, 2H) , 7.69-7.60 (m, 2H) , 7.46-7.41 (m, 1H) , 5.72-5.62 (m, 1H) , 5.52-5.39 (m, 1H) , 4.70-4.64 (m, 1H) , 4.56-4.42 (m, 4H) , 3.88-3.55 (m, 6H) , 3.27-3.23 (m, 1H) , 2.61-2.40 (m, 2H) , 2.36-2.27 (m, 1H) , 2.24-2.17 (m, 2H) , 2.09-1.99 (m, 1H) , 1.41-1.31 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -106.83, -147.60, -174.05; LC-MS: m/z = 604.3 [M+H] ⁺.

Compound 75: 2- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetonitrile (Compound 75)

¹H NMR (400 MHz, CD₃OD) : δ 8.04-7.95 (m, 2H) , 7.63-7.47 (m, 2H) , 7.38-7.27 (m, 1H) , 5.32-5.13 (m, 1H) , 4.82 (d, J = 3.6 Hz, 1H) , 4.72 (d, J = 16.8 Hz, 1H) , 4.61-4.54 (m, 1H) , 4.45 (t, J = 15.6 Hz, 1H) , 4.33 (s, 2H) , 4.25-4.17 (m, 1H) , 3.54-3.43 (m, 1H) , 3.32-3.24 (m, 1H) , 3.18-3.09 (m, 2H) , 3.00-2.92 (m, 1H) , 2.31-2.05 (m, 3H) , 1.97-1.77 (m, 3H) , 1.38 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -106.65, -145.84, -173.64; LC-MS: m/z = 585.2 [M+H] ⁺.

Compound 76: 4- ( (5S, 9R) -8, 10-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 76)

¹H NMR (400 MHz, CD₃OD) δ 7.85 (m, 1H) , 7.36-7.28 (m, 2H) , 7.13 (d, J = 2.8 Hz, 1H) , 5.66-5.56 (s, 1H) , 5.45-5.32 (m, 1H) , 4.68-4.64 (m, 1H) , 4.45-4.30 (m, 4H) , 3.85-3.75 (m, 2H) , 3.61-3.45 (m, 3H) , 3.37-3.34 (m, 1H) , 3.24-3.16 (m, 1H) , 2.53-2.35 (m, 2H) , 2.28-2.08 (m, 4H) , 1.38 (d, J = 6.8 Hz, 3H) , 1.34 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -111.41, -138.10, -139.95, -174.08; LC-MS: m/z = 637.3 [M+H] ⁺.

Compound 77: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( ( (S) -pyrrolidin-2-yl) methyl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 77)

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.08 (m, 2H) , 7.70-7.56 (m, 2H) , 7.47-7.41 (m, 1H) , 5.38-5.25 (m, 1H) , 4.67-4.61 (m, 1H) , 4.54-4.48 (m, 1H) , 4.44-4.34 (m, 2H) , 4.30-4.20 (m, 1H) , 3.99-3.84 (m, 2H) , 3.64-3.58 (m, 1H) , 3.55-3.50 (m, 1H) , 3.43-3.33 (m, 4H) , 3.25-3.06 (m, 2H) , 2.64-2.51 (m, 1H) , 2.49-2.29 (m, 2H) , 2.25-2.17 (m, 2H) , 2.12-2.00 (m, 2H) , 1.98-1.83 (m, 1H) , 1.45-1.43 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.83, -145.83, -173.53; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 78: (1- ( (S) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopropyl) methanol (Compound 78)

¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.11 (m, 2H) , 7.76-7.50 (m, 3H) , 5.43-5.18 (m, 1H) , 5.00 (s, 1H) , 4.65-3.94 (m, 7H) , 3.31-2.80 (m, 5H) , 2.23-1.97 (m, 3H) , 1.94-1.69 (m, 3H) , 1.23 (s, 3H) , 1.20-1.10 (m, 2H) , 1.09-0.96 (m, 2H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.70, -147.89, -172.02; LC-MS: m/z =616.3 [M+H] ⁺.

Compound 79: 4- ( (S) -10-ethyl-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 79)

¹H NMR (400 MHz, CD₃OD) : δ 7.87-7.80 (m, 1H) , 7.35-7.28 (m, 2H) , 7.26-7.13 (m, 1H) , 5.47-5.33 (m, 1H) , 4.69-4.60 (m, 1H) , 4.50-4.44 (m, 1H) , 4.42-4.14 (m, 4H) , 3.67-3.41 (m, 5H) , 3.24-3.14 (m, 1H) , 2.54-2.33 (m, 2H) , 2.24-1.97 (m, 4H) , 1.44-1.36 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -111.70, -146.98, -173.87; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 80: 10- ( (1S, 2R, 4R) -rel-7-azabicyclo [2.2.1] heptan-2-yl) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1,3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 80)

LC-MS: m/z = 627.3 [M+H] ⁺.

Compound 81: (1R, 2R) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) -N-methylcyclopentan-1-amine (Compound 81)

¹H NMR (400 MHz, CD₃OD) δ 8.11 (m, 2H) , 7.68-7.59 (m, 2H) , 7.45-7.41 (t, J = 8.8 Hz, 1H) , 5.90-5.46 (m, 1H) , 4.77-4.22 (m, 5H) , 4.07-3.89 (m, 2H) , 3.81-3.48 (m, 5H) , 3.26-3.17 (m, 1H) , 2.74-2.72 (d, J =4.4 Hz, 3H) , 2.53-2.26 (m, 3H) , 2.24-2.12 (m, 3H) , 2.09-1.85 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -108.34, -148.64, -175.67; LC-MS: m/z = 629.4 [M+H] ⁺.

Compound 82: (1R, 2R) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopentan-1-amine (Compound 82)

¹H NMR (400 MHz, CD₃OD) δ 8.11-8.08 (m, 2H) , 7.66-7.60 (m, 2H) , 7.46-7.41 (m, 1H) , 5.79-5.73 (m, 1H) , 5.52-5.37 (m, 1H) , 4.77-4.46 (m, 4H) , 4.07-3.46 (m, 8H) , 2.63-2.43 (m, 2H) , 2.35-2.27 (m, 2H) , 2.24-1.95 (m, 8H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.82, -147.24, -174.31; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 83: Synthesis of N- ( (1R, 2R) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2-( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopentyl) -2, 2, 2-trifluoroacetamide (Compound 83)

To a solution of Compound 82-4 (56 mg, 0.0783 mmol) in 1, 4-dioxane (2 mL) was added trifluoroacetic acid (4 mL) . The mixture was stirred at 35 ℃ for 2 hours. The mixture was partitioned between DCM (80 mL) and saturated sodium carbonate solution (30 mL) . The organic layer was washed with brine (30 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by Prep-TLC (MeOH/DCM = 1/8) to afford Compound 83 (15.2 mg, 27%yield) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.10-8.07 (m, 2H) , 7.67-7.62 (m, 2H) , 7.47-7.41 (m, 1H) , 5.97-5.70 (m, 1H) , 5.47-5.34 (m, 1H) , 4.83-4.60 (m, 2H) , 4.52-4.37 (m, 3H) , 4.18-4.06 (m, 1H) , 3.96-3.90 (m, 1H) , 3.67-3.48 (m, 4H) , 3.24-3.18 (m, 1H) , 2.48-2.42 (m, 1H) , 2.35-2.25 (m, 2H) , 2.19-2.13 (m, 3H) , 2.03-1.91 (m, 6H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -77.10, -106.76, -147.84, -174.02. LC-MS: m/z = 711.3 [M+H] ⁺.

Compound 84: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- (3-methylpyrrolidin-3-yl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 84)

¹H NMR (400 MHz, DMSO-d₆) : δ 8.24-8.18 (m, 2H) , 7.70-7.59 (m, 3H) , 5.64-5.51 (m, 1H) , 4.73-4.50 (m, 4H) , 4.29-4.24 (m, 1H) , 4.15-4.01 (m, 2H) , 3.94-3.69 (m, 4H) , 3.59-3.55 (m, 1H) , 3.47-3.44 (m, 1H) , 3.29-3.17 (m, 3H) , 2.45-2.33 (m, 4H) , 2.21-1.96 (m, 4H) , 1.68 (s, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ-105.62, -146.01, -172.30; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 85: (1S, 3r) -3- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclobutan-1-ol (Compound 85)

¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.15 (m, 2H) , 7.69-7.58 (m, 3H) , 5.63-5.38 (m, 2H) , 5.20 (d, J =4.0 Hz, 1H) , 4.65-4.34 (m, 4H) , 4.35-4.27 (m, 1H) , 4.16 (s, 1H) , 4.05-3.99 (m, 1H) , 3.90-3.85 (m, 1H) , 3.61 (s, 3H) , 3.23-3.15 (m, 1H) , 2.46-1.90 (m, 10H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -73.44, -105.72, -146.70; LC-MS: m/z = 602.3 [M+H] ⁺.

Compound 86: 3- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) bicyclo [1.1.1] pentan-1-amine (Compound 86)

¹H NMR (400 MHz, CD₃OD) δ 8.16-8.04 (m, 2H) , 7.70-7.58 (m, 2H) , 7.49-7.40 (t, J = 8.8 Hz, 1H) , 5.68-5.46 (m, 1H) , 4.86-4.60 (m, 4H) , 4.12-3.81 (m, 5H) , 3.66-3.59 (m, 1H) , 3.50-3.40 (m, 1H) , 2.77 (s, 6H) , 2.67-2.55 (m, 1H) , 2.52-2.44 (m, 1H) , 2.20-2.49 (m, 2H) , 2.24-2.15 (m, 1H) , 1.66-1.5 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -106.79, -147.23, -174.25; LC-MS: m/z = 613.3 [M+H] ⁺.

Compound 87: 10-cyclobutyl-5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 87)

¹H NMR (400 MHz, DMSO-d6) δ 8.23-8.14 (m, 2H) , 7.74-7.46 (m, 2H) 3H) , 5.40-5.10 (m, 2H) , 4.64-4.37 (m, 2H) , 4.24-4.07 (m, 2H) , 4.08-3.96 (m, 2H) , 3.91-3.82 (m, 1H) , 3.15-3.00 (m, 3H) , 2.88-2.79 (m, 1H) , 2.35-2.17 (m, 4H) , 2.17-2.10 (m, 1H) , 2.08-1.94 (m, 2H) , 1.90-1.65 (m, 5H) . ¹⁹F NMR (376 MHz, DMSO-d6) δ -105.84, -146.82, -172.04. LC-MS: m/z = 586.5 [M+H] ⁺.

Compound 88: 10-cyclopropyl-5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 88)

¹H NMR (400 MHz, DMSO-d6) δ 8.27-8.11 (m, 2H) , 7.70-7.55 (m, 3H) , 5.29 (d, J = 55.2 Hz, 1H) , 4.52 (s, 2H) , 4.21-4.13 (m, 1H) , 4.11-4.02 (m, 1H) , 4.01-3.87 (m, 2H) , 3.07-3.17 (m, 3H) , 3.02 (s, 1H) , 2.78-2.91 (m, 2H) , 2.14 (s, 1H) , 2.06-1.96 (m, 2H) , 1.89-1.74 (m, 3H) , 0.95 (d, J = 7.2 Hz, 2H) , 0.87-0.76 (m, 2H) . ¹⁹F NMR (377 MHz, DMSO-d6) δ -105.80, -146.63, -172.02. LC-MS: m/z = 571.8 [M+H] ⁺.

Compound 89: (R) -2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propan-1-ol (Compound 89)

¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.13 (m, 2H) , 7.61 (t, J = 6.8, 1H) , 7.63-7.58 (m, 2H) , 5.58-5.14 (m, 2H) , 4.97-4.85 (m, 1H) , 4.63-4.55 (m, 2H) , 4.43-3.96 (m, 3H) , 3.95-3.70 (m, 2H) , 3.68-3.54 (m, 2H) , 3.31-2.69 (m, 4H) , 2.28-1.74 (m, 6H) , 1.20 (dd, J = 6.8, 3.2 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.74, -146.70, -172.27; LC-MS: m/z = 590.3 [M+H] ⁺.

Compound 90: 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetamide (Compound 90)

Step 1: Synthesis of tert-butyl (2-hydroxyethyl) glycinate (Compound 90-1) .

A mixture of tert-butyl 2-bromoacetate (5.00 g, 25.63 mmol) , 2-aminoethan-1-ol (1.56 g, 25.63 mmol) and N, N-diisopropylethylamine (3.30 g, 25.63 mmol) in methanol (50 mL) was stirred at 80 ℃ for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was triturated with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to afford Compound 90-1 (3.1 g, about 30%product of crude) as a yellow oil, which was used in the next step without further purification.

Step 2: Synthesis of tert-butyl N- (5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) -N- (2-hydroxyethyl) glycinate (Compound 90-2) .

To a solution of Intermediate 2 (400 mg, 1.34 mmol) in dichloromethane (40 mL) at 0 ℃ under N₂ atmosphere was added N, N-diisopropylethylamine (864 mg, 6.70 mmol) and Compound 90-1 (2.3 g, 13.4 mmol) . The reaction mixture was stirred at 0 ℃ for 10 minutes, diluted with ethyl acetate (150 mL) , washed with water (150 mL) , 0.5 M HCl (100 mL) and brine (100 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 90-2 (540 mg, crude) as a black solid. It was used for next step without further purification. LC-MS: m/z = 437.1 [M+H] +.

Step 3: Synthesis of tert-butyl 2- (5-chloro-4-fluoro-2- (methylthio) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetate (Compound 90-3) .

A mixture of Compound 90-2 (540 mg, crude) , triethylenediamine (150 mg, 1.34 mmol) and cesium carbonate (1.3 g, 4.02 mmol) in N, N-dimethylformamide (8 mL) and tetrahydrofuran (8 mL) was stirred at 50 ℃ for 2 hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) , and washed with water (200 mL x3) and brine (100 mL) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to afford Compound 90-3 (303 mg, 56%yield of two steps) as a yellow solid.

Step 4: Synthesis of tert-butyl 2- (5-chloro-4-fluoro-2- (methylsulfinyl) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetate (Compound 90-4) .

To a solution of Compound 90-3 (303 mg, 0.756 mmol) in dichloromethane (20 mL) at 0 ℃under N₂ atmosphere was added 3-chloroperoxybenzoic acid (184 mg, 0.907 mmol, wt 85%) . The reaction mixture was stirred at 0 ℃ for 30 minutes. Then, it was diluted with ethyl acetate (150 mL) and washed with saturated aqueous NaHCO₃ (150 mL) , water (150 mL) and brine (100 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 90-4 (313 mg, crude) as a yellow solid. It was used for next step without further purification.

Step 5: Synthesis of tert-butyl 2- (5-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetate (Compound 90-5) .

To a solution of Compound 90-4 (310 mg, crude) and 4-a (240 mg, 1.512 mmol) in toluene (10 mL) at 0 ℃ under N2 atmosphere was added sodium tert-butoxide (145 mg, 1.512 mmol) . The mixture was stirred at 0 ℃ for 30 minutes and quenched with water (150 mL) . Then, it was extracted with ethyl acetate (150 mL x2) . The combined organic layers were washed with brine (100 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH =40/1) to afford Compound 90-5 (133 mg, 34%yield of two steps) as a yellow solid. LC-MS: m/z = 512.2 [M+H] +.

Step 6: Synthesis of 2- (5-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetic acid (Compound 90-6) .

To a solution of Compound 90-5 (133 mg, 0.260 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL) at 25 ℃. The resulting solution was stirred at 25 ℃ for 4 hours. The reaction mixture was concentrated to afford Compound 90-6 (170 mg, crude) as a yellow oil, which was used in the next step without further purification. LC-MS: m/z = 456.2 [M+H] +.

Step 7: Synthesis of 2- (5-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetamide (Compound 90-7) .

To a solution of Compound 90-6 (170 mg, crude) in N, N-dimethylformamide (5 mL) at room temperature was added N, N-diisopropylethylamine (335 mg, 2.60 mmol) , ammonium chloride (70 mg, 1.30 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluroniumhexafluorophosphate (494 mg, 1.30 mmol) . The mixture was stirred at room temperature for 3 hours, diluted with water (100 mL) , and extracted with ethyl acetate (150 mL x2) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) to afford Compound 90-7 (137 mg, crude) as a yellow solid, which was used in the next step without further purification. LC-MS: m/z = 455.2 [M+H] ⁺.

Step 8: Synthesis of 2- (4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetamide (Compound 90-8) .

A mixture of Compound 90-7 (137 mg, 0.301 mmol) , 3-b (204 mg, 0.452 mmol) , cesium carbonate (196 mg, 0.602 mmol) and methanesulfonato (2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1, 1'-biphenyl) (2'-amino-1, 1'-biphenyl-2-yl) palladium (II) (50 mg, 0.0602 mmol) in ethanol/water (10 mL/3 mL) was stirred at 90 ℃ for 1 hour under N₂ atmosphere. After cooled to room temperature, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x2) . The combined organic layers were washed with water (100 mL) and brine (100 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) to afford Compound 90-8 (92 mg, 47%yield of three steps) as a yellow solid. LC-MS: m/z = 745.4 [M+H] ⁺.

Step 9: Synthesis of 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) acetamide (Compound 90) .

To a solution of Compound 90-8 (92 mg, 0.124 mmol) in N, N-dimethylformamide (5 mL) was added cesium fluoride (563 mg, 3.70 mmol) . The mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate (100 mL) , washed with water (100 mL x3) and brine (100 mL) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 7/1) to afford Compound 90 (41mg, 56%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.12 (m, 2H) , 7.76-7.53 (m, 4H) , 7.22 (s, 1H) , 5.46-5.20 (m, 1H) , 4.69-4.51 (m, 3H) , 4.34 (dd, J = 16.4, 5.2 Hz, 1H) , 4.29-3.91 (m, 5H) , 3.28-2.80 (m, 4H) , 2.29-1.99 (m, 3H) , 1.97-1.71 (m, 3H); ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.72, -146.47, -172.10; LC-MS: m/z = 589.3 [M+H] ⁺.

Compound 91: 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) -N,N-dimethylacetamide (Compound 91)

Compound 91 was synthesized by following procedures described in the synthesis of Compound 90 with corresponding reagents. ¹H NMR (400 MHz, CD₃OD) δ 8.13-8.08 (m, 2H) , 7.65 (d, J = 5.2 Hz, 2H) , 7.44 (t, J = 7.6 Hz, 1H) , 5.41 (d, J = 53.2 Hz, 1H) , 5.00-4.94 (m, 1H) , 4.77-4.69 (m, 3H) , 4.45-4.30 (m, 2H) , 4.08-4.03 (m, 2H) , 3.62-3.49 (m, 4H) , 3.20 (s, 4H) , 3.02 (s, 3H) , 2.49-2.31 (m, 2H) , 2.21-2.13 (m, 3H) , 2.02-1.96 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -106.83, -147.03, -173.95; LC-MS:m/z = 617.3 [M+H] ⁺.

Compound 92: 2- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) -1-morpholinoethan-1-one (Compound 92)

Compound 92 was synthesized by following procedures described in the synthesis of Compound 90 with corresponding reagents. ¹H NMR (400 MHz, CD₃OD) δ 8.12-8.08 (m, 2H) , 7.66-7.65 (m, 2H) , 7.44 (t, J = 8.8 Hz, 1H) , 5.40 (d, J = 53.6 Hz, 1H) , 5.01-4.96 (m, 1H) , 4.77-4.70 (m, 3H) , 4.46-4.30 (m, 2H) , 4.08-4.06 (m, 2H) , 3.81-3.79 (m, 2H) , 3.74-3.72 (m, 2H) , 3.67-3.62 (m, 6H) , 3.52-3.47 (m, 2H) , 3.24-3.18 (m, 1H) , 2.49-2.36 (m, 2H) , 2.18-2.11 (m, 3H) , 2.02-1.96 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD ) δ -106.82, -146.98, -174.00; LC-MS: m/z = 659.3 [M+H] ⁺.

Compound 93: 3- (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) propanamide (Compound 93)

Compound 93 was synthesized by following procedures described in the synthesis of Compound 90 with corresponding reagents. LC-MS: m/z = 603.3 [M+H] ⁺.

Compound 94: tert-butyl ( (1R, 2R) -2- (4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) cyclopentyl) (methyl) carbamate (Compound 94)

¹H NMR (400 MHz, CD₃OD) δ 8.14-8.04 (m, 2H) , 7.69-7.57 (m, 3H) , 7.45-7.41 (t, J = 9.2 Hz, 1H) , 6.40-6.39 (d, J = 2.0 Hz, 1H) , 5.46-5.28 (m, 1H) , 5.26-5.17 (m, 2H) , 4.67-4.55 (m, 2H) , 4.30-4.12 (m, 2H) , 4.12-4.05 (t, J = 3.6 Hz, 2H) , 3.62-3.61 (d, J = 4.0 Hz, 1H) , 3.56-3.38 (m, 3H) , 3.21-3.10 (m, 1H) , 2.46-2.26 (m, 2H) , 2.22-2.15 (m, 1H) , 2.14-2.04 (m, 2H) , 1.98-1.90 (s, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -108.45, -148.45, -175.38; LC-MS: m/z = 612.3 [M+H] ⁺.

Compound 95: 5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (1-methyl-1H-pyrazol-3-yl) methyl) -9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalene (Compound 95)

LC-MS: m/z = 626.3 [M+H] ⁺.

Compound 96: 3- ( (5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 9-dihydro-10H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-10-yl) methyl) pyridin-2-amine (Compound 96)

Synthesis of 2- ( ( (2-aminopyridin-3-yl) methyl) amino) ethan-1-ol (Compound 96-3)

Step 1: Synthesis of (2-aminopyridin-3-yl) methanol (Compound 96-1) .

To a solution of 2-aminonicotinic acid (CAS: 5345-47-1, 5.0 g, 36.2 mmol) in tetrahydrofuran (100 mL) at 0℃ was added lithium aluminum hydride (2.7 g, 72.4 mmol) . The mixture was stirred at 70℃ for 18 hours. After cooled to room temperature, the reaction was quenched with water (2.7 mL) , 15%sodium hydroxide solution (2.7 mL) and water (8.5 mL) . After stirring for 15 min, the mixture was filtered through celite and the filtrate was concentrated to afford Compound 96-1 (3.82 g, crude) as a yellow oil. It was used in the next step without further purification. LC-MS: m/z = 125.2 [M+H] ⁺.

Step 2: Synthesis of 2-aminonicotinaldehyde (Compound 96-2) .

To a solution of Compound 96-1 (3.82 g, crude) in dichloromethane (100 mL) was added manganese dioxide (31.5 g, 362 mmol) , and the suspension was stirred at 25 ℃ for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to afford Compound 96-2 (1.61 g, crude) as a yellow solid. It was used in the next step without further purification. LC-MS: m/z =123.1 [M+H] ⁺.

Step 3: Synthesis of 2- ( ( (2-aminopyridin-3-yl) methyl) amino) ethan-1-ol (Compound 96-3) .

A solution of Compound 96-2 (1.6 g, crude) and 2-aminoethanol (800 mg, 13.1 mmol) in toluene (40 mL) was stirred at 130℃ for 3 hours. The solvent was removed under vacuum. The crude product was dissolved in methanol (30 mL) and cooled to 0 ℃. After the addition of sodium borohydride (991 mg, 26.2 mmol) , the mixture was stirred for 2 hours at the same temperature. Then, it was diluted with ethyl acetate (200 mL) , washed with water (100 mL x3) and brine (100 mL) , dried over Na₂SO₄, filtered and concentrated. The crude product was purified using silica gel flash chromatography (DCM/MeOH =10/1～5/1) to afford Compound 96-3 (1.77 g, 29.2%yield of three steps) as a yellow oil. LC-MS: m/z =168.1 [M+H] ⁺.

Other steps were following the similar procedures described in the synthesis of Compound 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.15 (m, 2H) , 7.93 (d, J = 4.0 Hz, 1H) , 7.68 (t, J = 7.6 Hz, 1H) , 7.61 (t, J = 8.0 Hz, 2H) , 7.38 (d, J = 7.2 Hz, 1H) , 6.58 (dd, J = 7.2, 5.2 Hz, 1H) , 6.18 (s, 2H) , 5.41 (d, J = 56.0 Hz, 1H) , 5.02-4.96 (m, 1H) , 4.88-4.73 (m, 1H) , 4.59 (s, 2H) , 4.32 (s, 2H) , 4.20 (s, 1H) , 3.96 (d, J = 4.4 Hz, 2H) , 3.66-3.47 (m, 3H) , 3.07 (s, 1H) , 2.37-2.19 (m, 2H) , 2.07-1.79 (m, 4H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -105.72, -146.10, -172.54; LC-MS: m/z = 638.3 [M+H] ⁺.

Compound 97: 5-ethynyl-6-fluoro-4- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (S) -1-hydroxypropan-2-yl) -9-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-5-yl) naphthalen-2-ol (Compound 97)

¹H NMR (400 MHz, CD₃OD) δ 7.85 (dd, J = 9.2, 5.6 Hz , 1H) , 7.36-7.29 (m, 2H) , 7.28-7.17 (m, 1H) , 5.74-5.59 (m, 1H) , 5.58-5.41 (m, 1H) , 4.71-4.53 (m, 3H) , 4.49-4.39 (m, 2H) , 3.93-3.65 (m, 5H) , 3.49 (s, 1H) , 3.41-3.33 (m, 1H) , 2.69-2.48 (m, 2H) , 2.41-2.31 (m, 1H) , 2.30-2.21 (m, 2H) , 2.18-2.02 (m, 1H) , 1.42-1.30 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -111.60, -148.12, -174.14; LC-MS: m/z = 620.3 [M+H] ⁺.

Compound 98 and Compound 99: (2R, 5aS) -3-chloro-2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 98) and (2S, 5aS) -3-chloro-2-(8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 99)

Step 1: Synthesis of (5aS) -3-chloro-1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 98-1) .

A mixture of Compound 27-2 (200 mg, 0.48 mmol) , 3-b (326 mg, 0.72 mmol) , potassium phosphate tribasic (204 mg, 0.96 mmol) , 3- (tert-butyl) -4- (2, 6-dimethoxyphenyl) -2, 3-dihydrobenzo [d] [1, 3] oxaphosphole (32 mg, 0.096 mmol) and tris (dibenzylideneacetone) dipalladium (88 mg, 0.096 mmol) in toluene (15 mL) and water (3 mL) was stirred at 100 ℃ for 5 hours under N₂ atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) , washed with water (15 mL x2) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified using silica gel column chromatography (EtOAc/PE = 10%-50%) to afford Compound 98-1 (200 mg, 63.0%yield) as a yellow solid.

Step 2: Synthesis of (5aS) -3-chloro-1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 98-2) .

To a solution of Compound 98-1 (200 mg, 0.30 mmol) in dichloromethane (15 mL) at 0 ℃under N₂ atmosphere was added 3-chloroperoxybenzoic acid (67 mg, 0.33 mmol, wt 85%) , and the mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) , washed with sat. NaHCO₃ (20 mL x2) , water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 98-2 (210 mg, crude) as a yellow solid, which was used in the next step without further purification.

Step 3: Synthesis of (5aS) -3-chloro-1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 98-3) .

To a solution of Compound 98-2 (210 mg, crude) and 4-a (96 mg, 0.60 mmol) in toluene (10 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (95 mg, 0.90 mmol) , and the mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (MeOH/DCM = 0-5%) to afford Compound 98-3 (50 mg, 21.4%yield of two steps) and Compound 99-3 (50 mg, 21.4%yield of two steps) as an off-yellow solid. LC-MS: m/z = 388.3 [M/2+H] ^-. (Note: The atropisomers’ configuration is assigned arbitrarily without the confirmation of X-ray diffraction. )

Step 4: Synthesis of (2R, 5aS) -3-chloro-2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 98) .

To a solution of Compound 98-3 (50 mg, 0.064 mmol) in N, N-dimethylformamide (6 mL) was added cesium fluoride (196 mg, 1.29 mmol) . The mixture was stirred at 15℃ for 4 hours. The mixture was diluted with ethyl acetate (30 mL) , washed with water (20 mL x3) and brine (20 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 98 (32 mg, 80.8%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.10-8.06 (m, 2H) , 7.65-7.60 (m, 1H) , 7.45-7.39 (m, 2H) , 5.44-5.26 (m, 2H) , 4.55-4.51 (m, 1H) , 4.44-4.39 (m, 2H) , 4.33-4.29 (m, 1H) , 3.99-3.93 (m, 1H) , 3.57-3.38 (m, 4H) , 3.17-3.04 (m, 2H) , 2.48-2.31 (m, 2H) , 2.25-2.20 (m, 1H) , 2.13-2.01 (m, 3H) , 1.94-1.64 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.84, -132.32, -173.96; LC-MS: m/z = 619.3 [M+H] ⁺.

Step 5: Synthesis of (2S, 5aS) -3-chloro-2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 99) .

The procedure followed that described in Step 4. ¹H NMR (400 MHz, CD₃OD) δ 8.12-8.06 (m, 2H) , 7.65-7.60 (m, 1H) , 7.46-7.39 (m, 2H) , 5.49-5.34 (m, 1H) , 5.29-5.23 (m, 1H) , 4.54-4.37 (m, 4H) , 4.05-3.99 (m, 1H) , 3.71-3.54 (m, 3H) , 3.49-3.47 (m, 1H) , 3.28-3.20 (m, 1H) , 3.13-3.05 (m, 1H) , 2.56-2.39 (m, 2H) , 2.31-2.25 (m, 1H) , 2.21-2.15 (m, 2H) , 2.04-1.72 (m, 7H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.82, -132.70, -174.12; LC-MS: m/z = 619.3 [M+H] ⁺.

Compound 100 and Compound 101: (S) -2- ( (5S, 9R) -8-chloro-9- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H-[1,4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propan-1-ol (Compound 100) and (S) -2- ( (5S, 9S) -8-chloro-9-(8-ethynyl-7-fluoronaphthalen-1-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propan-1-ol (Compound 101)

Compound 100: ¹H NMR (400 MHz, CD₃OD) : δ 8.12-8.08 (m, 2H) , 7.64 (t, J = 7.2 Hz, 1H) , 7.48-7.40 (m, 2H) , 5.60 (s, 1H) , 5.53-5.39 (m, 1H) , 4.75-4.70 (m, 1H) , 4.55 (s, 2H) , 4.46 (d, J = 12.4 Hz, 1H) , 4.40-4.33 (m, 1H) , 3.88-3.63 (m, 5H) , 3.37-3.33 (m, 2H) , 2.65-2.44 (m, 2H) , 2.35-2.21 (m, 3H) , 2.09-2.00 (m, 1H) , 1.40 (d, J = 6.8 Hz, 3H) , 1.34 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -106.68, -135.37, -174.43; LC-MS: m/z = 637.2 [M+H] ⁺.

Compound 101: ¹H NMR (400 MHz, CD₃OD) : δ 8.12-8.08 (m, 2H) , 7.64 (t, J = 7.6 Hz, 1H) , 7.48-7.41 (m, 2H) , 5.60 (s, 1H) , 5.53-5.40 (m, 1H) , 4.75-4.71 (m, 1H) , 4.64-4.45 (m, 3H) , 4.38-4.35 (m, 1H) , 3.91-3.63 (m, 5H) , 3.48-3.35 (m, 2H) , 2.63-2.49 (m, 2H) , 2.39-2.19 (m, 3H) , 2.08-1.94 (m, 1H) , 1.39 (d, J =6.8 Hz, 3H) , 1.32 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -106.75, -135.17, -174.57; LC-MS:m/z = 637.2 [M+H] ⁺.

Compound 102: (S) -2- ( (5S, 9R) -8-chloro-9- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propan-1-ol (Compound 102)

Step 1: Synthesis of (E) -N- (3-bromo-2, 4, 5-trifluorophenyl) -2- (hydroxyimino) acetamide (Intermediate 4-1) .

A mixture of 3-bromo-2, 4, 5-trifluoroaniline (4.0 g, 17.7 mmol) , chloral hydrate (3.8 g, 23.0 mmol) , hydroxylamine hydrochloride (3.7 g, 53.1 mmol) , ethanol (20 mL) and con. HCl (5 mL) in water (20 mL) was added to a stirred solution of sodium sulfate (20.1 g, 141.6 mmol) in water (100 ml) at room temperature. The resulting mixture was stirred at 60 ℃ for 16 hours. The mixture solution was cooled to room temperature and filtered. The filter cake was washed with water (10 mL x3) and dried under vacuum to afford Intermediate 4-1 (4.8 g, 91%yield) as an off white solid.

Step 2: Synthesis of 6-bromo-4, 5, 7-trifluoroindoline-2, 3-dione (Intermediate 4-2) .

Intermediate 4-1 (4.8 g, 16.15 mmol) was dissolved in con. H₂SO₄ (30 mL) at room temperature. The resulting mixture was stirred at 80 ℃ for 16 hours. After cooling to room temperature, the mixture was poured into ice water, and extracted with ethyl acetate (200 mL x2) . The organic phase was combined and washed with saturated sodium carbonate (100 mL) and brine (100 mL) , dried over Na₂SO₄, and concentrated. The residue was purified using silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to afford Intermediate 4-2 (1.9 g, 42%yield) as a yellow solid. LC-MS: m/z =277.9 [M-H] ^-.

Step 3: Synthesis of 2-amino-4-bromo-3, 5, 6-trifluorobenzoic acid (Intermediate 4-3) .

To a solution of Intermediate 4-2 (1.9 g, 6.78 mmol) in aqueous sodium hydroxide solution (34 mL, 67.8 mmol, 2M) was added hydrogen peroxide (4.3 g, 33.9 mmol, wt 30%) , and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated Na₂SO₃ and filtered. The filtrate was washed with tert-butyl methyl ether (100 mL) . The aqueous phase was acidified with con. HCl to pH = 2～3 and extracted with ethyl acetate (150 mL x2) . The combined organic phases were washed with brine (100 mL) , dried over Na₂SO₄, filtered and concentrated to afford Intermediate 4-3 (880 mg, crude) as a yellow solid. It was used for next step without further purification. LC-MS: m/z =269.9 [M-H] ^-.

Step 4: Synthesis of 7-bromo-5, 6, 8-trifluoro-2-mercaptoquinazolin-4-ol (Intermediate 4-4) .

A solution of Intermediate 4-3 (880 mg, 3.26 mmol) in thionyl chloride (30 mL) was stirred at 50 ℃ for 3 hours. The resulting mixture was concentrated, then the crude product was dissolved in acetone (5 mL) . A solution of ammonium thiocyanate (298 mg, 3.91 mmol) in acetone (40 ml) was added to the above mixture at 0 ℃ under N₂ atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x2) . The organic phases were combined and washed with brine (100 mL) , dried over Na₂SO₄, filtered, and concentrated to afford Intermediate 4-4 (843 mg, crude) as a yellow solid. It was used in the next step without further purification. LC-MS: m/z = 310.9 [M+H] ⁺.

Step 5: Synthesis of 7-bromo-5, 6, 8-trifluoro-2- (methylthio) quinazolin-4-ol (Intermediate 4) .

An aq. solution of sodium hydroxide (217 mg, 5.42 mmol, 10 mL) was added to the solution of Intermediate 4-4 (843 mg, 2.71 mmol) in methanol (15 ml) at 0 ℃. The mixture was stirred at room temperature for 2 hours. It was diluted with water (100 mL) and adjusted with con. HCl to pH = 2～3. The precipitate was collected by filtration and washed with water (10 mL x3) , dried under vacuum to afford Intermediate 4 (780 mg, 35%yield of three steps) as a yellow solid.

Synthesis of (S) -2- ( (5S, 9R) -8-chloro-9- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propan-1-ol (Compound 102)

Compounds 102 was prepared by following the procedures described in the synthesis of Compound 98 and Compound 99. ¹H NMR (400 MHz, CD3OD) δ 8.14-8.08 (m, 2H) , 7.65-7.57 (m, 2H) , 7.44 (t, J = 9.0 Hz, 1H) , 5.70-5.55 (m, 1H) , 5.49-5.36 (m, 1H) , 4.71-4.64 (m, 1H) , 4.57-4.31 (m, 4H) , 3.88-3.53 (m, 5H) , 3.47-3.44 (m, 1H) , 3.28-3.21 (m, 1H) , 2.60-2.14 (m, 5H) , 2.07-1.92 (m, 1H) , 1.41-1.31 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -106.45, -137.99, -139.52, -174.37; LC-MS: m/z =621.3 [M+H] ⁺.

Compound 103: 4- ( (5S, 9S) -8, 10-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -5-ethynyl-6-fluoronaphthalen-2-ol (Compound 103)

LC-MS: m/z = 637.3 [M+H] ⁺.

Compound 104: (S) -2- ( (S) -9- (8-ethynyl-7-fluoronaphthalen-1-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propan-1-ol (Compound 104)

Intermediate 5 was prepared by following the procedures described in the synthesis of Intermediate 4.

Compound 104 was prepared by following the scheme below, which is similar to the procedures used for preparing Compound 98 and Compound 99.

¹H NMR (400 MHz, DMSO-d₆) : δ 8.23-8.14 (m, 2H) , 7.67-7.53 (m, 3H) , 7.78-6.72 (m, 1H) , 5.56-5.26 (m, 2H) , 4.53-4.78 (m, 1H) , 4.83-4.47 (m, 1H) , 4.31-4.01 (m, 5H) , 3.74-3.59 (m, 4H) , 3.14-2.87 (m, 2H) , 2.36-1.75 (m, 6H) , 1.28-1.18 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -105.49, 105.61, -135.99, 136.69, -172.30; LC-MS: m/z = 603.3 [M+H] ⁺.

Compound 105: 2-amino-7-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 105)

Step 1: tert-butyl (S) - (3-cyano-7-fluoro-4- (1-fluoro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 105-1)

A mixture of Compound 1-2 (340 mg, 1.00 mmol) , 5-a (607 mg, 1.50 mmol) , cesium carbonate (978 mg, 3.00 mmol) and methanesulfonato (2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1, 1'-biphenyl) (2'-amino-1, 1'-biphenyl-2-yl) palladium (II) (84 mg, 0.10 mmol) in toluene (15 mL) was stirred at 100 ℃ for 2 hours under N₂ atmosphere. The mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL x2) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified using silica gel column chromatography (EtOAc/PE = 10%-50%) to afford Compound 105-1 (240 mg, 40.3%yield) as a yellow solid. LC-MS: m/z = 597.2 [M+H] ^-.

Step 2: tert-butyl (3-cyano-7-fluoro-4- ( (5aS) -1-fluoro-11- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 105-2)

To a solution of Compound 105-1 (220 mg, 0.37 mmol) in dichloromethane (10 mL) at 0 ℃under N₂ atmosphere was added 3-chloroperoxybenzoic acid (90 mg, 0.44 mmol, wt 85%) . The mixture was stirred at 18 ℃ for 1 hour, diluted with dichloromethane (30 mL) and washed with sat. NaHCO₃ (20 mL x2) , water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford Compound 105-2 (200 mg, crude) as a yellow solid. It was used for next step without further purification.

Step 3: tert-butyl (3-cyano-7-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 105-3)

To a solution of Compound 105-2 (200 mg, crude) and 4-a (105 mg, 0.66 mmol) in toluene (10 mL) was added sodium tert-butoxide (95 mg, 0.99 mmol) at 0 ℃ under N₂ atmosphere. The mixture was stirred at 18 ℃ for 1.5 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 105-3 (135 mg, 51.7%yield of two steps) as a yellow solid. LC-MS: m/z = 708.3 [M+H] ^-.

Step 4: 2-amino-7-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 105)

To a solution of Compound 105-3 (80 mg, 0.113 mmol) in dichloromethane (2 mL) was added TFA (2 mL) . The mixture was stirred at 16 ℃ for 0.5 hour. The mixture was quenched with sodium carbonate aqueous solution (20 mL) and extracted with dichloromethane (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 105 (30 mg, 34.9%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.35 (m, 1H) , 7.04-6.99 (m, 1H) , 5.40-5.36 (m, 1H) , 5.35-5.24 (m, 1H) , 4.53-4.48 (m, 2H) , 4.33-4.21 (m, 2H) , 3.98-3.93 (m, 1H) , 3.39-3.31 (m, 1H) , 3.29-3.23 (m, 2H) , 3.12-3.02 (m, 2H) , 2.40-2.22 (m, 2H) , 2.19-2.12 (m, 1H) , 2.04-1.97 (m, 3H) , 1.93-1.78 (s, 5H) , 1.66-1.58 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -117.98, -145.66, -173.71; LC-MS: m/z = 608.3 [M+H] ⁺.

Compound 106: 3-chloro-4-cyclopropyl-5- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) phenol (Compound 106)

Compounds 106 was prepared by following the procedures described in the synthesis of Compound 105. ¹H NMR (400 MHz, CD₃OD) δ 6.96-6.90 (d, J = 2.4 Hz, 1H) , 6.75 (d, J = 2.4 Hz, 1H) , 5.44-5.25 (m, 2H) , 4.54-4.47 (d, J = 2.8 Hz, 2H) , 4.38-4.33 (m, 1H) , 4.31-4.24 (m, 1H) , 4.00-3.91 (d, J =8.8 Hz, 1H) , 3.51-3.32 (m, 3H) , 3.15-3.03 (m, 2H) , 2.47-2.27 (m, 2H) , 2.23-2.16 (m, 1H) , 2.11-2.01 (m, 3H) , 1.97-1.88 (m, 2H) , 1.87-1.76 (m, 4H) , 1.62-1.55 (m, 1H) , 0.75-0.53 (m, 2H) , 0.20-0.02 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -144.80, -173.74; LC-MS: m/z = 584.3 [M+H] ⁺.

Compound 107: 2-amino-4- ( (S) -1, 3-difluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 107)

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 2H) , 7.33 (dd, J = 8.4, 5.2 Hz, 1H) , 7.16 (t, J = 9.2 Hz, 1H) , 5.47-5.27 (m, 1H) , 5.08 (d, J = 12.0 Hz, 1H) , 4.54-4.35 (m, 2H) , 4.31-4.04 (m, 2H) , 4.00-3.89 (m, 1H) , 3.32-3.20 (m, 3H) , 3.10-2.88 (m, 2H) , 2.37-2.06 (m, 3H) , 2.04-1.69 (m, 7H) , 1.63-1.43 (m, 2H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -115.98, -133.43, -141.09, -172.33; LC-MS: m/z = 625.2 [M+H] ⁺.

Compound 108 and Compound 109: 2-amino-4- ( (2S, 5aS) -1, 3-difluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 108) and 2-amino-4- ( (2R, 5aS) -1, 3-difluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 109)

Compound 108 and Compound 109 were obtained by chiral Prep-HPLC separation of Compound 107 with Boc protection on a CHIRALPAK AD-H column, followed by the treatment of TFA. Compound 108 was from the first fraction and Compound 109 was from the second fraction eluting from the column.

Compound 108: ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 2H) , 7.34-7.31 (m, 1H) , 7.16 (t, J = 9.2 Hz, 1H) , 5.52-5.38 (m, 1H) , 5.11 (d, J = 12.8 Hz, 1H) , 4.52-4.36 (m, 4H) , 4.04-3.91 (m, 1H) , 3.50 (s, 3H) , 3.07-3.01 (m, 2H) , 2.45-2.12 (m, 3H) , 2.09-1.43 (m, 9H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -115.93, -133.39, -140.76, -172.59; LC-MS: m/z = 625.3 [M+H] ⁺.

Compound 109: ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 2H) , 7.35-7.31 (m, 1H) , 7.23-7.10 (m, 1H) , 5.44 (d, J = 52.4 Hz, 1H) , 5.09 (d, J = 12.8 Hz, 1H) , 4.56-4.08 (m, 4H) , 3.97 (d, J = 11.2 Hz, 1H) , 3.81-3.39 (m, 2H) , 3.20-2.91 (m, 2H) , 2.42-2.11 (m, 3H) , 2.03-1.46 (m, 10H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -115.97, -133.41, -140.73, -172.62; LC-MS: m/z = 625.3 [M+H] ⁺.

Compound 110: 2-amino-4- ( (S) -3-chloro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 110)

Synthesis of 5, 6, 7-trichloro-2- (methylthio) pyrido [2, 3-d] pyrimidin-4-ol (Intermediate 6) and 4, 5, 6, 7-tetrachloro-2- (methylthio) pyrido [2, 3-d] pyrimidine (Intermediate 7)

Step 1: Synthesis of methyl 2-amino-4, 5, 6-trichloronicotinate (Intermediate 6-1)

To a solution of methyl 2-amino-4, 6-dichloropyridine-3-carboxylate (10.0 g, 45.2 mmol) in N, N-dimethylformamide (50 mL) was added N-chlorosuccinimide (9.1 g, 67.9 mmol) . The mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (250 mL) and stirred at room temperature for 30 mins. A large amount of yellow solid was collected by filtration. The filter cake was washed with water (30 mL ×2) and dried to afford Intermediate 6-1 (9.8 g, 84.8%yield) as a yellow solid.

Step 2: Synthesis of 2-amino-4, 5, 6-trichloronicotinic acid (Intermediate 6-2)

To a solution of Intermediate 6-1 (9.8 g, 38.4 mmol) in methanol (50 mL) was added sodium hydroxide (48 mL, 8 N in water) . The mixture was stirred at room temperature for 3 hours. The solvent was removed under concentration. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL) . The aqueous phase was acidified to pH = 5 with hydrochloric acid (3 M in water) . A large amount of yellow solid was collected by filtration. The filter cake was washed with water (50 mL ×2) and dried to afford Intermediate 6-2 (7.8 g, 84.2%yield) as a yellow solid. LC-MS: m/z = 241.0 [M+H] ⁺.

Step 3: Synthesis of 5, 6, 7-trichloro-2-mercaptopyrido [2, 3-d] pyrimidin-4-ol (Intermediate 6-3)

A solution of Intermediate 6-2 (7.8 g, 32.3 mmol) in thionyl dichloride (100 mL) was stirred at 55 ℃ for 4 hours. The solvent was removed under vacuum and the residue was dissolved in acetone (100 mL) , followed by the addition of ammonium thiocyanate (7.4 g, 96.9 mmol) in batches to the above solution at 0 ℃. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was dissolved in water (80 mL) , acidified to pH = 5 with hydrochloric acid (3 M in water) and extracted with dichloromethane/methanol (v/v = 10/1, 100 mL x2) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated to afford Intermediate 6-3 (6.0 g, crude) as a brown oil. It was used for next step without further purification.

Step 4: Synthesis of 5, 6, 7-trichloro-2- (methylthio) pyrido [2, 3-d] pyrimidin-4-ol (Intermediate 6)

To a solution of Intermediate 6-3 (4.5 g, crude) in methanol (200 mL) was added a solution of sodium hydroxide (1.9 g, 47.8 mmol) in water (200 mL) , followed by the addition of iodomethane (2.3 g, 15.9 mmol) . The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified to pH = 5 with hydrochloric acid (3 M in water) and extracted with dichloromethane (100 mL x2) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/DCM = 0%-10%) to afford Intermediate 6 (800 mg, 11.1%yield of two steps) as a yellow solid. LC-MS: m/z = 295.9 [M+H] ⁺.

Step 5: Synthesis of 4, 5, 6, 7-tetrachloro-2- (methylthio) pyrido [2, 3-d] pyrimidine (Intermediate 7)

To a solution of Intermediate 6 (800 mg, 2.7 mmol) in 1, 4-dioxane (30 mL) was added ethyl diisopropyl amine (1.7 g, 13.5 mmol) and phosphoryl trichloride (2.1 g, 13.5 mmol) . The mixture was stirred at 100 ℃ for 1 hour. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate (50 mL) , washed with water (20 mL) and brine (20 mL) , then dried over Na₂SO₄, and concentrated. The residue was purified by silica gel flash chromatography (DCM/PE = 0%-35%) to afford Intermediate 7 (430 mg, 50.6%yield) as a yellow solid. LC-MS: m/z = 313.9 [M+H] ⁺. Synthesis of 2-amino-4- ( (S) -3-chloro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 110)

Step 1: Synthesis of (S) - (1- (5, 6, 7-trichloro-2- (methylthio) pyrido [2, 3-d] pyrimidin-4-yl) piperidin-2-yl) methanol (Compound 110-1)

To a solution of Intermediate 7 (430 mg, 1.4 mmol) in dichloromethane (15 mL) was added N, N-diisopropylethylamine (266 mg, 2.1 mmol) and [ (2S) -piperidin-2-yl] methanol (158 mg, 1.4 mmol) at -50 ℃. The mixture was stirred at -10 ℃ for 3 hours. The reaction mixture was warmed to room temperature, diluted with water (20 mL) and extracted with dichloromethane (25 mL x2) . The combined organic layers were washed with brine (15 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified using silica gel flash chromatography (MeOH/DCM = 0%-7%) to afford Compound 110-1 (530 mg, 98.3%yield) as a yellow solid. LC-MS: m/z = 393.0 [M+H] ⁺.

Step 2: Synthesis of (S) -2, 3-dichloro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 110-2)

To a solution of Compound 110-1 (470 mg, 1.2 mmol) in toluene (15 mL) was added cesium carbonate (1.9 g, 6.0 mmol) . The mixture was stirred at 100 ℃ for 5 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (15 mL x2) . The combined organic layers were washed with brine (8 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%-30%) to afford Compound 110-2 (132 mg, 31.1%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.04-5.01 (m, 1H) , 4.69-4.57 (m, 2H) , 4.04-3.95 (m, 1H) , 3.07-3.01 (m, 1H) , 2.50 (s, 3H) , 1.87-1.84 (m, 2H) , 1.73-1.55 (m, 3H) , 1.49-1.38 (m, 1H) . LC-MS: m/z = 357.1 [M+H] ⁺.

Step 3: Synthesis of tert-butyl (S) - (4- (3-chloro-11- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 110-3)

A mixture of Compound 110-2 (100 mg, 0.28 mmol) , tert-butyl 5-a (340 mg, 0.84 mmol) , cesium carbonate (365 mg, 1.1 mmol) and methanesulfonato (2-dicyclohexylphosphino-2’, 6’-di-i-propoxy-1-1’-biphenyl) (2’-amino-1, 1’-biphenyl-2-yl) palladium (Ⅱ) (23 mg, 0.028 mmol) in toluene (2 mL) was stirred at 100 ℃ for 1 hour under N₂ atmosphere. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (15 mL x2) . The combined organic layers were washed with brine (10 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 30%-75%) to afford Compound 110-3 (32 mg, 18.7%yield) as a yellow solid.

Step 4: Synthesis of tert-butyl (4- ( (5aS) -3-chloro-11- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 110-4)

To a solution of Compound 110-3 (32 mg, 0.052 mmol) in dichloromethane (1 mL) at 0 ℃under N₂ atmosphere was added 3-chloroperoxybenzoic acid (13 mg, 0.062 mmol, wt. 85%) . The mixture was stirred at 0 ℃ for 10 minutes. The reaction solution was diluted with dichloromethane (10 mL) and washed with sat. NaHCO₃ (6 mL) , water (6 mL) and brine (6 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 110-4 (35 mg, crude) as a yellow solid. It was used in the next step without further purification.

Step 5: Synthesis of tert-butyl (4- ( (S) -3-chloro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 110-5)

To a solution of Compound 110-4 (35 mg, crude) and 4-a (18 mg, 0.11 mmol) in toluene (1 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (11 mg, 0.11 mmol) . The mixture was stirred at 0 ℃ for 10 minutes. The reaction was quenched with water (6 mL) and extracted with ethyl acetate (8 mL x2) . The combined organic layers were washed with brine (6 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified using prep-TLC (MeOH/DCM = 1/14) to afford Compound 110-5 (20 mg, 53.1%yield of two steps) as a yellow solid. LC-MS: m/z = 362.7 [M/2+H] ⁺.

Step 6: Synthesis of 2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 110)

A mixture of Compound 110-5 (20 mg, 0.028 mmol) in 2, 2, 2-trifluoroacetic acid (0.5 mL) and dichloromethane (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with sat. NaHCO₃ (6 mL) and extracted with ethyl acetate (8 mL x3) . The combined organic layers were washed with brine (6 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified using prep-TLC (MeOH/DCM = 1/10) to afford Compound 110 (4.64 mg, 26.6%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.33-7.30 (m, 1H) , 7.02 (t, J = 8.8 Hz, 1H) , 5.49-5.36 (m, 1H) , 5.25 (d, J = 13.2 Hz, 1H) , 4.70-4.39 (m, 4H) , 4.02-4.00 (m, 1H) , 3.69-3.56 (m, 3H) , 3.26-3.08 (m, 2H) , 2.55-2.26 (m, 3H) , 2.21-2.13 (m, 2H) , 2.02-1.93 (m, 3H) , 1.89-1.75 (m, 3H) , 1.62-1.57 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.28, -174.19; LC-MS: m/z = 622.2 [M-H] ^-.

Compound 111: (S) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 111)

Step 1: Synthesis of tert-butyl ( (S) -4- ( (S) -3-chloro-1-fluoro-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 111-1) and tert-butyl ( (R) -4- ( (S) -3-chloro-1-fluoro-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 112-1)

A mixture of Compound 27-2 (980 mg, 2.34 mmol) , 5-a (2.84 g, 7.02 mmol) , cesium carbonate (3.8 g, 11.7 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (379 mg, 0.468 mmol) in toluene (20 mL) was stirred at 105 ℃ for 2 hours under N₂ atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to afford Compound 111-1 (Peak 1, less polar, 450 mg, 30.5%yield) and Compound 112-1 (Peak 2, more polar, 356 mg, 24.1%yield) as a white solid.

The other steps for preparing compound 111 were carried out following the procedures described in the synthesis of Compound 27.

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.30-5.24 (m, 1H) , 4.66-4.54 (m, 2H) , 4.53-4.40 (m, 2H) , 4.02-3.96 (m, 1H) , 3.68-3.61 (m, 2H) , 3.29-3.19 (m, 2H) , 3.13-3.05 (m, 1H) , 2.33-2.23 (m, 2H) , 2.22-2.14 (m, 2H) , 2.12-2.00 (m, 5H) , 1.96-1.91 (m, 1H) , 1.88-1.73 (m, 3H) , 1.71-1.63 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.68, -133.14; LC-MS: m/z = 623.3 [M+H] ⁺.

Compound 112: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 112)

Compound 112 was obtained by following the procedures described in the synthesis of Compound 27 from compound 112-1.

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.18 (m, 1H) , 7.05-7.01 (m, 1H) , 5.27-5.24 (m, 1H) , 4.61-4.54 (m, 1H) , 4.51-4.48 (m, 2H) , 4.44-4.36 (m, 1H) , 4.04-3.96 (m, 1H) , 3.60-3.49 (m, 2H) , 3.22-3.03 (m, 3H) , 2.31-2.12 (m, 4H) , 2.09-1.98 (m, 5H) , 1.94-1.68 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.71, -132.81; LC-MS: m/z = 623.2 [M+H] ⁺.

Compound 113 and Compound 114: (2S, 5aS) -2- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-15- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -N, N-dimethyl-5,5a, 6, 7-tetrahydro-12H-pyrazolo [5” , 1” : 3', 4'] [1, 4] diazepino [7', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline-10-carboxamide (Compound 113) and (2R, 5aS) -2- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-15- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -N, N-dimethyl-5, 5a, 6, 7-tetrahydro-12H-pyrazolo [5” , 1” : 3', 4'] [1, 4] diazepino [7', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline-10-carboxamide (Compound 114)

The racemic Boc-protecting precursors of Compound 113 and Compound 114 were separated using Prep-TLC (DCM/MeOH = 15/1) , then Compound 113-Boc (Less polar) and Compound 114-Boc (More polar) were treated with TFA separately.

Compound 113: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.12 (m, 1H) , 7.02 (t, J = 8.8 Hz, 1H) , 6.73 (s, 1H) , 6.22 (d, J = 15.2 Hz, 1H) , 5.51-5.31 (m, 1H) , 4.83-4.75 (m, 1H) , 4.68-4.61 (m, 2H) , 4.55-4.40 (m, 5H) , 3.63-3.45 (m, 3H) , 3.33 (s, 3H) , 3.26-3.16 (m, 1H) , 3.06 (s, 3H) , 2.55-2.33 (m, 3H) , 2.28-2.14 (m, 4H) , 2.07-1.98 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.80, -131.84, -173.85; LC-MS: m/z = 764.3 [M+H] ⁺.

Compound 114: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.10 (m, 1H) , 7.01 (t, J = 8.8 Hz, 1H) , 6.72 (m, 1H) , 6.24 (d, J = 15.2 Hz, 1H) , 5.60-5.38 (m, 1H) , 4.81-4.75 (m, 1H) , 4.71-4.63 (m, 2H) , 4.46-4.56 (m, 2H) , 4.55-4.40 (m, 3H) , 3.90-3.61 (m, 3H) , 3.33 (s, 3H) , 3.26-3.22 (m, 1H) , 3.06 (s, 3H) , 2.62-2.34 (m, 4H) , 2.32-2.18 (m, 2H) , 2.16-2.00 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -114.77, -128.08, -170.82; LC-MS: m/z = 764.3 [M+H] ⁺.

Compound 115 and Compound 116: 2-amino-4- ( (2S, 5aS) -3-chloro-1-fluoro-15- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-5, 5a, 6, 7-tetrahydro-12H-pyrazolo [5” , 1” : 3', 4'] [1, 4] diazepino [7', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 115) and 2-amino-4- ( (2R, 5aS) -3-chloro-1-fluoro-15-( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-5, 5a, 6, 7-tetrahydro-12H-pyrazolo [5” , 1” : 3', 4'] [1, 4] diazepino [7', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 116)

Compound 115 (Less polar) and Compound 116 (More polar) were obtained from their atropisomeric mixture by Prep-TLC (DCM/MeOH = 9/1) separation.

Compound 115: ¹H NMR (400 MHz, CD₃OD) δ 7.18 (dd, J = 8.4, 5.2 Hz, 1H) , 7.02 (t, J = 9.2 Hz, 1H) , 6.19 (s, 1H) , 6.15 (d, J = 15.6 Hz, 1H) , 5.50-5.31 (m, 1H) , 4.78 (dd, J = 12.8, 4.4 Hz, 1H) , 4.54-4.34 (m, 7H) , 3.68-3.42 (m, 3H) , 3.27-3.18 (m, 1H) , 2.56-2.12 (m, 10H) , 2.07-1.93 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.77, -132.14, -173.92; LC-MS: m/z = 707.2 [M+H] ⁺.

Compound 116: ¹H NMR (400 MHz, CD₃OD) δ 7.15 (dd, J = 8.0, 4.8 Hz, 1H) , 7.00 (t, J = 9.2 Hz, 1H) , 6.21-6.11 (m, 2H) , 5.50-5.33 (m, 1H) , 4.77 (dd, J = 12.8, 4.4 Hz, 1H) , 4.58-4.34 (m, 7H) , 3.66-3.42 (m, 3H) , 3.24-3.15 (m, 1H) , 2.53-2.25 (m, 4H) , 2.21-1.92 (m, 7H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.83, -131.86, -173.91; LC-MS: m/z = 707.2 [M+H] ⁺.

Compound 117: 2-amino-4- ( (5S, 5aS, 6S, 9R) -3-chloro-1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5a, 6, 7, 8, 9, 10-hexahydro-5H-6, 9-epiminoazepino [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 117)

¹H NMR (400 MHz, CD₃OD) : δ 7.22-7.17 (m, 1H) , 7.07-7.01 (m, 1H) , 5.55-5.41 (m, 2H) , 4.59-4.35 (m, 3H) , 4.22-4.18 (m, 1H) , 3.89-3.67 (m, 5H) , 3.43-3.31 (m, 1H) , 3.25-3.23 (m, 1H) , 2.62-2.32 (m, 3H) , 2.27-2.17 (m, 3H) , 2.09-1.99 (m, 1H) , 1.93-1.78 (m, 3H) , 1.62 (t, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.63, -132.07, -174.18; LC-MS: m/z = 682.2 [M+H] ⁺.

Compound 118 and Compound 119: (S) -2-amino-4- ( (5S, 5aS, 6S, 9R) -3-chloro-1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5a, 6, 7, 8, 9, 10-hexahydro-5H-6, 9-epiminoazepino [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 118) and (R) -2-amino-4- ( (5S, 5aS, 6S, 9R) -3-chloro-1-fluoro-13- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5a, 6, 7, 8, 9, 10-hexahydro-5H-6, 9-epiminoazepino [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 119)

Compound 118 and Compound 119 were obtained by following procedures described in the synthesis of Compound 111 and Compound 112.

Compound 118: ¹H NMR (400 MHz, CD₃OD) : δ 7.23-7.14 (m, 1H) , 7.07-6.99 (m, 1H) , 5.48-5.44 (m, 1H) , 5.39-5.23 (m, 1H) , 4.33-4.26 (m, 2H) , 4.19 (d, J = 10.4 Hz, 1H) , 4.11 (d, J = 10.0 Hz, 1H) , 3.68 (d, J = 6.0 Hz, 1H) , 3.57-3.51 (m, 1H) , 3.26-3.15 (m, 4H) , 3.06-2.97 (m, 1H) , 2.36-2.12 (m, 4H) , 2.05-1.95 (m, 3H) , 1.76-1.73 (m, 2H) , 1.73-1.69 (m, 1H) , 1.60 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : -118.98, -131.58, -173.68; LC-MS: m/z = 680.1 [M-H] ^-.

Compound 119: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.06-6.98 (m, 1H) , 5.43-5.30 (m, 2H) , 4.39-4.25 (m, 3H) , 4.09 (d, J = 9.2 Hz, 1H) , 3.69 (d, J = 4.8 Hz, 1H) , 3.60-3.54 (m, 1H) , 3.52-3.33 (m, 3H) , 3.19-3.09 (m, 2H) , 2.45-2.30 (m, 2H) , 2.25-2.19 (m, 1H) , 2.17-2.03 (m, 3H) , 1.98-1.89 (m, 1H) , 1.86-1.69 (m, 3H) , 1.59 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : -118.88, -131.75, -173.90; LC-MS: m/z = 682.2 [M+H] ⁺.

Compound 120: 2-amino-4- ( (5S, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 120)

Step 1: Synthesis of 7-bromo-6-chloro-8-fluoro-2- (methylthio) -5- ( (S) -1- ( (S) -piperidin-2-yl) ethoxy) quinazolin-4-ol (Compound 120-1)

To a solution of 1-c (1.61 g, 7.03 mmol) in THF (30 mL) cooled at 0 ℃ was added NaH (60%mineral oil, 702.6 mg, 17.57 mmol) , and the reaction was stirred at 25 ℃ for 1 hour before addition of Intermediate 3 (1.2 g, 3.51 mmol) . It was stirred at 50 ℃ for another 2 hours. The resulting mixture was diluted with water (200 mL) , extracted with ethyl acetate (200 mL) . The combined organic layers were, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-60%) to afford Compound 120-1 (500 mg, 31.5%yield) as a yellow solid. LC-MS: m/z = 451.8 [M+H] ⁺.

Step 2: Synthesis of (5S, 5aS) -2-bromo-3-chloro-1-fluoro-5-methyl-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 120-2a) and (5R, 5aS) -2-bromo-3-chloro-1-fluoro-5-methyl-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 120-2b)

To a solution of Compound 120-1 (480 mg, 1.06 mmol) in dichloromethane (10 mL) were added Hunig’s base (2.06 g, 15.97 mmol) , bis (2-oxooxazolidin-3-yl) phosphinic chloride (1.08 g, 4.26 mmol) , and the reaction was stirred at 25 ℃ for 5 hours. The resulting mixture was diluted with dichloromethane (200 mL) and water (200 mL) . The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether 0-40%) to afford Compound 120-2a (120 mg, 26.0%yield) and Compound 120-2b (100 mg, 21.7%yield) as a yellow solid. LC-MS: m/z = 433.8 [M+H] ⁺.

Step 3: Synthesis of (5S, 5aS) -2-bromo-3-chloro-1-fluoro-5-methyl-12- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 120-3)

To a solution of Compound 120-2a (110 mg, 0.254 mmol) in dichloromethane (3 mL) at 0 ℃was added m-CPBA (56.77 mg, 0.279 mmol) , and the mixture was stirred at 0 ℃ for 30 min. The reaction was diluted with water (100 mL) , extracted with ethyl acetate (100 mL x3) . The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with dichloromethane in methanol 0-10%) to afford Compound 120-3 (80 mg, 70.1%yield) as a yellow solid. LC-MS: m/z = 449.3 [M+H] ⁺.

Step 4: Synthesis of (5S, 5aS) -2-bromo-3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 120-4)

To a solution of 4-a (133.04 mg, 0.835 mmol) in toluene (4 mL) was added sodium tert-butoxide (80.31 mg, 0.835 mmol) , and the reaction was stirred at 25 ℃ for 10 min. Then, Compound 120-3 (75 mg, 0.167 mmol) was added, and the reaction was stirred at 25 ℃ for 2 hours. The resulting mixture was diluted water (200 mL) , extracted with ethyl acetate (200 mL x3) . The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-10%methanol in dichloromethane) to afford Compound 120-4 (65 mg, 71.5%yield) as a yellow solid. LC-MS: m/z = 545.0 [M+H] ⁺.

Step 5: Synthesis of tert-butyl (4- ( (5S, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 120-5)

To a solution of Compound 120-4 (60 mg, 0.110 mmol) in toluene (3 mL) were added 5-a(133.80 mg, 0.330 mmol) , bis (diphenylphosphinophenyl) ether palladium (II) dichloride (31.59 mg, 0.044 mmol) and cesium carbonate (107.84 mg, 0.330 mmol) , and the reaction was stirred at 110 ℃ for 2 hours. The resulting mixture was diluted with ethyl acetate (200 mL x3) and water (200 mL) . The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography (eluting with 0-10%methanol in dichloromethane) to afford Compound 120-5 (70 mg, 84.0%yield) as a yellow solid. LC-MS: m/z = 755.0 [M+H] ⁺.

Step 6: Synthesis of 2-amino-4- ( (5S, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 120)

To a solution of Compound 120-5 (65 mg, 0.086 mmol) in acetonitrile (2.5 mL) was added 4M HCl in dioxane (0.5 mL) , and the mixture was stirred at 25 ℃ for an hour before concentrated. Ammonia methanol solution was added to adjust the pH value to 8. A large amount of NH₄Cl solid formed, it was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (MeCN/water/NH₄HCO₃) to afford Compound 120 (26 mg, 46.1%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.23 (td, J = 8.4, 5.2 Hz, 1H) , 7.17-7.10 (m, 1H) , 5.28 (d, J =53.2 Hz, 1H) , 4.76 (s, 1H) , 4.24 (ddd, J = 88.0, 9.2, 6.4 Hz, 1H) , 4.09 (d, J = 10.4 Hz, 1H) , 3.98 (dd, J =10.0, 3.6 Hz, 1H) , 3.89 (dd, J = 18.0, 8.8 Hz, 1H) , 3.15-3.03 (m, 3H) , 3.01 (s, 1H) , 2.82 (dd, J = 14.8, 8.8 Hz, 1H) , 2.09 (ddd, J = 36.8, 18.8, 11.2 Hz, 3H) , 1.90-1.68 (m, 8H) , 1.46 (dd, J = 19.6, 6.4 Hz, 3H) , 1.40-1.25 (m, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.60, -130.41, -172.11; LC-MS: m/z = 655.0 M+H] ⁺.

Compound 121 and Compound 122: (S) -2-amino-4- ( (5S, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 121) and (R) -2-amino-4- ( (5S, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 122)

Compound 121 and Compound 122 were obtained by SFC separation of Compound 120 on a column. Compound 121 was the first fraction and Compound 122 was the second fraction eluting from the column.

Compound 121: ¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H) , 7.23 (d, J = 5.2 Hz, 1H) , 7.13 (t, J = 8.8 Hz, 1H) , 5.28 (d, J = 55.2 Hz, 1H) , 4.74 (d, J = 12.8 Hz, 1H) , 4.10 (d, J = 10.4 Hz, 2H) , 3.99 (d, J = 10.4 Hz, 1H) , 3.90 (s, 1H) , 3.09 (s, 3H) , 3.01 (s, 1H) , 2.83 (s, 1H) , 2.13-1.99 (m, 3H) , 1.76 (d, J = 23.2 Hz, 9H) , 1.48 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.60, -130.50, -172.10; LC-MS: m/z = 655.0 [M+H] ⁺.

Compound 122: ¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H) , 7.24-7.20 (m, 1H) , 7.13 (t, J = 8.8 Hz, 1H) , 5.21 (s, 1H) , 4.75 (s, 1H) , 4.36 (s, 1H) , 4.13-4.07 (m, 1H) , 4.05-3.91 (m, 1H) , 3.86 (s, 1H) , 3.09 (s, 3H) , 3.03-2.99 (m, 1H) , 2.87-2.81 (m, 1H) , 2.07 (s, 3H) , 1.74 (s, 9H) , 1.43 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.60, -130.40, -172.20; LC-MS: m/z = 655.0 [M+H] ⁺.

Compound 123 and Compound 124: (S) -2-amino-4- ( (5R, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 123) and (R) -2-amino-4- ( (5R, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 124)

Mixture of Compound 123 and Compound 124 were obtained by following the procedures described in the synthesis of Compound 120. Prep-HPLC (MeCN/water/NH₄HCO₃) separation afforded Compound 123 as the first fraction and Compound 124 as the second fraction.

Compound 123: ¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H) , 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.16 –7.10 (m, 1H) , 5.34 (s, 1H) , 5.20 (s, 1H) , 4.49 (d, J = 6.4 Hz, 1H) , 4.09 (d, J = 10.0 Hz, 1H) , 3.94 (d, J =10.4 Hz, 1H) , 3.79 (d, J = 11.6 Hz, 1H) , 3.08 (d, J = 8.8 Hz, 2H) , 3.04 –2.97 (m, 2H) , 2.82 (d, J = 6.8 Hz, 1H) , 2.17 –2.10 (m, 1H) , 2.00 (dd, J = 30.8, 21.6 Hz, 4H) , 1.88 –1.51 (m, 7H) , 1.44 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.60, -130.49, -172.10; LC-MS: m/z = 655.0 [M+H] ⁺.

Compound 124: ¹H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2H) , 7.23 (dd, J = 8.4, 5.2 Hz, 1H) , 7.16-7.10 (m, 1H) , 5.19 (s, 2H) , 4.64 (d, J = 6.8 Hz, 1H) , 4.08 (s, 1H) , 3.96 (s, 1H) , 3.78 (d, J = 11.2 Hz, 1H) , 3.08 (s, 2H) , 3.03 (s, 2H) , 2.83 (s, 1H) , 2.09 (d, J = 25.2 Hz, 4H) , 1.76 (s, 6H) , 1.71-1.48 (m, 2H) , 1.43 (d, J =6.4 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.60, -130.49, -172.10; LC-MS: m/z = 655.0 [M+H] ⁺.

Compound 125: 2-amino-7-fluoro-4- ( (S) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 125)

Step 1: Synthesis of (S) -7-bromo-8-fluoro-2- (methylthio) -5- (piperidin-2-ylmethoxy) quinazoline (Compound 125-1)

To a solution of (S) -piperidin-3-ylmethanol (375 mg, 3.26 mmol) in toluene (10 mL) at 0 ℃under N₂ atmosphere was added sodium tert-butoxide (626 mg, 6.51 mmol) . The mixture was stirred at 0 ℃ for 30 minutes before addition of Intermediate 5 (500 mg, 1.63 mmol) . It was heated to 50 ℃ and stirred for another2 hours. The reaction was cooled to room temperature and quenched with water (10 mL) , extracted with ethyl acetate (100 mL) and washed with brine (50 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated to afford Compound 125-1 (530 mg, crude) as a light yellow oil. It was used in the next step without further purification.

Step 2: Synthesis of (S) -2-bromo-1-fluoro-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 125-2)

To a solution of Compound 125-1 (530 mg, crude) in N, N-dimethylacetamide (5 mL) at 25 ℃under N₂ atmosphere was added N, N-diisopropylethylamine (708 mg, 5.49 mmol) and HATU (1.04 g, 2.74 mmol) . The mixture was stirred at 25 ℃ for 1 hour. The mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%～15%) to afford Compound 125-2 (180 mg, 29%yield of two steps) as a white solid.

Step 3: Synthesis of tert-butyl (S) - (3-cyano-7-fluoro-4- (1-fluoro-12- (methylthio) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 125-3)

A mixture of Compound 125-2 (180 mg, 0.47 mmol) , 5-a (568 mg, 1.41 mmol) , cesium carbonate (768 mg, 2.34 mmol) and Pd (dppf) Cl₂. CH₂Cl₂ (81 mg, 0.10 mmol) in toluene (15 mL) was stirred at 100 ℃ for 2 hours under N₂ atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate (70 mL) and washed with water (25 mL) and brine (25 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%～15%) to afford Compound 125-3 (120 mg, 43%yield) as a yellow oil.

Step 4: Synthesis of tert-butyl (3-cyano-7-fluoro-4- ( (5aS) -1-fluoro-12- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 125-4)

To a solution of Compound 125-3 (120 mg, 0.20 mmol) in dichloromethane (5 mL) at 0 ℃under N₂ atmosphere was added 3-chloroperoxybenzoic acid (49 mg, 0.24 mmol, wt 85%) , and the mixture was stirred at 0 ℃ for 20 minutes. Then the mixture was diluted with ethyl acetate (50 mL) , washed with sat. NaHCO₃ (30 mL) , water (30 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 125-4 (140 mg, crude) as a yellow oil. It was used for next step without further purification.

Step 5: Synthesis of tert-butyl (3-cyano-7-fluoro-4- ( (S) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 125-5)

To a mixture of Compound 125-4 (140 mg, crude) and 4-a (96 mg, 0.60 mmol) in toluene (3 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (58 mg, 0.60 mmol) . The mixture was stirred at 0 ℃ for 30 mins and quenched with water (15 mL) . The separated aqueous phase was extracted with ethyl acetate (50 mL) . The combined organic phases were washed with brine (25 mL) , dried over Na₂SO₄, filtered, and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1: 15) to afford Compound 125-5 (98 mg, 69 %yield of two steps) as a yellow oil. LC-MS: m/z = 707.3 [M+H] ⁺. Step 6: Synthesis of 2-amino-7-fluoro-4- ( (S) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 125)

To a mixture of Compound 125-5 (98 mg, 0.14 mmol) in dichloromethane (3 mL) was added TFA (1 mL) , and the mixture was stirred at 20 ℃ for 3 hours. Then, the mixture was diluted with ethyl acetate (50 mL) and washed with sat. Na₂CO₃ (50 mL) , water (50 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (MeOH/DCM = 1/10) to afford Compound 125 (52 mg, 62%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.23 (dd, J = 13.6, 6.8 Hz, 1H) , 7.00 (t, J = 8.8 Hz, 1H) , 6.78 (d, J = 6.0 Hz, 1H) , 5.46-5.29 (m, 2H) , 4.54-4.43 (m, 2H) , 4.40-4.31 (m, 2H) , 3.92 (d, J = 7.2 Hz, 1H) , 3.66-3.49 (m, 3H) , 3.27-3.17 (m, 1H) , 3.05 (d, J = 12.8 Hz, 1H) , 2.57-2.29 (m, 3H) , 2.21-2.12 (m, 2H) , 2.06-1.95 (m, 2H) , 1.90-1.73 (m, 4H) , 1.68-1.61 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.09, -135.89, -174.12; LC-MS: m/z = 607.2 [M+H] ⁺.

Compound 126: Synthesis of (S) -2- ( (S) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline-3-carbonitrile (Compound 126)

A mixture of Compound 28 (150 mg, 0.23 mmol) , zinc cyanide (138 mg, 1.17 mmol) , and methanesulfonato (2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1, 1'-biphenyl) (2'-amino-1, 1'-biphenyl-2-yl) palladium (II) (98 mg, 0.12 mmol) in dimethylacetamide (5 mL) was stirred at 100 ℃ for 1.5 hours under N₂ atmosphere upon microwave irradiation. The mixture was cooled to room temperature, diluted with water (100 mL) , and extracted with ethyl acetate (100 mL x2) . The combined organic layers were washed with brine (100 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-HPLC to afford Compound 126 (31mg, 21.4%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.32-7.21 (m, 1H) , 7.04 (t, J = 8.8 Hz, 1H) , 5.40-5.39 (m, 2H) , 4.54 (d, J = 3.2 Hz, 2H) , 4.29 (d, J = 10.8 Hz, 1H) , 4.19 (d, J = 10.4 Hz, 1H) , 4.09-3.92 (m, 1H) , 3.34-3.30 (m, 1H) , 3.25-3.18 (m, 2H) , 3.15-3.06 (m, 1H) , 3.03-2.95 (m, 1H) , 2.39-2.09 (m, 3H) , 2.06-1.93 (m, 4H) , 1.89-1.73 (m, 4H) , 1.70-1.53 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -117.91, -132.19, -173.71; LC-MS: m/z = 632.2 [M+H] ⁺.

Compound 127: 2-amino-7-fluoro-4- ( (S) -11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-1, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 127)

Step 1-Step 4: Synthesis of 4, 5, 7-trichloro-2- (methylthio) pyrido [2, 3-d] pyrimidine (Intermediate 8)

Intermediate 8 was obtained by following the procedures step 2 through 5bdescribed in the synthesis of Intermediate 6 and Intermediate 7from methyl 2-amino-4, 6-dichloronicotinate.

Compound 127 was obtained by following the procedures described in the synthesis of Compound 110 from Intermediate 8. ¹H NMR (400 MHz, CD₃OD) : δ 7.45-7.32 (m, 1H) , 7.07-6.92 (m, 1H) , 6.86-6.72 (m, 1H) , 5.51-5.29 (m, 2H) , 4.66-4.60 (m, 1H) , 4.54-4.44 (m, 2H) , 4.22-4.07 (m, 1H) , 3.95-3.84 (m, 1H) , 3.69-3.66 (m, 1H) , 3.57-3.47 (m, 3H) , 3.23-3.18 (m, 1H) , 2.53-2.13 (m, 6H) , 2.04-1.95 (m, 2H) , 1.87-1.66 (m, 4H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -114.30, -169.98; LC-MS: m/z = 590.2 [M+H] ⁺.

Compound 128: 2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 128)

Synthesis of ( (2S, 4R) -4- ( (tert-butyldimethylsilyl) oxy) piperidin-2-yl) methanol (Compound 128-4) .

Step1: Synthesis of 1- (tert-butyl) 2-methyl (2S, 4R) -4-hydroxypiperidine-1, 2-dicarboxylate (Compound 128-1a) and 1- (tert-butyl) 2-methyl (2S, 4S) -4-hydroxypiperidine-1, 2-dicarboxylate (Compound 128-1b)

To a solution of 1- (tert-butyl) 2-methyl (S) -4-oxopiperidine-1, 2-dicarboxylate (7.9 g, 30.70 mmol) in THF (50 mL) was added lithium triisobutyl hydroborate (46.0 mL, 46.06 mmol) at -65 ℃. The mixture was stirred at -65 ℃ for 1.5 hours before it was quenched with ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc/PE = 20%-50%) to afford the mixture of 1- (tert-butyl) 2-methyl (2S, 4R) -4-hydroxypiperidine-1, 2-dicarboxylate (Compound 128-1a) and 1- (tert-butyl) 2-methyl (2S, 4S) -4-hydroxypiperidine-1, 2-dicarboxylate (Compound 128-1b) (3.9 g, 49.0%yield) as an off-yellow oil. The ratio of Compound 128-1a to Compound 128-1b was around 3.5 to 1.

Step 2: Synthesis of methyl (2S, 4R) -4-hydroxypiperidine-2-carboxylate (Compound 128-2)

A mixture of Compound 128-1a/1b (1.9 g, 7.33 mmol) in 4M HCl/dioxane (15 mL) was stirred at 20 ℃ for 3 hours. The mixture was concentrated to afford Compound 128-2 (1.5 g, crude) as an off-white solid. It was used in the next step without further purification.

Step 3: Synthesis of methyl (2S, 4R) -4- ( (tert-butyldimethylsilyl) oxy) piperidine-2-carboxylate (Compound 128-3)

To a solution of Compound 128-2 (1.43 g, crude) in DMF (20 mL) at 0 ℃ under N₂ atmosphere was added imidazole (2.49 g, 36.6 mmol) and TBSCl (1.33 g, 8.82 mmol) . The mixture was stirred at 25 ℃ for 2 hours. The mixture was diluted with EtOAc (50 mL) and washed with sat. Na₂SO₄ (50 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 1/1) to afford Compound 128-3 (1.01 g, 50.4%yield of two steps) as a yellow oil.

Step 4: Synthesis of ( (2S, 4R) -4- ( (tert-butyldimethylsilyl) oxy) piperidin-2-yl) methanol (Compound 128-4)

To a solution of Compound 128-3 (1.01 g, 3.69 mmol) in THF (20 mL) at 0 ℃ under N₂ atmosphere was added LAH (696 mg, 18.3 mmol) . The mixture was heated to reflux for 2 hours. After cooling to room temperature, water (2.0 mL) was added dropwise to the above mixture solution carefully. The inorganic material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford Compound 128-4 (863 mg, 95%yield) as yellow oil. LC-MS: m/z = 246.3 [M+H] ⁺.

Synthesis of 2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 128)

Compound 128 was obtained by following the procedures described in the synthesis of Compound 27. ¹H NMR (400 MHz, CD₃OD) : δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (t, J = 8.8 Hz, 1H) , 5.57-5.37 (m, 1H) , 5.30-5.20 (m, 1H) , 4.62-4.39 (m, 4H) , 4.08-3.96 (m, 2H) , 3.87-3.66 (m, 3H) , 3.09 (t, J = 13.6 Hz, 1H) , 2.63-1.95 (m, 9H) , 1.68-1.49 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.70, -132.54, -174.27; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 129 and Compound 130: (S) -2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 129) and (R) -2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 130)

Compound 129 and Compound 130 were obtained by chiral Prep-HPLC separation of Compound 128 on a CHIRALPAK AD-H column. Compound 129 was the first fraction and Compound 130 was the second fraction eluting from the column.

Compound 129: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (dd, J = 9.2, 8.4 Hz, 1H) , 5.38 (d, J = 52.4 Hz, 1H) , 5.27-5.20 (m, 1H) , 4.59-4.51 (m, 1H) , 4.48-427 (m, 3H) , 4.07-3.96 (m, 2H) , 3.66-3.43 (m, 3H) , 3.27-3.18 (m, 1H) , 3.14-3.03 (m, 1H) , 2.55-2.33 (m, 2H) , 2.27-2.21 (m, 1H) , 2.19-2.09 (m, 4H) , 2.06-1.97 (m, 1H) , 1.63-1.54 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.80, -132.12, -174.04; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 130: ¹H NMR (400 MHz, CD₃OD) δ 7.18 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (dd, J = 9.2, 8.4 Hz, 1H) , 5.38 (d, J = 53.21 Hz, 1H) , 5.24 (dt, J = 13.2, 3.6 Hz, 1H) , 4.56-4.52 (m, 1H) , 4.46-4.37 (m, 2H) , 4.34-4.27 (m, 1H) , 4.06-3.94 (m, 2H) , 3.59-3.39 (m, 3H) , 3.20-3.13 (m, 1H) , 3.11-3.03 (m, 1H) , 2.48-2.33 (m, 2H) , 2.29-2.21 (m, 1H) , 2.19-2.07 (m, 4H) , 2.03-1.94 (m, 1H) , 1.64 (dd, J = 23.6, 12.0 Hz, 1H) , 1.58-1.50 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.86, -132.00, -173.96; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 131 and Compound 132: (R) -2-amino-4- ( (5aS, 7S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 131) and (S) -2-amino-4- ( (5aS, 7S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 132)

Compound 131 and Compound 132 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 131 eluted out as the first fraction and Compound 132 as the second fraction after the Suzuki coupling step.

Compound 131: ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 2H) , 7.22 (dd, J = 8.4, 5.6 Hz, 1H) , 7.18-7.10 (m, 1H) , 5.44 (d, J = 53.2 Hz, 1H) , 5.00 (d, J = 2.8 Hz, 1H) , 4.89 (d, J = 12.8 Hz, 1H) , 4.41-4.19 (m, 5H) , 4.15 (s, 1H) , 3.83-3.35 (m, 4H) , 3.09 (s, 1H) , 2.42-1.72 (m, 10H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.55, -130.25, -172.57; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 132: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 2H) , 7.23 (dd, J = 8.4, 5.6 Hz, 1H) , 7.18-7.10 (m, 1H) , 5.39 (d, J = 54.4 Hz, 1H) , 4.99 (d, J = 2.8 Hz, 1H) , 4.88 (d, J = 12.8 Hz, 1H) , 4.56-4.50 (m, 1H) , 4.37-4.04 (m, 5H) , 3.55-3.33 (m, 4H) , 3.01 (s, 1H) , 2.37-2.07 (m, 3H) , 2.01-1.74 (m, 7H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.54, -130.22, -172.40; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 133: 2-amino-7-fluoro-4- ( (5aS, 7R) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 133)

Compound 133 was obtained by following the procedures described in the synthesis of Compound 105. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 2H) , 7.39-7.36 (m, 1H) , 7.14-7.10 (t, J = 9.2 Hz, 1H) , 5.40-5.26 (m, 1H) , 5.09-5.06 (m, 1H) , 4.98-4.97 (d, J = 4.4 Hz, 1H) , 4.49-4.41 (m, 2H) , 4.25-4.17 (m, 1H) , 4.13-4.05 (m, 1H) , 3.97-3.81 (m, 2H) , 3.26-3.08 (m, 3H) , 3.05-2.96 (s, 1H) , 2.91 (s, 1H) , 2.24-1.79 (m, 8H) , 1.50-1.41 (m, 1H) , 1.34-1.31 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.01, -145.02, -172.25; LC-MS: m/z = 624.3 [M+H] ⁺.

Compound 134: 2-amino-4- ( (2R, 5aS, 8S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 134)

Synthesis of ( (2S, 5S) -5- ( (tert-butyldimethylsilyl) oxy) piperidin-2-yl) methanol (Compound 134-4)

Step 1: Synthesis of 1- (tert-butyl) 2-ethyl (2S, 5S) -5-hydroxypiperidine-1, 2-dicarboxylate (Compound 134-1)

To a solution of 1- (tert-butyl) 2-ethyl (S) -5-oxopiperidine-1, 2-dicarboxylate (1.0 g, 3.7 mmol) in tetrahydrofuran (10 mL) was added sodium borohydride (155 mg, 4.1 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, diluted with water (30 mL) and extracted with ethyl acetate (100 mL x2) . The combined organic layers were washed with water (100 mL x2) and brine (50 mL) , dried over Na₂SO₄, filtered, and concentrated to afford Compound 134-1 (950 mg, crude) as a colorless oil. It was used for the next step without further purification. LC-MS: m/z=174.2 [M-Boc+H] ⁺.

Step 2: Synthesis of ethyl (2S, 5S) -5-hydroxypiperidine-2-carboxylate 2, 2, 2-trifluoroacetate (Compound 134-2)

To a solution of Compound 134-1 (950 mg, crude) in dichloromethane (21 mL) was added trifluoroacetic acid (7 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with sat. NH₄Cl (30 mL) , extracted with ethyl acetate (50 mL x2) . The combined organic phases were washed with water (30 mL x3) and brine (30 mL) and dried over sodium sulfate. The filtrate was concentrated to afford Compound 134-2 (780 mg, crude) as a yellow oil. It was used in the next step without further purification.

Step 3: Synthesis of ethyl (2S, 5S) -5- ( (tert-butyldimethylsilyl) oxy) piperidine-2-carboxylate (Compound 134-3)

To a mixture of Compound 134-2 (780 mg, crude) and imidazole (503 mg, 7.4 mmol) in tetrahydrofuran (20 mL) was added tert-butyldimethylsilyl chloride (844 mg, 5.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. It was diluted with water (50 mL) , extracted with ethyl acetate (30 mL x2) and washed with brine (30 mL) . The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (hexane/ethyl acetate = 5/1) to afford Compound 134-3 (550 mg, 52%yield of three steps) as a white solid. LC-MS: m/z = 288.2 [M+H] ⁺.

Step 4: Synthesis of ( (2S, 5S) -5- ( (tert-butyldimethylsilyl) oxy) piperidin-2-yl) methanol (Compound 134-4)

To a solution of Compound 134-3 (550 mg, 1.9 mmol) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (153 mg, 3.8 mmol) at 0 ℃. Then the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (0.5 mL) and the resulting solid was filtered off. The filtrate was concentrated under reduced pressure to afford Compound 134-4 (406 mg, 87%yield) as an off-yellow oil. LC-MS: m/z = 246.2 [M+H] ⁺.

Synthesis of 2-amino-4- ( (2R, 5aS, 8S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 134)

Compound 134 was obtained by following the procedures described in the synthesis of Compound 111. ¹H NMR (400 MHz, CD₃OD) : δ 7.20-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.55 (t, J = 3.6 Hz, 0.5H) , 5.43-5.40 (m, 1.5H) , 4.64-4.47 (m, 4H) , 4.14 (s, 1H) , 4.96-3.66 (m, 4H) , 3.38-3.34 (m, 1H) , 3.30-3.28 (m, 1H) , 2.66-2.47 (m, 2H) , 2.39-2.17 (m, 4H) , 2.09-1.99 (m, 3H) , 1.80-1.76 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.73, 132.99, -174.26; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 135: 2-amino-7-fluoro-4- ( (S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5a, 6, 8, 9-tetrahydro-5H-4, 7-dioxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 135)

Compound 135 was obtained by following the procedures described in the synthesis of Compound 105. ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 2H) , 7.37 (dd, J = 8.4, 5.6 Hz, 1H) , 7.13 (t, J = 11.6 Hz, 1H) , 5.38 (d, J = 53.2 Hz, 1H) , 4.95 (d, J = 13.6 Hz, 1H) , 4.53-4.47 (m, 2H) , 4.40-4.07 (m, 3H) , 4.06-3.94 (m, 2H) , 3.62-3.44 (m, 3H) , 3.33-2.77 (m, 4H) , 2.28-1.81 (m, 6H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -115.92, -144.52, -172.34; LC-MS: m/z = 610.2 [M+H] ⁺.

Compound 136: (R) -2-amino-4- ( (5aS, 7S) -3-chloro-1, 7-difluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 136)

Synthesis of tert-butyl (2S) -4-fluoro-2- (hydroxymethyl) piperidine-1-carboxylate (Compound 136-2)

Step 1: Synthesis of 1- (tert-butyl) 2-methyl (2S) -4-fluoropiperidine-1, 2-dicarboxylate (Compound 136-1)

Diethylaminosulfur trifluoride (2.2 g, 13.9 mmol) was added dropwise to a mixture of Compound 128-1a and Compound 128-1b (1.8 g, 6.94 mmol) in DCM (36 mL) at 0 ℃. The mixture was stirred for 16 hours while the reaction was allowed to warm up to room temperature gradually. The reaction was quenched with sat. NaHCO₃ (30 mL) and extracted with dichloromethane (30 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%-20%) to afford Compound 136-1 (880 mg, 48.5%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) : δ 6.01-5.62 (m, 1H) , 5.07-4.77 (m, 1H) , 4.63-4.04 (m, 1H) , 3.75 (d, J = 3.2 Hz, 3H) , 3.57-2.99 (m, 2H) , 2.73-2.00 (m, 2H) , 1.83-1.60 (m, 1H) , 1.48-1.43 (m, 9H) .

Step 2: Synthesis of tert-butyl (2S) -4-fluoro-2- (hydroxymethyl) piperidine-1-carboxylate (Compound 136-2)

To a solution of Compound 136-1 (880 mg, 3.37 mmol) in THF (10 mL) and ethanol (10 mL) was added lithium bromide (1.5 g, 16.9 mmol) and sodium borohydride (637 mg, 16.9 mmol) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (15 mL) at 0 ℃ and extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 10%-30%) to afford Compound 136-2 (720 mg, yield 91.6%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) : δ 5.97-5.61 (m, 1H) , 4.87-4.40 (m, 1H) , 4.14-3.87 (m, 1H) , 3.73-3.55 (m, 2H) , 3.08-2.93 (m, 1H) , 2.38-2.09 (m, 1H) , 2.00-1.93 (m, 1H) , 1.81-1.63 (m, 2H) , 1.48-1.47 (m, 9H) .

Compound 136 was obtained starting from Compound 136-2 by following the procedures described in the synthesis of Compound 111. ¹H NMR (400 MHz, DMSO-d₆) : δ 8.12 (s, 2H) , 7.23-7.20 (m, 1H) , 7.17-7.12 (m, 1H) , 5.54-5.33 (m, 1H) , 5.17 (d, J = 48.0 Hz, 1H) , 4.98 (d, J = 13.2 Hz, 1H) , 4.54-4.40 (m, 3H) , 4.28-4.24 (m, 1H) , 3.84-3.41 (m, 3H) , 3.28-2.93 (m, 3H) , 2.38-1.76 (m, 10H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -116.48, -130.05, -172.72, -182.76; LC-MS: m/z = 657.2 [M-H] ^-.

Compound 137: (S) -2-amino-4- ( (5aS, 7S) -3-chloro-1, 7-difluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 137)

Compound 137 was obtained starting from Compound 136-2 by following the procedures described in the synthesis of Compound 111.

¹H NMR (400 MHz, DMSO-d₆) : δ 8.13 (s, 2H) , 7.25-7.22 (m, 1H) , 7.17-7.12 (m, 1H) , 5.55-5.42 (m, 1H) , 5.17 (d, J = 47.6 Hz, 1H) , 5.00 (d, J = 10.8 Hz, 1H) , 4.62-4.32 (m, 4H) , 4.25-4.22 (m, 1H) , 3.72-3.47 (m, 3H) , 3.32-3.01 (m, 2H) , 2.38-1.83 (m, 10H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -116.45, -129.89, -172.68, -182.75; LC-MS: m/z = 657.1 [M-H] ^-.

Compound 138 and Compound 139: (R) -2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 138) and (S) -2-amino-4- ( (5aS, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 139)

Compound 138 and Compound 139 were obtained by chiral Prep-HPLC separation on a CHIRALPAK AD-H column. Compound 138 was the first fraction and Compound 139 was the second fraction eluting from the column.

Compound 138: LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 139: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.16 (m, 1H) , 7.04-7.00 (m, 1H) , 5.39-5.26 (m, 1H) , 5.15-5.10 (m, 1H) , 4.55-4.51 (m, 1H) , 4.37-4.24 (m, 3H) , 4.06-4.00 (m, 1H) , 3.48-3.32 (m, 2H) , 3.27-3.24 (m, 1H) , 3.17-3.04 (m, 2H) , 2.33-2.14 (m, 4H) , 2.07-1.99 (m, 3H) , 1.87-1.82 (m, 3H) , 1.45 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -118.95, -131.63, -173.74; LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 140 and Compound 141: (S) -2-amino-4- ( (5aS, 7S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 140) and (R) -2-amino-4- ( (5aS, 7S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 141)

Compound 140 (Less polar) and Compound 141 (More polar) were obtained by Prep-TLC (MeOH/DCM = 1/9) separation.

Compound 140: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.17 (m, 1H) , 7.05-7.00 (m, 1H) , 5.46-5.33 (m, 1H) , 5.14-5.10 (m, 1H) , 4.59-4.27 (m, 5H) , 3.64-3.39 (m, 4H) , 3.24-3.18 (m, 1H) , 2.53-2.36 (m, 2H) , 2.27-2.11 (m, 3H) , 1.89-1.74 (m, 4H) , 1.61-1.56 (m, 1H) , 1.30 (s, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -118.84, -132.23, -174.00; LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 141: ¹H NMR (400 MHz, CD₃OD) δ 7.18-7.15 (m, 1H) , 7.04-7.00 (m, 1H) , 5.46-5.33 (m, 1H) , 5.14-5.10 (m, 1H) , 4.59-4.25 (m, 5H) , 3.61-3.39 (m, 4H) , 3.21-3.15 (m, 1H) , 2.48-2.33 (m, 2H) , 2.26-2.17 (m, 2H) , 2.12-2.02 (m, 2H) , 1.88-1.70 (m, 3H) , 1.61-1.59 (m, 1H) , 1.31 (s, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.88, -132.20, -174.00; LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 142: 2-amino-7-fluoro-4- ( (5aS, 7S) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-

tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 142)

Compound 142 was obtained by following the procedures described in the synthesis of Compound 105. ¹H NMR (400 MHz, CD₃OD) : δ 7.38 (dd, J = 8.4, 5.2 Hz, 1H) , 7.05-7.00 (m, 1H) , 5.41 (d, J = 53.2 Hz, 1H) , 5.27-5.19 (m, 1H) , 4.59-4.56 (m, 1H) , 4.51-4.45 (m, 2H) , 4.41-4.36 (m, 1H) , 4.33-4.26 (m, 1H) , 3.65-3.40 (m, 4H) , 3.25-3.13 (m, 1H) , 2.54-2.32 (m, 2H) , 2.28-2.08 (m, 3H) , 2.04-1.89 (m, 2H) , 1.83-1.64 (m, 3H) , 1.29 (s, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -117.83, -145.68, -173.92; LC-MS: m/z = 638.3 [M+H] ⁺.

Compound 143: 2-amino-7-fluoro-4- ( (5aS, 7R) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-hydroxy-7-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 143)

Compound 143 was obtained by following the procedures described in the synthesis of Compound 105. ¹H NMR (400 MHz, DMSO-d₆) : δ 8.11 (s, 2H) , 7.37 (dd, J = 8.4, 5.2 Hz, 1H) , 7.17-7.07 (m, 1H) , 5.33 (d, J = 54.0 Hz, 1H) , 5.02-4.90 (m, 1H) , 4.73 (s, 1H) , 4.53-4.37 (m, 2H) , 4.31-4.02 (m, 2H) , 4.00-3.92 (m, 1H) , 3.28-3.00 (m, 4H) , 2.95-2.80 (m, 1H) , 2.30-2.01 (m, 3H) , 1.91-1.77 (m, 4H) , 1.73- 1.67 (m, 2H) , 1.62-1.51 (m, 1H) , 1.33 (s, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -116.01, -144.96, -172.21; LC-MS: m/z = 638.2 [M+H] ⁺.

Compound 144 and Compound 145: 2-amino-4- ( (2R, 5aS, 8S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-hydroxy-8-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 144) and 2-amino-4- ( (2S, 5aS, 8S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-hydroxy-8-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 145)

Compound 144 (Less polar) and Compound 145 (More polar) were obtained by Prep-TLC (MeOH/DCM = 1/15) separation.

Compound 144: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.15 (m, 1H) , 7.05-7.00 (m, 1H) , 5.43-5.18 (m, 2H) , 4.52-4.51 (m, 2H) , 4.43-4.26 (m, 2H) , 3.85 (d, J = 10.8 Hz, 1H) , 3.52-3.40 (m, 3H) , 3.13-3.08 (m, 2H) , 2.45-2.00 (m, 7H) , 1.98-1.76 (m, 4H) , 1.31 (s, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.97, -132.28, -173.92; LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 145: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.17 (m, 1H) , 7.05-7.01 (m, 1H) , 5.45-5.16 (m, 2H) , 4.50-4.36 (m, 4H) , 3.90 (d, J = 10.4 Hz, 1H) , 3.59-3.38 (m, 3H) , 3.23-3.09 (m, 2H) , 2.52-1.75 (m, 11H) , 1.31 (s, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.84, -132.10, -173.97; LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 146: 2-amino-4- ( (2R, 5aR, 6S, 7R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 146)

¹H NMR (400 MHz, CD₃OD) : δ 7.24-7.18 (m, 1H) , 7.02 (t, J = 9.2 Hz, 1H) , 5.49-5.34 (m, 1H) , 5.05-4.95 (m, 1H) , 4.70 (dd, J = 13.2, 5.2 Hz, 1H) , 4.54-4.45 (m, 2H) , 4.36 (d, J = 11.6 Hz, 1H) , 4.18 (dd, J = 10.0, 4.8 Hz, 1H) , 3.87-3.81 (m, 2H) , 3.72-3.43 (m, 3H) , 3.26-3.17 (m, 1H) , 3.14-3.03 (m, 1H) , 2.52-2.27 (m, 3H) , 2.19-2.12 (m, 3H) , 2.03-1.98 (m, 1H) , 1.85-1.76 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.84, -132.15, -174.07; LC-MS: m/z = 673.2 [M+H] ⁺.

Compound 147 and Compound 148: (S) -2-amino-4- ( (S) -3-chloro-1, 7, 7-trifluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 147) and (R) -2-amino-4- ( (S) -3-chloro-1, 7, 7-trifluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 148)

Compound 147 and Compound 148 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 147 was the first fraction and Compound 148 was the second fraction of the separation of the Suzuki coupling product.

Compound 147: ¹H NMR (400 MHz, CD₃OD) : δ 7.21-7.16 (m, 1H) , 7.03 (t, J = 8.8 Hz, 1H) , 5.50-5.26 (m, 2H) , 4.74-4.57 (m, 1H) , 4.50-4.29 (m, 3H) , 4.23-4.11 (m, 1H) , 3.59-3.39 (m, 3H) , 3.25-3.13 (m, 2H) , 2.47-1.91 (m, 10H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -93.62, -103.93, -120.31, -133.06, -175.48; LC-MS: m/z = 675.1 [M-H] ^-.

Compound 148: ¹H NMR (400 MHz, CD₃OD) : δ 7.23-7.09 (m, 1H) , 7.02 (t, J = 8.8 Hz, 1H) , 5.41-5.27 (m, 2H) , 4.75-4.43 (m, 2H) , 4.39-4.21 (m, 2H) , 4.17-4.10 (m, 1H) , 3.53-3.32 (m, 3H) , 3.28-3.18 (m, 1H) , 3.16-3.02 (m, 1H) , 2.41-1.88 (m, 10H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -93.55, -104.06, -120.41, -132.83, -175.36; LC-MS: m/z = 675.2 [M-H] ^-.

Compound 149 and Compound 150: 2-amino-4- ( (2S, 5aR, 6R) -rel-3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 149) and 2-amino-4- ( (2R, 5aR, 6R) -rel-3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 150)

Compound 149 and Compound 150 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 149 was the first fraction and Compound 150 was the second fraction of separation of Suzuki coupling products.

Compound 149: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.22-7.09 (m, 2H) , 5.28 (d, J = 54.4 Hz, 1H) , 4.89 (d, J = 3.6 Hz, 1H) , 4.70 (d, J = 7.6 Hz, 2H) , 4.30-4.18 (m, 2H) , 4.07 (d, J = 4.0 Hz, 1H) , 4.02-3.97 (m, 1H) , 3.78 (s, 1H) , 3.10 (s, 2H) , 3.01 (s, 2H) , 2.83 (s, 1H) , 2.08 (d, J = 15.6 Hz, 4H) , 1.80 (d, J =28.8 Hz, 5H) , 1.54 (s, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.6, -130.3, -171.8; LC-MS: m/z =657.1 [M+H] ⁺.

Compound 150: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.28-7.24 (m, 1H) , 7.14 (t, J = 8.0 Hz, 1H) , 5.55-5.07 (m, 1H) , 4.90 (s, 1H) , 4.69 (s, 2H) , 4.26 (d, J = 16.0 Hz, 3H) , 4.17-4.07 (m, 1H) , 3.80 (s, 1H) , 3.07 (s, 5H) , 2.10 (s, 4H) , 1.83 (s, 5H) , 1.55 (s, 1H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.6, -130.1, -171.5; LC-MS: m/z = 657.1 [M+H] ⁺.

Compound 151: 2-amino-4- ( (2R, 5aR, 6R) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-hydroxy-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 151)

Compound 151 was obtained from the chiral headpiece (2R, 3R) -2- (hydroxymethyl) piperidin-3-ol, by following the procedures described in the synthesis of compound 111. ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.17 (m, 1H) , 7.05-6.99 (m, 1H) , 5.42-5.26 (m, 1H) , 5.05-5.00 (m, 1H) , 4.69-4.63 (m, 1H) , 4.48-4.39 (m, 2H) , 4.27-4.18 (m, 2H) , 3.96 (s, 1H) , 3.49-3.32 (m, 3H) , 3.15-3.06 (m, 2H) , 2.45-2.19 (m, 4H) , 2.08-1.84 (m, 5H) , 1.65-1.59 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.00, -131.88, -173.85; LC-MS: m/z = 657.2 [M+H] ⁺.

Compound 152 and Compound 153: 2-amino-4- ( (2S, 5aS) -3-chloro-1, 8, 8-trifluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 152) and 2-amino-4- ( (2R, 5aS) -3-chloro-1, 8, 8-trifluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 153)

Compound 152 and Compound 153 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 152 was the first fraction and Compound 153 was the second fraction of separation of Suzuki coupling product.

Compound 152: ¹H NMR (400 MHz, CD₃OD) δ 7.20 (dd, J = 8.4, 5.2 Hz, 1H) , 7.06-6.98 (m, 1H) , 5.56-5.35 (m, 2H) , 4.63-4.45 (m, 4H) , 4.04 (d, J = 9.2 Hz, 1H) , 3.67-3.36 (m, 4H) , 2.61-1.97 (m, 10H) , 1.28 (s, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -100.89, -105.88, -118.68, -131.63, -174.13; LC-MS: m/z = 677.2 [M+H] ⁺.

Compound 153: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.06-7.00 (m, 1H) , 5.50 (s, 1H) , 5.36 (s, 1H) , 4.61-4.40 (m, 4H) , 4.01 (d, J = 10.4 Hz, 1H) , 3.61-3.40 (m, 4H) , 2.40-1.97 (m, 10H) , 1.33 (s, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -100.93, -106.10, -118.67, -131.63, -174.13; LC-MS: m/z = 677.2 [M+H] ⁺.

Compound 154 and Compound 155: (S) -2-amino-4- ( (S) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3, 4, 13, 13a-tetrahydro-1H- [1, 4] oxazino [3', 4': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 154) and (R) -2-amino-4- ( (S) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3, 4, 13, 13a-tetrahydro-1H- [1, 4] oxazino [3', 4': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrileoxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 155)

Compound 154 and Compound 155 were obtained from separation of their atropisomeric mixture by Prep-HPLC (NH₄HCO₃) . Compound 154 was the first fraction and Compound 155 was the second fraction eluting from the column.

Compound 154: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.14 (t, J = 8.8 Hz, 1H) , 5.27 (d, J = 53.6 Hz, 1H) , 4.77 (d, J = 13.2 Hz, 1H) , 4.53 (dd, J = 13.2, 3.2 Hz, 1H) , 4.38 (dd, J = 13.2, 4.8 Hz, 1H) , 4.10 (d, J = 10.4 Hz, 1H) , 4.06 (s, 1H) , 3.97 (d, J = 10.0 Hz, 3H) , 3.58 (t, J =10.8 Hz, 2H) , 3.26 (t, J = 11.2 Hz, 1H) , 3.05 (dd, J = 24.4, 10.0 Hz, 3H) , 2.83 (t, J = 7.2 Hz, 1H) , 2.14-1.98 (m, 3H) , 1.79 (dt, J = 14.8, 11.6 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.50, -129.70, -172.10; LC-MS: m/z = 643.1 [M+H] ⁺.

Compound 155: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.14 (t, J = 8.8 Hz, 1H) , 5.27 (d, J = 54.2 Hz, 1H) , 4.79 (d, J = 13.2 Hz, 1H) , 4.44 (ddd, J = 16.8, 13.6, 4.4 Hz, 2H) , 4.10 (d, J = 10.4 Hz, 2H) , 4.01 –3.95 (m, 3H) , 3.56 (t, J = 10.8 Hz, 2H) , 3.29-3.22 (m, 1H) , 3.110-3.00 (m, 3H) , 2.82 (dd, J = 14.8, 8.4 Hz, 1H) , 2.14-1.98 (m, 3H) , 1.87-1.73 (m, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.50, -129.80, -172.10; LC-MS: m/z = 643.1 [M+H] ⁺.

Compound 156 and Compound 157: 2-amino-4- ( (10S) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 2-dioxido-3, 4, 13, 13a-tetrahydro-1H- [1, 4] thiazino [3', 4': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 156) and 2-amino-4- ( (10R) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro- 1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 2-dioxido-3, 4, 13, 13a-tetrahydro-1H- [1, 4] thiazino [3', 4': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 157)

Compound 156 and Compound 157 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 156 was the first fraction and Compound 157 was the second fraction of separation of Suzuki coupling products.

Compound 156: LC-MS: m/z = 691.1 [M+H] ⁺.

Compound 157: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.14 (m, 1H) , 7.02 (dd, J= 8.8 Hz, J= 0.8 Hz, 1H) , 5.39-5.26 (m, 1H) , 5.48-5.26 (m, 1H) , 4.64-4.57 (m, 2H) , 4.56-4.50 (m, 1H) , 4.37-4.29 (m, 1H) , 4.28-4.21 (m, 1H) , 3.65-3.56 (m, 2H) , 3.50-3.35 (m, 3H) , 3.28-3.22 (m, 2H) , 3.11-3.01 (m, 1H) , 2.42-2.33 (m, 1H) , 2.32-2.11 (m, 3H) , 2.08-1.98 (m, 2H) , 1.97-1.86 (m, 1H) , 1.37-1.29 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD-d₄) δ -118.82, -130.65, -173.76; LC-MS: m/z = 691.1 [M+H] ⁺.

Compound 158: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 158)

Compound 158 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 2H) , 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.19-7.10 (m, 1H) , 5.02 (d, J = 12.8 Hz, 1H) , 4.54-4.40 (m, 4H) , 4.05-3.92 (m, 1H) , 3.03 (t, J = 12.0 Hz, 1H) , 2.87-2.58 (m, 3H) , 2.51 (s, 3H) , 2.21-2.04 (m, 1H) , 2.03-1.67 (m, 8H) , 1.53-1.48 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.55, -130.23; LC-MS: m/z = 597.2 [M+H] ⁺.

Compound 159: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 159)

Compound 159 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, CD₃OD) δ 7.12-7.13 (m, 1H) , 7.07-6.96 (t, J = 8.8 Hz, 1H) , 5.28-5.17 (d, J = 13.2 Hz, 1H) , 4.90-4.82 (m, 1H) , 4.45-4.34 (m, 5H) , 4.00-3.89 (m, 1H) , 3.49-3.41 (m, 1H) , 3.12-3.02 (m, 1H) , 2.66-2.44 (m, 4H) , 2.09-1.97 (m, 3H) , 1.93-1.59 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.98, -131.96; LC-MS: m/z = 613.2 [M-H] ⁺.

Compound 160: 2-amino-4- ( (2R, 5aS) -3-chloro-1-fluoro-12- ( ( (2S, 4R) -4-hydroxy-1-methylpyrrolidin-2-yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2’, 1’: 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 160)

Compound 160 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, CD₃OD) δ 7.12-7.13 (m, 1H) , 7.07-6.96 (t, J = 8.8 Hz, 1H) , 5.28-5.17 (d, J = 13.2 Hz, 1H) , 4.90-4.82 (m, 1H) , 4.45-4.34 (m, 5H) , 4.00-3.89 (m, 1H) , 3.49-3.41 (m, 1H) , 3.12-3.02 (m, 1H) , 2.66-2.44 (m, 4H) , 2.09-1.97 (m, 3H) , 1.93-1.59 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.98, -131.96; LC-MS: m/z = 613.2 [M+H] ⁺.

Compound 161: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 161)

Compound 161 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.13 (m, 1H) , 7.06-6.97 (t, J = 8.8 Hz, 1H) , 5.27-5.18 (d, J = 12.4 Hz, 1H) , 4.54-4.36 (m, 4H) , 4.01-3.89 (m, 2H) , 3.45-3.37 (m, 1H) , 3.35-3.33 (s, 3H) , 3.19-2.98 (m, 2H) , 2.56-2.52 (s, 3H) , 2.45-2.36 (m, 1H) , 2.13-2.00 (m, 2H) , 1.97-1.88 (m, 2H) , 1.86-1.77 (m, 2H) , 1.74-1.62 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -115.11, -127.72; LC-MS: m/z = 627.2 [M+H] ⁺.

Compound 162: (R) -2-amino-4- ( (S) -3-chloro-12- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 162)

Compound 162 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, CD₃OD) δ 7.14-7.05 (s, 1H) , 7.02-6.87 (s, 1H) , 5.20-5.06 (m, 1H) , 4.87-4.81 (m, 1H) , 4.57-4.28 (m, 3H) , 4.25-4.14 (s, 1H) , 3.95-3.81 (s, 1H) , 3.11-2.92 (m, 2H) , 2.83-2.74 (s, 6H) , 1.98-1.80 (m, 2H) , 1.78-1.64 (m, 3H) , 1.59-1.16 (m, 1H) , 0.89-0.79 (m, 2H) , 0.77-0.67 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.76, -133.99; LC-MS: m/z = 611.2 [M+H] ⁺.

Compound 163: (R) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitril (Compound 163)

Compound 163 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 112. ¹H NMR (400 MHz, CD₃OD) δ 7.17 (dd, J = 8.0, 4.8 Hz, 1H) , 7.04-6.99 (m, 1H) , 5.22 (d, J = 12 Hz, 1H) , 4.63 (s, 1H) , 4.52-4.47 (m, 1H) , 4.41-4.36 (m, 2H) , 3.93 (s, 1H) , 3.64 (d, J = 10.0 Hz, 4H) , 3.48 (s, 1H) , 3.08 (dd, J = 25.2, 12.0 Hz, 2H) , 2.51 (s, 4H) , 2.02 (s, 1H) , 1.82 (dd, J = 26.0, 12.8 Hz, 5H) , 0.69 (s, 2H) , 0.48 (s, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.13, -131.63; LC-MS: m/z = 653.2 [M+H] ⁺.

Compound 164: ( (3S, 7aS) -rel-7a- ( ( ( (S) -2- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-12-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate (Compound 164)

Step 1: Synthesis of tert-butyl ( (R) -4- ( (S) -12- ( ( (3S, 7aS) -3- ( ( (tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 164-1)

To a solution of Compound 112-2 (101 mg, 0.16 mmol) and 1-d (131 mg, 0.32 mmol) in toluene (8 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (46 mg, 0.48 mmol) . The mixture was stirred at 0 ℃ for 0.5 h before quenched with water (20 mL) . The reaction was extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH =20/1) to afford Compound 164-1 (51 mg, 32 %yield) as a white solid. LC-MS: m/z = 496.3 [M/2+H] ⁺.

Step 2: Synthesis of tert-butyl ( (R) -4- ( (S) -3-chloro-1-fluoro-12- ( ( (3S, 7aS) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 164-2)

To a solution of Compound 164-1 (51 mg, 0.05 mmol) in THF (5 mL) at 20 ℃ was added tetrabutylammonium fluoride (131 mg, 0.50 mmol) . The mixture was stirred at 20 ℃ for 5 hours, quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2) . The organic layers were combined and washed with brine (50 mL) , dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 20/1) to afford Compound 164-2 (35 mg, 93%yield) as a white solid. LC-MS: m/z = 377.2 [M/2+H] ⁺.

Step 3: Synthesis of (3S, 7aS) -7a- ( ( ( (S) -2- ( (R) -2- ( (tert-butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-12-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate (Compound 164-3)

To a solution of Compound 164-2 (35 mg, 0.05 mmol) in THF (5 mL) at 0 ℃ was added sodium hydride (4 mg, 0.10 mmol, 60%in mineral oil) . The mixture was stirred at 0 ℃ for 0.5 hour before addition of dimethylcarbamic chloride (11 mg, 0.10 mmol) . The mixture was stirred at 0 ℃ for another 1.5 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2) . The organic layers were combined and washed with brine (50 mL) , dried over Na₂SO₄, filtered, and concentrated to afford Compound 164-3 (30 mg, crude) as a yellow solid. It was used for the next step without further purification. LC-MS: m/z = 824.3 [M+H] ⁺.

Step 4: Synthesis of ( (3S, 7aS) -rel-7a- ( ( ( (S) -2- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-12-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate (Compound 164)

To a solution of Compound 164-3 (30 mg, crude) in dichloromethane (3 mL) was added trifluoroacetic acid (4 mL) at 20 ℃. The resulting mixture was stirred at 20 ℃ for 3 hours. The mixture was partitioned between dichloromethane (40 mL) and saturated sodium carbonate solution (20 mL) . The separated organic layer was washed with brine (30 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 164 (12 mg, 33%yield of two steps) as a white solid. ¹H NMR (400 MHz, CD₃OD) : δ 7.22-7.17 (m, 1H) , 7.07-7.02 (m, 1H) , 5.28 (d, J = 10.8 Hz, 1H) , 4.71-4.34 (m, 6H) , 4.22 (br, 1H) , 4.01-3.97 (m, 1H) , 3.57-3.55 (m, 1H) , 3.44-3.37 (m, 1H) , 3.14-3.07 (m, 1H) , 2.91-2.87 (m, 6H) , 2.45-1.64 (m, 14H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.68, -132.34; LC-MS: m/z = 724.2 [M+H] ⁺.

Compound 165 and Compound 166: ( (3R, 7aR) -7a- ( ( ( (S) -2- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-12-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate (Compound 165) and ( (3S, 7aS) -7a- ( ( ( (S) -2- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -3-chloro-1-fluoro-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-12-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate (Compound 166)

Compound 165 and Compound 166 were obtained by chiral Prep-HPLC separation of Compound 164 on a Nanomicro UNICHIRAL AD-5H column. Compound 165 was the first fraction and Compound 166 was the second fraction eluting from the column.

Compound 165: ¹H NMR (400 MHz, CD₃OD) : δ 7.21-7.17 (m, 1H) , 7.06-7.02 (m, 1H) , 5.28 (d, J =12.8 Hz, 1H) , 4.67-4.34 (m, 6H) , 4.21 (br, 1H) , 4.01-3.98 (m, 1H) , 3.57-3.55 (m, 1H) , 3.44-3.37 (m, 1H) , 3.13-3.06 (m, 1H) , 2.90 (d, J = 7.28 Hz, 6H) , 2.41-2.02 (m, 9H) , 1.95-1.64 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.73, -132.42; LC-MS: m/z = 724.2 [M+H] ⁺.

Compound 166: ¹H NMR (400 MHz, CD₃OD) : δ 7.20-7.17 (m, 1H) , 7.05-7.01 (m, 1H) , 5.27 (d, J = 12.8 Hz, 1H) , 4.54-4.47 (m, 2H) , 4.43-4.31 (m, 4H) , 3.98-3.90 (m, 2H) , 3.30-3.30 (m, 1H) , 3.17-3.05 (m, 2H) , 2.91 (d, J = 14.8 Hz, 6H) , 2.42-2.16 (m, 2H) , 2.20-1.60 (m, 12H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.85, -131.98; LC-MS: m/z = 724.2 [M+H] ⁺.

Compound 167: 2-amino-4- ( (5aS, 6aR, 7aR) -3-chloro-1-fluoro-10- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 6a, 7, 7a-hexahydrocyclopropa [4', 5'] pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 167)

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.13 (m, 1H) , 7.03 (dd, J = 11.6, 2.8 Hz, 1H) , 5.35 (s, 1H) , 4.69 (d, J = 10.4 Hz, 1H) , 4.60 (s, 3H) , 4.47-4.38 (m, 1H) , 4.14 (dd, J = 12.8, 8.8 Hz, 1H) , 3.98 (s, 1H) , 3.48 (s, 2H) , 3.19 (s, 1H) , 2.46 (dd, J = 10.8, 7.6 Hz, 1H) , 2.19 (t, J = 7.6 Hz, 2H) , 2.11 (s, 2H) , 2.03 (d, J = 4.8 Hz, 2H) , 1.60 (s, 2H) , 0.99 (d, J = 7.2 Hz, 1H) , 0.88-0.83 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -76.94, -118.96, -174.07; LC-MS: m/z = 639.2 [M+H] ⁺.

Compound 168: 2-amino-4- ( (12aS) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 168)

¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 2H) , 7.26-7.12 (m, 2H) , 5.48 (d, J = 52.0 Hz, 1H) , 4.84-4.79 (m, 1H) , 4.42 (s, 2H) , 4.23-4.08 (m, 2H) , 3.87-3.76 (m, 2H) , 3.68-3.46 (m, 3H) , 3.21-3.07 (m, 1H) , 2.43-2.33 (m, 2H) , 2.25-2.21 (m, 2H) , 2.10-1.86 (m, 5H) , 1.78-1.70 (m, 1H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.61, -131.43, -172.54. LC-MS: m/z = 627.2 [M+H] ⁺.

Compound 169: 2-amino-4- ( (1R, 12aR) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1-hydroxy-2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 169)

¹H NMR (400 MHz, CD₃OD) δ 7.20-7.15 (m, 1H) , 7.06-6.99 (t, J = 20.0 Hz, 1H) , 5.53-5.34 (m, 1H) , 4.97 (d, J = 11.2 Hz, 1H) , 4.67-4.62 (m, 1H) , 4.58-4.48 (m, 2H) , 4.28-4.17 (m, 3H) , 4.01-3.93 (m, 1H) , 3.84-3.55 (m, 4H) , 2.47-2.40 (m, 1H) , 2.35-2.27 (m, 1H) , 2.21-2.14 (m, 3H) , 2.12-1.96 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.87, -133.79, -174.19; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 170 and Compound 171: 2-amino-4- ( (2S, 9S, 12aS) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2-hydroxy-2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 170) and 2-amino-4- ( (2S, 9R, 12aS) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2-hydroxy-2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 171)

Compound 170 and Compound 171 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 170 was the first fraction and Compound 171 was the second fraction of separation of Suzuki coupling products.

Compound 170: ¹H NMR (400 MHz, CD₃OD) δ 7.17 (dd, J = 12.0, 8.0 Hz, 1H) , 7.03 (m, 1H) , 5.46 (d, J = 52.4 Hz, 1H) , 4.76 (d, J = 11.2 Hz, 1H) , 4.65-4.52 (m, 4H) , 4.40-4.21 (m, 2H) , 4.05-3.94 (m, 2H) , 3.92-3.66 (m, 2H) , 3.42-3.33 (m, 1H) , 3.65-2.47 (m, 3H) , 2.41-2.21 (m, 3H) , 2.12-1.99 (m, 1H) , 1.94-1.85 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.75, -134.22, -174.38; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 171: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.18 (m, 1H) , 7.07-7.01 (m, 1H) , 5.47 (d, J = 80.0 Hz, 1H) , 4.72 (d, J = 20.0 Hz, 1H) , 4.71-4.66 (m, 1H) , 4.55-4.51 (m, 1H) , 4.41-4.33 (m, 1H) , 4.32-4.25 (m, 1H) , 4.04-3.93 (m, 3H) , 3.91-3.69 (m, 3H) , 3.41-3.35 (m, 1H) , 2.58-2.46 (m, 3H) , 2.34-2.16 (m, 3H) , 2.05-1.99 (m, 1H) , 1.94-1.88 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.73, -134.71, -174.46; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 172 and Compound 173: 2-amino-4- ( (2R, 9R, 12aS) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2-hydroxy-2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 172) and 2-amino-4- ( (2R, 9S, 12aS) -10-chloro-8-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2-hydroxy-2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 173)

Compound 172 and Compound 173 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 172 was the first fraction and Compound 173 was the second fraction of separation of Suzuki coupling products.

Compound 172: ¹H NMR (400 MHz, CD₃OD) : δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.05-6.99 (m, 1H) , 5.49-5.30 (m, 1H) , 4.81 (d, J = 12.0 Hz, 1H) , 4.55-4.43 (m, 3H) , 4.36 (d, J = 11.6 Hz, 1H) , 4.25-4.11 (m, 2H) , 3.90-3.83 (m, 1H) , 3.65-3.44 (m, 3H) , 3.23-3.13 (m, 1H) , 2.48-2.22 (m, 4H) , 2.17-2.07 (m, 2H) , 2.03-1.93 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.91, -133.66, -174.03; LC-MS: m/z = 643.2 [M+H] ⁺. Compound 173: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (t, J = 8.8 Hz, 1H) , 5.46 (d, J = 52.8 Hz, 1H) , 4.82 (d, J = 12.4 Hz, 1H) , 4.60-4.45 (m, 4H) , 4.24-4.13 (m, 2H) , 3.90-3.83 (m, 2H) , 3.77-3.64 (m, 2H) , 3.37-3.33 (m, 1H) , 2.57-2.46 (m, 2H) , 2.37-2.17 (m, 4H) , 2.09-1.93 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.79, -133.92, -174.28; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 174: 2-amino-4- ( (12aS) -10-chloro-2, 2, 8-trifluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 3, 12, 12a-tetrahydro-1H-pyrrolo [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 174)

¹H NMR (400 MHz, CD₃OD) : δ 7.22-7.16 (m, 1H) , 7.06-7.00 (m, 1H) , 5.52-5.33 (m, 1H) , 4.83 (d, J =12.4 Hz, 1H) , 4.60-4.40 (m, 4H) , 4.37-4.28 (m, 1H) , 4.21 (t, J = 17.6 Hz, 1H) , 3.68-3.51 (m, 3H) , 3.28-3.21 (m, 1H) , 2.81-2.69 (m, 1H) , 2.60-2.37 (m, 3H) , 2.35-2.27 (m, 1H) , 2.20-2.13 (m, 2H) , 2.06-1.97 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -97.27, -108.60, -118.76, -132.59, -174.05; LC-MS: m/z = 663.2 [M+H] ⁺.

Compound 175: 2-amino-4- ( (2R, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (hydroxymethyl) -1, 2, 11, 11a- tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 175)

¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H) , 7.23-7.05 (m, 2H) , 5.42-5.06 (m, 2H) , 4.82-4.65 (m, 3H) , 4.45-4.24 (m, 2H) , 4.16-3.88 (m, 2H) , 3.63-3.51 (m, 1H) , 3.23-2.93 (m, 3H) , 2.85 (s, 1H) , 2.48-2.44 (m, 1H) , 2.31-2.22 (m, 1H) , 2.21-1.69 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d6) δ -116.72, -131.61, -131.94; LC-MS: m/z = 643.2 M+H] .

Compound 176: 2-amino-4- ( (2S, 11aR) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (hydroxymethyl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 176)

¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H) , 7.23-7.06 (m, 2H) , 5.43-5.08 (m, 2H) , 4.83-4.64 (m, 3H) , 4.45-4.23 (m, 2H) , 4.15-3.87 (m, 2H) , 3.65-3.51 (m, 1H) , 3.22-2.96 (m, 3H) , 2.84 (s, 1H) , 2.48-2.43 (m, 1H) , 2.31-2.22 (m, 1H) , 2.17-1.70 (m, 6H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.74, -131.60, -172.08; LC-MS: m/z = 643.2 M+H] ⁺.

Compound 177 and Compound 178: 2-amino-4- ( (2S, 8S, 11aR) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (hydroxymethyl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 177) and 2-amino-4- ( (2S, 8R, 11aR) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (hydroxymethyl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 178)

Compound 177 and Compound 178 were obtained by SFC separation of Compound 176 on a column. Compound 177 was the first fraction and Compound 178 was the second fraction eluting from the column.

Compound 177: ¹H NMR (400 MHz, DMSO-d4) δ 8.07 (s, 2H) , 7.24-7.05 (m, 2H) , 5.39-5.07 (m, 2H) , 4.84-4.63 (m, 3H) , 4.44-4.24 (m, 2H) , 4.10-3.89 (m, 2H) , 3.60-3.52 (m, 1H) , 3.15-2.97 (m, 3H) , 2.86-2.78 (m, 1H) , 2.30-2.20 (m, 1H) , 2.18-1.67 (m, 7H) . ¹⁹F NMR (377 MHz, DMSO-d4) δ -116.72, -131.53, -172.05. LC-MS: m/z = 643.3 [M+H] ⁺.

Compound 178: ¹H NMR (400 MHz, DMSO-d4) δ 8.07 (s, 2H) , 7.22-7.05 (m, 2H) , 5.37-5.14 (m, 2H) , 4.83-4.62 (m, 3H) , 4.47-4.24 (m, 2H) , 4.09-3.87 (m, 2H) , 3.63-3.49 (m, 1H) , 3.16-2.95 (m, 3H) , 2.87-2.76 (m, 1H) , 2.34-2.25 (m, 1H) , 2.21-1.67 (m, 7H) . ¹⁹F NMR (377 MHz, DMSO-d4) δ -116.75, -131.66, -172.01. LC-MS: m/z = 643.3 [M+H] ⁺.

Compound 179: (2R, 11aS) -8- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline-2-carboxamide (Compound 179)

¹H NMR (400 MHz, CD₃OD) δ 7.40-7.19 (m, 1H) , 7.06-7.00 (m, 1H) , 6.94-6.86 (m, 1H) , 5.30-5.10 (m, 2H) , 5.05-4.97 (m, 1H) , 4.86-4.80 (m, 2H) , 4.66-4.54 (m, 2H) , 4.10 (dd, J = 39.2, 10.8 Hz, 2H) , 3.13 (d, J = 7.2 Hz, 1H) , 2.93 (d, J = 5.2 Hz, 1H) , 2.78-2.70 (m, 1H) , 2.41-2.18 (m, 2H) , 2.12-2.05 (m, 2H) , 1.97-1.83 (m, 3H) ; ¹⁹F NMR (376 MHz, CD₃OD) δ -119.10, -132.60, -173.70; LC-MS: m/z = 656.2 [M+H] ⁺.

Compound 180: (2S, 11aS) -8- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazoline-2-carboxamide (Compound 180)

¹H NMR (400 MHz, CD₃OD) δ 7.41-7.35 (m, 1H) , 7.27-7.24 (m, 1H) , 7.13-7.08m, , 1H) , 6.97-6.90 (m, 1H) , 5.27 (dd, J = 28.0, 23.2 Hz, 2H) , 5.08-5.03 (m, 1H) , 4.97-4.84 (m, 2H) , 4.67-4.50 (m, 1H) , 4.32-4.18 (m, 2H) , 4.02-3.98 (m, 1H) , 3.46-3.43 (m, 1H) , 3.38 (d, J = 1.6 Hz, 1H) , 2.80-2.70 (m, 1H) , 2.15-2.07 (m, 2H) , 2.06-1.97 (m, 2H) , 1.97-1.79 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, 133.60, -173.90; LC-MS: m/z = 656.3 [M+H] ⁺.

Compound 181: 2-amino-7-fluoro-4- ( (2R, 10aS) -rel-6-fluoro-4- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 10, 10a-tetrahydro-9-oxa-2a, 3, 5, 8-tetraazacyclobuta [4, 5] cyclohepta [1, 2, 3-de] naphthalen-7-yl) benzo [b] thiophene-3-carbonitrile (Compound 181)

Synthesis of 2- ( (2S, 4R) -rel-4- (hydroxymethyl) azetidin-2-yl) propan-2-ol (Intermediate 9)

Step 1: Synthesis of ( (2S, 4R) -rel-1-benzyl-4- ( ( (tert-butyldiphenylsilyl) oxy) methyl) azetidin-2-yl) methanol (Intermediate 9-1)

To a stirred solution of ( (2S, 4R) -rel-1-benzylazetidine-2, 4-diyl) dimethanol (20 g, 96.6 mmol) and imidazole (6.6 g, 96 mmol) in DMF (200 mL) were added TBDPSCl (16 g, 58 mmol) dropwise at 0 ℃under N₂. The reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with EA (250 mL x 3) . The combined organic phases were washed with brine (250 mL x 2) , dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA= 4/1) to afford Intermediate 9-1 (12 g, 30.2%yield) as a light yellow liquid. LC-MS: m/z = 445.9 [M+H] ⁺.

Step 2: Synthesis of (2S, 4R) -rel-1-benzyl-4- ( ( (tert-butyldiphenylsilyl) oxy) methyl) azetidine-2-carbaldehyde (Intermediate 9-2)

To a solution of oxalyl chloride (8.5 g, 67 mmol) in DCM (250 mL) was dropwise added dimethyl sulfoxide (10.5 g, 134 mmol) in DCM (50 mL) at -78 ℃ under N₂. After addition, the solution was stirred for 30 minutes at this temperature. Then, to the reaction was added Intermediate 9-1 (12 g, 26.4 mmol) in DCM (250 mL) and the mixture was stirred for 2 hours. TEA (100 mL) was added at -78 ℃ and the mixture was allowed to warm to room temperature. The mixture was quenched with water (100 mL) and extracted with EA (500 mL x 3) . The combined organic phases were washed with brine (200 mL x 2) , dried over Na₂SO₄ and concentrated under vacuum to afford Intermediate 9-2 (12 g, 100%yield) as a light-yellow oil. LC-MS: m/z = 443.9 [M+H] ⁺.

Step 3: Synthesis of 1- ( (2S, 4R) -rel-1-benzyl-4- ( ( (tert-butyldiphenylsilyl) oxy) methyl) azetidin-2-yl) ethan-1-ol (Intermediate 9-3)

To a solution of Intermediate 9-2 (12 g, 27.05 mmol) in THF (200 mL) was added methylmagnesium bromide (27.3 mmol, 9.1 mL, 3M in ether) dropwise at 0 ℃ under N₂. Then the reaction solution was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with water (100 mL) , diluted with EtOAc (500 mL) . The separated organic layers were washed with water (500 mL) , brine (500 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 10/1) to afford Intermediate 9-3 (6.5 g, 63.0%yield) as a light-yellow oil. LC-MS: m/z = 457.9 [M+H] ⁺.

Step 4: Synthesis of 1- ( (2S, 4R) -rel-1-benzyl-4- ( ( (tert-butyldiphenylsilyl) oxy) methyl) azetidin-2-yl) ethan-1-one (Intermediate 9-4)

To a solution of oxalyl chloride (4.5 g, 35 mmol) in DCM (50 mL) was dropwise added dimethyl sulfoxide (5.5 g, 70 mmol) in DCM (10 mL) at -78 ℃ under N₂. After addition, the solution was stirred for 30 minutes at this temperature. Then, to the reaction was added Intermediate 9-3 (6.5 g, 14 mmol) in DCM (50 mL) and the mixture was stirred for 2 hours. TEA (100 mL) was added at -78 ℃ and the mixture was allowed to warm to room temperature. The mixture was quenched with water (100 mL) and extracted with EA (500 mL x 3) . The combined organic phases were washed with brine (200 mL x 2) , dried over Na₂SO₄ and concentrated under vacuum to afford Intermediate 9-4 (6.5 g, 100%yield) as a light yellow oil. LC-MS: m/z = 457.9 [M+H] ⁺.

Step 5: Synthesis of 2- ( (2S, 4R) -rel-1-benzyl-4- ( ( (tert-butyldiphenylsilyl) oxy) methyl) azetidin-2-yl) propan-2-ol (Intermediate 9-5)

To a solution of Intermediate 9-4 (6.5 g, 14 mmol) in THF (200 mL) was added methylmagnesium bromide (42 mmol, 14 mL, 3M in ether) dropwised at 0 ℃ under N₂. Then the reaction solution was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with water (100 mL) , diluted with EtOAc (500 mL) and washed with water (250 mL) and brine (250 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 4/1) to afford Intermediate 9-5 (5.5 g, 81.7%yield) as a light oil. LC-MS: m/z = 457.9 [M+H] ⁺.

Step 6: Synthesis of 2- ( (2S, 4R) -rel-1-benzyl-4- (hydroxymethyl) azetidin-2-yl) propan-2-ol (Intermediate 9-6)

To a stirred solution of Intermediate 9-5 (5.5 g, 12 mmol) in THF (110 mL) was added TBAF solution in THF (14 mL, 14 mmol) dropwise at 0 ℃ under N₂. The reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL x 3) . The combined organic phases were washed with brine (100 mL x 2) , dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) to afford Intermediate 9-6 (2.7 g, 98.8%yield) as a light yellow oil. LC-MS: m/z = 235.9 [M+H] ⁺.

Step 7: Synthesis of 2- ( (2S, 4R) -4- (hydroxymethyl) azetidin-2-yl) propan-2-ol (Intermediate 9)

To a stirred mixture of Intermediate 9-6 (2.7g, 11.48 mmol) and Pd/C (1.35 g) in MeOH (15 mL) weas added HCO₂NH₄ (1.44 g, 22.8 mmol) . The reaction was stirred at 80 ℃ for 1 hour. The mixture was filtered through a pad of celite and the filtration was concentrated to afford Intermediate 9 (1.4 g, 84.0%yield) as a light yellow oil. LC-MS: m/z = 146.0 [M+H] ⁺.

Synthesis of 2-amino-7-fluoro-4- ( (2R, 10aS) -rel-6-fluoro-4- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 10, 10a-tetrahydro-9-oxa-2a, 3, 5, 8-tetraazacyclobuta [4, 5] cyclohepta [1, 2, 3-de] naphthalen-7-yl) benzo [b] thiophene-3-carbonitrile (Compound 181)

Compound 181 was obtained by following the procedures described in the synthesis of Compound 72. ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H) , 7.39 –7.32 (m, 1H) , 7.11 (d, J = 9.2 Hz, 1H) , 6.42 (s, 1H) , 5.26 (d, J = 55.2 Hz, 1H) , 4.76 –4.63 (m, 3H) , 4.45 –4.21 (m, 1H) , 4.09 (dt, J = 17.2, 10.4 Hz, 2H) , 3.30 (s, 1H) , 3.07 (d, J = 8.8 Hz, 2H) , 2.99 (s, 1H) , 2.82 (s, 1H) , 2.11 (dd, J = 21.6, 14.4 Hz, 2H) , 1.99 (t, J = 18.0 Hz, 2H) , 1.86 –1.71 (m, 3H) , 1.22 (s, 3H) , 1.05 (s, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -115.90, -146.02, -171.80; LC-MS: m/z = 638.1 [M+H] ⁺.

Compound 182 and Compound 183: 2-amino-4- ( (2R, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 182) and 2-amino-4- ( (2S, 11aR) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 183)

Compound 182-4 was chiral separated by SFC to give Compound 182-5 and Compound 183-5 on acolumn. Compound 182-5 was the first fraction and Compound 183-5 was the second fraction eluting from the column.

Compound 182: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.23-7.06 (m, 2H) , 6.31 (d, J = 68.4 Hz, 1H) , 5.28 (d, J = 54.4 Hz, 1H) , 4.81-4.57 (m, 3H) , 4.37-4.21 (m, 1H) , 4.21-3.89 (m, 2H) , 3.25-2.92 (m, 3H) , 2.91-2.74 (m, 1H) , 2.24-1.63 (m, 8H) , 1.19 (s, 3H) , 1.08 (d, J = 12.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO) δ -116.50, -130.70, -171.80; LC-MS: m/z = 671.1 [M+H] ⁺.

Compound 183: ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H) , 7.22-7.10 (m, 2H) , 6.30 (d, J = 72.8 Hz, 1H) , 5.26 (d, J = 55.2 Hz, 1H) , 4.76-4.60 (m, 3H) , 4.35-4.24 (m, 1H) , 4.19-3.94 (m, 2H) , 3.21-2.92 (m, 3H) , 2.92-2.73 (m, 1H) , 2.22-1.69 (m, 8H) , 1.20 (s, 3H) , 1.08 (d, J = 13.6 Hz, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.20, -130.60, -171.80; LC-MS: m/z = 671.1 [M+H] ⁺.

Compound 184 and Compound 185: 2-amino-4- ( (2R, 8R, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 184) and 2-amino-4- ( (2R, 8S, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (2-hydroxypropan-2-yl) -1, 2, 11, 11a- tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 185)

Compound 184 and Compound 185 were obtained by SFC separation of Compound 182 on a column. Compound 184 was the first fraction and Compound 185 was the second fraction eluting from the column.

Compound 184: ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H) , 7.25-7.07 (m, 2H) , 6.41 (s, 1H) , 5.26 (d, J = 54.4 Hz, 1H) , 4.81-4.55 (m, 3H) , 4.40-4.23 (m, 1H) , 4.16-3.94 (m, 2H) , 3.14-2.93 (m, 3H) , 2.87-2.73 (m, 1H) , 2.24-1.58 (m, 8H) , 1.19 (s, 3H) , 1.06 (s, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.50, -130.80, -171.80. LC-MS: m/z = 671.2 [M+H] ⁺.

Compound 185: ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H) , 7.30-7.01 (m, 2H) , 6.23 (s, 1H) , 5.27 (d, J = 51.2 Hz, 1H) , 4.80-4.50 (m, 3H) , 4.34-4.18 (m, 1H) , 4.17-3.84 (m, 2H) , 3.24-2.90 (m, 3H) , 2.90-2.73 (m, 1H) , 2.24-1.60 (m, 8H) , 1.19 (s, 3H) , 1.09 (s, 3H) ; ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.50, -130.60, -171.80. LC-MS: m/z = 671.3 [M+H] ⁺.

Compound 186: 2-amino-4- ( (11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 186)

¹H NMR (400 MHz, CD₃OD) δ 7.17 (dd, J =4.0, 8.0 Hz, 1H) , 7.08-6.99 (m, 1H) , 5.49-5.32 (m, 1H) , 5.18-5.08 (m, 1H) , 4.80-4.66 (m, 1H) , 4.58-4.27 (m, 5H) , 3.67-3.43 (m, 3H) , 3.28-3.17 (m, 1H) , 2.66-2.40 (m, 3H) , 2.40-2.34 (m, 1H) , 2.34-2.23 (m, 1H) , 2.20-2.09 (m, 2H) , 2.00-1.91 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.88, -133.56, -174.15; LC-MS: m/z = 613.2 [M+H] ⁺.

Compound 187 and Compound 188: 2-amino-4- ( (8S, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3- carbonitrile (Compound 187) and 2-amino-4- ( (8R, 11aS) -9-chloro-7-fluoro-5- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 11, 11a-tetrahydroazeto [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-8-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 188)

Compound 187 and Compound 188 were obtained by chiral Prep-HPLC separation of Compound 186 on a CHIRALPAK AD-H column. Compound 187 was the first fraction and Compound 188 was the second fraction eluting from the column.

Compound 187: LC-MS: m/z = 307.1 [M/2+H] ⁺.

Compound 188: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.18 (m, 1H) , 7.06-7.01 (m, 1H) , 5.50-5.38 (m, 1H) , 4.64-4.62 (m, 2H) , 4.50 (s, 2H) , 4.09-4.05 (m, 4H) , 3.95-3.93 (m, 2H) , 3.78-3.58 (m, 3H) , 3.24-3.30 (m, 1H) , 2.59-2.42 (m, 2H) , 2.32-2.17 (m, 3H) , 2.07-1.99 (m, 1H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -114.88, -129.94, -170.25. LC-MS: m/z = 613.1 [M+H] ⁺.

Compound 189 and Compound 190 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 189) and 2-amino-4- ( (R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 190)

Compound 189 and Compound 190 were obtained by chiral Prep-HPLC separation of Compound 30 on a UNICHIRAL AD-5H column. Compound 189 was the first fraction and Compound 190 was the second fraction eluting from the column.

Compound 189: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.18 (m, 1H) , 7.06-7.01 (m, 1H) , 5.50-5.38 (m, 1H) , 4.64-4.62 (m, 2H) , 4.50 (s, 2H) , 4.09-4.05 (m, 4H) , 3.95-3.93 (m, 2H) , 3.78-3.58 (m, 3H) , 3.24-3.30 (m, 1H) , 2.59-2.42 (m, 2H) , 2.32-2.17 (m, 3H) , 2.07-1.99 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -114.88, -129.94, -170.25; LC-MS: m/z = 631.2 [M+H] ⁺.

Compound 190: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.50-5.38 (m, 1H) , 4.64-4.62 (m, 2H) , 4.55-4.39 (m, 2H) , 4.10-4.05 (m, 4H) , 3.95-3.93 (m, 2H) , 3.78-3.58 (m, 3H) , 3.24-3.30 (m, 1H) , 2.59-2.29 (m, 3H) , 2.22-2.14 (m, 2H) , 2.03-1.95 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -114.90, -129.87, -170.23; LC-MS: m/z = 631.2 [M+H] ⁺.

Compound 191: 2- (9- (2-amino-7-fluorobenzo [d] thiazol-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethan-1-ol (Compound 191)

¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 2H) , 7.18 (dd, J = 8.4, 5.6 Hz, 1H) , 7.05 (t, J = 8.8 Hz, 1H) , 5.63-5.41 (m, 1H) , 4.90 (t, J = 5.6 Hz, 1H) , 4.67-4.43 (m, 4H) , 4.09-3.89 (m, 4H) , 3.87-3.60 (m, 5H) , 3.28-3.16 (m, 1H) , 2.46-2.39 (m, 1H) , 2.33-1.88 (m, 5H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -112.58, -131.05, -172.38; LC-MS: m/z = 607.2 [M+H] ⁺.

Compound 192 and Compound 193: 2-amino-4- ( (R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 192) and 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 193)

Compound 192 and Compound 193 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 192 came from the first fraction and Compound 193 came from the second fraction at the Suzuki coupling eluting from the column.

Compound 192: ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 2H) , 7.24-7.10 (m, 2H) , 5.48-5.24 (m, 1H) , 4.99 (d, J = 5.2 Hz, 1H) , 4.69-4.60 (m, 1H) , 4.57-4.49 (m, 1H) , 4.31-4.07 (m 3H) , 4.05-3.96 (m, 3H) , 3.57-3.49 (m, 1H) , 3.30-3.05 (m, 3H) , 3.03-2.86 (m, 1H) , 2.20-2.06 (m, 2H) , 2.03-1.80 (m, 4H) , 1.14-1.12 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.65, -131.40, -172.25; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 193: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 2H) , 7.24-7.19 (m, 1H) , 7.16-7.10 (m, 1H) , 5.51-5.27 (m, 1H) , 4.95 (d, J = 5.2 Hz, 1H) , 4.62-4.54 (m, 2H) , 4.33-4.04 (m, 5H) , 4.01-3.93 (m, 1H) , 3.65-3.38 (m, 4H) , 3.10-2.94 (m, 1H) , 2.24-2.09 (m, 2H) , 2.04-1.80 (m, 4H) , 1.13 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.64, -131.45, -172.35; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 194: 3- (9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) propanamide (Compound 194)

¹H NMR (400 MHz, CD₃OD) δ 7.26-7.14 (m, 1H) , 7.11-6.97 (m, 1H) , 5.64-5.45 (m, 1H) , 4.80-4.57 (m, 4H) , 4.30-3.74 (m, 7H) , 3.52-3.40 (m, 1H) , 2.82-2.53 (m, 4H) , 2.50-2.25 (m, 3H) , 2.23-2.08 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.52, -134.30, -174.28; LC-MS: m/z = 658.2 [M+H] ⁺.

Compound 195 and Compound 196: 4- ( (R) -4- ( (1S, 2R, 4R) -rel-7-azabicyclo [2.2.1] heptan-2-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -2-amino-7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 195) and 4- ( (S) -4- ( (1S, 2R, 4R) -rel-7-azabicyclo [2.2.1] heptan-2-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -2-amino-7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 196)

Compound 195 and Compound 196 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 195 came from the first fraction and Compound 196 came from the second fraction at the Suzuki coupling eluting from the column.

Compound 195: ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 2H) , 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.04 (t, J =8.8 Hz, 1H) , 5.43 (d, J = 51.6 Hz, 1H) , 4.73-4.57 (m, 3H) , 4.56-4.44 (m, 4H) , 4.06-3.96 (m, 2H) , 3.70-3.60 (m, 2H) , 3.57 (d, J = 14.4 Hz, 1H) , 2.57-2.45 (m, 2H) , 2.44-2.29 (m, 3H) , 2.24-2.14 (m, 2H) , 2.13-2.04 (m, 2H) , 2.03-1.97 (m, 1H) , 1.93-1.87 (m, 1H) , 1.85-1.77 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.63, -132.47, -174.36; LC-MS: m/z = 682.2 [M+H] ⁺.

Compound 196: LC-MS: m/z = 680.2 [M-H] ^-.

Compound 197: 2-amino-4- (8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 197)

Compound 197 was obtained by following the procedures described in the synthesis of Compound 27. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 2H) , 7.26-7.20 (m, 1H) , 7.18-7.10 (m, 1H) , 5.68-5.47 (m, 1H) , 5.44-5.33 (m, 1H) , 4.73-4.49 (m, 4H) , 4.06-3.70 (m, 5H) , 3.66-3.58 (m, 1H) , 3.55-3.47 (m, 1H) , 3.30-3.18 (m, 3H) , 2.47-2.29 (m, 3H) , 2.27-1.89 (m, 5H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.48, -130.66, -172.76; LC-MS: m/z = 656.3 [M+H] ⁺.

Compound 198 and Compound 199: 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 198) and 2-amino-4- ( (R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 199)

Compound 198 and Compound 199 were obtained by chiral Prep-HPLC separation of Compound 197 on a UNICHIRAL AD-5H column. Compound 198 was the first fraction and Compound 199 was the second fraction eluting from the column.

Compound 198: LC-MS: m/z = 656.1 [M+H] ⁺.

Compound 199: LC-MS: m/z = 656.3 [M+H] ⁺.

Compound 200: 2-amino-4- (8-chloro-4- (1, 3-dihydroxypropan-2-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 200)

Compound 200 was obtained by following the procedures described in the synthesis of Compound 27. ¹H NMR (400 MHz, CD₃OD) δ 7.25-7.16 (m, 1H) , 7.03 (t, J = 9.6 Hz, 1H) , 5.61-5.41 (m, 1H) , 5.41-5.31 (m, 1H) , 4.73-4.66 (m, 2H) , 4.66-4.50 (m, 2H) , 4.10-3.67 (m, 9H) , 3.44-3.34 (m, 1H) , 2.73-2.49 (m, 2H) , 2.48-2.21 (m, 3H) , 2.20-1.97 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.77, -134.54, -174.32; LC-MS: m/z = 661.2 [M+H] ⁺.

Compound 201 and Compound 202: 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 201) and 2-amino-4- ( (R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 202)

Compound 201 and Compound 202 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 201 came from the first fraction and Compound 202 came from the second fraction at the Suzuki coupling eluting from the column.

Compound 201: ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 2H) , 7.21 (dd, J = 8.4, 5.6 Hz, 1H) , 7.17-7.08 (m, 1H) , 5.46 (d, J = 52.8 Hz, 1H) , 5.01 (d, J = 4.8 Hz, 1H) , 4.72-4.63 (m, 1H) , 4.59-4.49 (m, 1H) , 4.48-4.12 (m, 3H) , 4.11-3.96 (m, 4.5 Hz, 3H) , 3.81-3.40 (m, 4H) , 3.12 (s, 1H) , 2.44-1.88 (m, 6H) , 1.15 (d, J =6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ-116.65, -131.41, -172.47; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 202: ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 2H) , 7.20 (dd, J = 8.4, 5.2 Hz, 1H) , 7.13 (t, J = 9.2 Hz, 1H) , 5.27 (d, J = 53.2 Hz, 1H) , 4.93 (d, J = 4.8 Hz, 1H) , 4.66-4.52 (m, 2H) , 4.22-4.12 (m, 1H) , 4.10-4.07 (m, 1H) , 4.01-3.99 (m, 3H) , 3.98-3.90 (m, 1H) , 3.49-3.44 (m, 1H) , 3.12-3.04 (m, 2H) , 3.01 (s, 1H) , 2.85-2.79 (m, 1H) , 2.20-2.02 (m, 2H) , 1.98-1.91 (m, 1H) , 1.90-1.70 (m, 3H) , 1.13 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.71, -131.35, -172.05; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 203: 2-amino-4- (8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxy-2-methylpropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 203)

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 2H) , 7.29-7.26 (m, 1H) , 7.21-7.12 (m, 1H) , 6.15-6.12 (m, 1H) , 5.39-5.24 (m, 1H) , 4.91-4.87 (m, 1H) , 4.20-3.96 (m, 3H) , 3.29-2.77 (m, 6H) , 2.28-1.75 (m, 8H) , 1.51-1.46 (m, 3H) , 1.20-1.12 (m, 3H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.47, -133.79, -172.17; LC-MS: m/z = 657.2 [M-H] ^-.

Compound 204 and Compound 205: 2-amino-4- ( (R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 204) and 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 205)

Compound 204 and Compound 205 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 204 was the first fraction and Compound 205 was the second fraction of separation of Suzuki coupling products.

Compound 204: ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 2H) , 7.24-7.10 (m, 2H) , 5.48-5.24 (m, 1H) , 4.99 (d, J = 5.2 Hz, 1H) , 4.69-4.60 (m, 1H) , 4.57-4.49 (m, 1H) , 4.31-4.07 (m 3H) , 4.05-3.96 (m, 3H) , 3.57-3.49 (m, 1H) , 3.30-3.05 (m, 3H) , 3.03-2.86 (m, 1H) , 2.20-2.06 (m, 2H) , 2.03-1.80 (m, 4H) , 1.14-1.12 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.65, -131.40, -172.25; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 205: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 2H) , 7.24-7.19 (m, 1H) , 7.16-7.10 (m, 1H) , 5.51-5.27 (m, 1H) , 4.95 (d, J = 5.2 Hz, 1H) , 4.62-4.54 (m, 2H) , 4.33-4.04 (m, 5H) , 4.01-3.93 (m, 1H) , 3.65-3.38 (m, 4H) , 3.10-2.94 (m, 1H) , 2.24-2.09 (m, 2H) , 2.04-1.80 (m, 4H) , 1.13 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.64, -131.45, -172.35; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 206: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 206)

Compound 206 was obtained by following the procedures described in the synthesis of Compound 27 shown above. ¹H NMR (400 MHz, CD₃OD) δ 7.18 (m, 1H) , 7.07-6.96 (m, 1H) , 5.40-5.18 (m, 1H) , 4.84-4.77 (m, 1H) , 4.69-4.60 (m, 1H) , 4.47-4.38 (m, 1H) , 4.32-4.22 (m, 2H) , 4.20-4.12 (m, 1H) , 3.81-3.63 (m, 2H) , 3.451-3.39 (m, 1H) , 3.27-3.17 (m, 3H) , 3.14-2.99 (m, 2H) , 2.50-2.37 (m, 1H) , 2.33-2.22 (m, 2H) , 2.18-2.12 (m, 2H) , 2.04-1.96 (m, 2H) , 1.90.1.81 (m, 1H) , 1.47-1.37 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.10, -132.26, 173.45; LC-MS: m/z = 670.3 [M+H] ⁺.

Compound 207 and Compound 208: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 207) and 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (R) -pyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 208)

Compound 207 and Compound 208 were obtained by chiral Prep-HPLC separation of Compound 206 on a CHIRALPAK AD-H column. Compound 207 was the first fraction and Compound 208 was the second fraction eluting from the column.

Compound 207: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.16 (m, 1H) , 7.05-7.01 (m, 1H) , 5.39-5.21 (m, 1H) , 4.81-4.74 (m, 1H) , 4.69-4.62 (m, 1H) , 4.49-4.36 (m, 2H) , 4.32-4.39 (m, 1H) , 4.21-4.13 (m, 1H) , 3.98-3.93 (m, 2H) , 3.62-3.52 (m, 1H) , 3.41-3.31 (m, 3H) , 3.24-3.02 (m, 2H) , 2.56-2.46 (m, 1H) , 2.43-2.35 (m, 1H) , 2.32-2.26 (m, 1H) , 2.24-2.15 (m, 2H) , 2.10-2.01 (m, 2H) , 1.95-1.85 (m , 1H) , 1.44-1.42 (d, J=6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -132.69, 173.63; LC-MS: m/z = 670.3 [M+H] ⁺.

Compound 208: ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.16 (m, 1H) , 7.07-7.02 (m, 1H) , 5.59-5.39 (m, 1H) , 4.80-4.65 (m, 3H) , 4.65-4.46 (d, J=12.8 Hz, 1H) , 4.29-4.21 (m, 1H) , 4.05-3.78 (m, 5H) , 3.70-3.59 (m, 1H) , 3.50-3.32 (m, 3H) , 2.66-2.59 (m, 1H) , 2.57-2.50 (m, 2H) , 2.49-2.38 (m, 2H) , 2.35-2.26 (m, 2H) , 2.09-2.00 (m, 1H) , 1.46-1.45 (d, J=6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.42, -134.03, 175.02; LC-MS: m/z = 670.3 [M+H] ⁺.

Compound 209 and Compound 210: 2-amino-4- ( (5S, 9S) -8-chloro-4-cyclopropyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 209) and 2-amino-4- ( (5S, 9R) -8-chloro-4-cyclopropyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 210)

Compound 209 and Compound 210 were obtained by chiral Prep-HPLC separation on a Unichiral AD-5H column. Compound 209 was the first fraction and Compound 210 was the second fraction eluting from the column.

Compound 209: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.16 (m, 1H) , 7.04-7.00 (m, 1H) , 5.47-5.34 (m, 1H) , 4.54-4.50 (m, 2H) , 4.46-4.39 (m, 2H) , 4.33-4.30 (m, 1H) , 3.63-3.46 (m, 3H) , 3.25-3.20 (m, 1H) , 3.17-3.12 (m, 1H) , 2.55-2.36 (m, 2H) , 2.27-2.32 (m, 1H) , 2.18-2.11 (m, 2H) , 2.03-1.98 (m, 1H) , 1.36 (d, J= 6.8, 3H) , 1.20-1.13 (m, 1H) , 1.09-1.02 (m, 1H) , 0.91-0.86 (m, 1H) , 0.84-0.78 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.94, -135.41, -173.93; LC-MS: m/z = 641.1 [M+H] ⁺.

Compound 210: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.17 (m, 1H) , 7.04-7.00 (m, 1H) , 5.46-5.33 (m, 1H) , 4.55-4.50 (m, 2H) , 4.41-4.38 (m, 2H) , 4.33-4.30 (m, 1H) , 3.63-3.46 (m, 3H) , 3.21-3.11 (m, 2H) , 2.50-2.35 (m, 2H) , 2.31-2.24 (m, 1H) , 2.16-2.08 (m, 2H) , 2.03-1.94 (m, 1H) , 1.38 (d, J= 6.8, 3H) , 1.20-1.14 (m, 1H) , 1.09-1.02 (m, 1H) , 0.91-0.81 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.93, -132.74, -173.91; LC-MS: m/z = 641.1 [M+H] ⁺.

Compound 211: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (1- (hydroxymethyl) cyclopropyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 211)

¹H NMR (400 MHz, DMSO-d₆) δ 8.09-8.07 (m, 2H) , 7.25-7.17 (m, 1H) , 7.16-7.10 (m, 1H) , 5.41-5.27 (m, 1H) , 5.09-4.94 (m, 1H) , 4.76-4.56 (m, 2H) , 4.48-4.00 (m, 5H) , 3.29-2.91 (m, 4H) , 2.26-2.02 (m, 3H) , 1.96-1.74 (m, 3H) , 1.37-1.26 (m, 2H) , 1.17-1.00 (m, 4H) , 0.91-0.81 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.74, -132.36, -172.13; LC-MS: m/z = 671.3 [M+H] ⁺.

Compound 212 and Compound 213: 2-amino-4- ( (5S, 9S) -8-chloro-4- (1-cyanocyclopropyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 212) and 2-amino-4- ( (5S, 9R) -8-chloro-4- (1-cyanocyclopropyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 213)

Compound 212 and Compound 213 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 212 was the first fraction and Compound 213 was the second fraction of separation of Suzuki coupling products.

Compound 212: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.15 (m, 1H) , 7.02 (t, J = 9.6 Hz, 1H) , 5.45-5.30 (m, 1H) , 4.65-4.53 (m, 2H) , 4.45-4.35 (m, 3H) , 3.54-3.34 (m, 3H) , 3.19-3.08 (m, 1H) , 2.52-2.29 (m, 2H) , 2.23-2.16 (m, 1H) , 2.13-1.92 (m, 4H) , 1.89-1.79 (m, 1H) , 1.76-1.58 (m, 2H) , 1.49 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -111.84, -131.92, -173.70; LC-MS: m/z = 666.2 [M+H] ⁺.

Compound 213: ¹H NMR (400 MHz, CD₃OD) : δ 7.24-7.18 (m, 1H) , 7.04 (t, J = 9.2 Hz, 1H) , 5.49-5.32 (m, 1H) , 4.69-4.53 (m, 2H) , 4.50-4.35 (m, 3H) , 3.55-3.40 (m, 3H) , 3.23-3.12 (m, 1H) , 2.51-2.36 (m, 2H) , 2.32-2.24 (m, 1H) , 2.19-2.10 (m, 2H) , 2.03-1.95 (m, 2H) , 1.87-1.81 (m, 1H) , 1.76-1.57 (m, 2H) , 1.52 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.76, -131.60, -173.84; LC-MS: m/z = 666.2 [M+H] ⁺.

Compound 214: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 214)

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.16 (m, 1H) , 7.05-7.00 (m, 1H) , 5.48-5.34 (m, 1H) , 4.66-4.61 (m, 1H) , 4.53-4.38 (m, 3H) , 4.12-4.07 (m, 1H) , 3.70-3.50 (m, 3H) , 3.44-3.43 (m, 3H) , 3.25-3.19 (m, 1H) , 2.57-2.38 (m, 2H) , 2.30-2.13 (m, 3H) , 2.02-1.95 (m, 1H) , 1.45-1.41 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -133.46, -174.07; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 215 and Compound 216: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 215) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 216)

Compound 215 (Less polar) and Compound 216 (More polar) were obtained from the separation of Compound 214 on Prep-TLC (MeOH/DCM = 1/11) .

Compound 215: ¹H NMR (400 MHz, CD₃OD) δ 7.24-7.20 (m, 1H) , 7.06-7.02 (m, 1H) , 5.52-5.39 (m, 1H) , 4.69-4.64 (m, 1H) , 4.60-4.53 (m, 2H) , 4.45-4.42 (m, 1H) , 4.12-4.08 (m, 1H) , 3.80-3.62 (m, 3H) , 3.44 (s, 3H) , 3.38-3.35 (m, 1H) , 2.62-2.43 (m, 2H) , 2.30-2.21 (m, 2H) , 2.11-2.01 (m, 2H) , 1.44-1.42 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.83, -133.41, -174.21; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 216: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.51-5.38 (m, 1H) , 4.67-4.57 (m, 2H) , 4.47-4.42 (m, 2H) , 4.14-4.08 (m, 1H) , 3.71-3.60 (m, 3H) , 3.45 (s, 3H) , 3.28-3.26 (m, 1H) , 2.54-2.44 (m, 2H) , 2.35-2.30 (m, 1H) , 2.22-2.16 (m, 2H) , 2.04-2.00 (m, 1H) , 1.45-1.44 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -133.46, -174.07; LC-MS: m/z = 615.3 [M+H] ⁺.

Compound 217: 2-amino-4- ( (5S) -8-chloro-4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 217)

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.18 (m, 1H) , 7.07-7.02 (m, 1H) , 5.58-5.45 (m, 1H) , 4.74-4.55 (m, 3H) , 4.39-4.36 (m, 1H) , 4.32-4.21 (m, 1H) , 4.19-4.12 (m, 1H) , 4.03-3.78 (m, 3H) , 3.67-3.57 (m, 1H) , 3.50-3.39 (m, 1H) , 2.74-2.52 (m, 2H) , 2.45-2.26 (m, 3H) , 2.12-1.99 (m, 1H) , 1.43-1.34 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.70, -134.76, -174.53; LC-MS: m/z = 629.2 [M+H] ⁺.

Compound 218 and Compound 219: 2-amino-4- ( (5S, 9S) -8-chloro-4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 218) and 2-amino-4- ( (5S, 9R) -8-chloro-4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 219)

Compound 218 and Compound 219 were obtained by chiral Prep-HPLC separation of Compound 217 with Boc protection on a CHIRALPAK AD-H column, followed by the treatment of TFA. Compound 218 was from the first fraction and Compound 219 was from the second fraction eluting from the column.

Compound 218: ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.17 (m, 1H) , 7.08-7.01 (m, 1H) , 5.58-5.35 (m, 1H) , 4.87-4.72 (m, 1H) , 4.68 (s, 2H) , 4.47-4.38 (m, 2H) , 4.34-4.20 (m, 1H) , 3.70-3.45 (m, 4H) , 3.27-3.22 (m, 1H) , 2.59-2.35 (m, 2H) , 2.30-2.12 (m, 3H) , 2.09-1.99 (m, 1H) , 1.41-1.36 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.92, -134.34, -174.10; LC-MS: m/z = 629.2 [M+H] ⁺.

Compound 219: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.15 (m, 1H) , 7.05-7.00 (m, 1H) , 5.46-5.33 (m, 1H) , 4.70-4.65 (m, 1H) , 4.49-4.46 (m, 1H) , 4.39-4.34 (m, 2H) , 4.29-4.24 (m, 1H) , 4.14-4.11 (m, 1H) , 3.64-3.41 (m, 4H) , 3.24-3.10 (m, 1H) , 2.52-2.35 (m, 2H) , 2.28-2.21 (m, 1H) , 2.16-2.09 (m, 2H) , 2.04-1.89 (m, 1H) , 1.43-1.36 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.97, -133.30, -174.00; LC-MS: m/z = 629.3 [M+H] ⁺.

Compound 220: 2-amino-4- ( (S) -4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 220)

Step 1: Synthesis of tert-butyl (3-cyano-4- ( (S) -4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 220-1)

A mixture of Compound 217-Boc (100 mg, 0.137 mmol) , Cs₂CO₃ (133 mg, 0.412 mmol) and BrettPhos Pd G3 (124 mg, 0.137 mmol) in ethanol/water (4 mL/1 mL) was stirred at 120 ℃ for 3 hours under N₂ atmosphere. The mixture was diluted with ethyl acetate (150 mL) and washed with water (100 mL) and brine (100 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Pre-TLC (DCM/MeOH = 10/1) to afford Compound 220-1 (120 mg, crude) as a yellow solid. It was used in the next step without further purification. LC-MS: m/z =695.3 [M+H] ⁺.

Step 2: Synthesis of 2-amino-4- ( (S) -4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 220)

To a solution of Compound 220-1 (120 mg, crude) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) . The mixture was stirred at 40 ℃ for 2 hours. The mixture solution was cooled to room temperature, adjusted with saturated sodium bicarbonate solution till pH = 8. The aqueous phase was extracted with ethyl acetate (100 mL) , washed with water (100 mL x3) and brine (100 mL) , dried over Na₂SO₄ and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 220 (15 mg, 18.4%yield of two steps) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.41 (m, 1H) , 7.32-7.28 (m, 1H) , 6.90-6.85 (t, J = 8.8 Hz, 1H) , 5.42-5.28 (m, 1H) , 4.88-4.83 (m, 1H) , 4.34-4.26 (m, 3H) , 4.19-4.07 (m, 4H) , 3.65-3.57 (m, 1H) , 3.26-3.20 (m, 1H) , 3.08-3.01 (m, 1H) , 2.30-2.17 (m, 3H) , 2.05-1.98 (m, 3H) , 1.49-1.44 (m, 3H) , 142-1.35 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -117.05, -131.15, -173.63; LC-MS: m/z = 595.3 [M+H] ⁺.

Compound 221: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 221)

¹H NMR (400 MHz, DMSO-d₆) δ 8.14-8.02 (m, 2H) , 7.27-7.21 (m, 1H) , 7.17-7.11 (m, 1H) , 5.48-5.26 (m, 1H) , 4.96-4.92 (m, 1H) , 4.71-4.65 (m, 1H) , 4.46-4.01 (m, 5H) , 3.92-3.81 (m, 1H) , 3.79-3.72 (m, 1H) , 3.65-3.56 (m, 1H) , 3.28-2.73 (m, 4H) , 2.23-1.83 (m, 6H) , 1.26-1.24 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.68, -131.14, -172.37; LC-MS: m/z = 645.3 [M+H] ⁺.

Compound 222 and Compound 223: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 222) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 223)

Compound 222 and Compound 223 were obtained by chiral Prep-HPLC separation of Compound 221 on a CHIRALPAK AD-H column. Compound 222 was the first fraction and Compound 223 was the second fraction eluting from the column.

Compound 222: ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 2H) , 7.29-7.21 (m, 1H) , 7.18-7.10 (m, 1H) , 5.27 (d, J = 54.4 Hz, 1H) , 4.91 (t, J = 4.4 Hz, 1H) , 4.66 (dd, J =12.8, 4.4 Hz, 1H) , 4.44 (d, J =12.8 Hz , 1H) , 4.25-3.92 (m, 4H) , 3.89-3.68 (m, 2H) , 3.65-3.53 (m, 1H) , 3.14-2.93 (m, 3H) , 2.82 (dd, J =14.4, 8.0 Hz, 1H) , 2.20-1.93 (m, 3H) , 1.90-1.68 (m, 3H) , 1.29-1.18 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ-116.76, -132.32, -172.04; LC-MS: m/z = 645.3 [M+H] ⁺.

Compound 223: ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 2H) , 7.26-7.18 (m, 1H) , 7.16-7.08 (m, 1H) , 5.27 (d, J = 53.6Hz, 1H) , 4.93 (t, J = 5.6 Hz, 1H) , 4.66 (dd, J =12.4 Hz, J =4.0 Hz, 1H) , 4.34 (d, J =12.4 Hz, 1H) , 4.25-4.10 (m, 2H) , 4.05 (dd, J =30.4 Hz, J =10.4 Hz, 2H) , 3.94-3.3.83 (m, 1H) , 3.78-3.69 (m, 1H) , 3.61-3.51 (m, 1H) , 3.14-2.97 (m, 3H) , 2.86-2.76 (m, 1H) , 2.16-1.94 (m, 3H) , 1.89-1.70 (m, 3H) , 1.32-1.25 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.74, -131.07, -172.09; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 224: 2-amino-7-fluoro-4- ( (S) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) benzo [b] thiophene-3-carbonitrile (Compound 224)

Compound 224 was obtained from the de-chlorination of Compound 221 following the procedures described in the synthesis of Compound 220. LC-MS: m/z = 611.3 [M+H] ⁺.

Compound 225 and Compound 226: (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 225) and (S) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-hydroxypropyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 226)

Compound 225 (More polar) and Compound 226 (Less polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 225: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 4.8 Hz, 1H) , 7.03 (t, J = 6.2 Hz, 1H) , 5.54-5.40 (m, 1H) , 4.69 (dd, J = 12.8, 4.4 Hz, 1H) , 4.61 (d, J = 12.4 Hz, 1H) , 4.52 (d, J = 12.8 Hz, 1H) , 4.48-4.35 (m, 4H) , 3.87-3.64 (m, 3H) , 3.37-3.33 (m, 1H) , 3.28-3.23 (m, 1H) , 2.60-2.52 (m, 1H) , 2.46 (s, 1H) , 2.34-2.17 (m, 3H) , 2.07-1.93 (m, 1H) , 1.37 (d, J = 6.8 Hz, 3H) , 1.29 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.76, -134.06, -174.28; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 226: ¹H NMR (400 MHz, CD₃OD) δ 7.23 (dd, J = 8.4, 5.2 Hz, 1H) , 7.04 (t, J = 9.2 Hz, 1H) , 5.59-5.34 (m, 1H) , 4.70 (dd, J = 12.8, 4.8 Hz, 1H) , 4.57-4.45 (m, 4H) , 4.41-4.31 (m, 2H) , 3.85-3.63 (m, 3H) , 3.39-3.33 (m, 1H) , 3.25 (dd, J = 13.6, 9.2 Hz, 1H) , 2.66-2.47 (m, 2H) , 2.27-2.17 (m, 3H) , 2.10-2.02 (m, 1H) , 1.36 (d, J = 6.8 Hz, 3H) , 1.29 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.79, -134.87, -174.31; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 227 and Compound 228: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (1-hydroxycyclopropyl) methyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 227) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (1-hydroxycyclopropyl) methyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 228)

Compound 227 (Less polar) and Compound 228 (More polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 227: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.15 (m, 1H) , 7.04-6.99 (m, 1H) , 5.47-5.32 (m, 2H) , 4.45-4.37 (m, 2H) , 4.13 (d, J = 15.6, 1H) , 3.81-3.44 (m, 6H) , 3.22-3.16 (m, 1H) , 2.53-2.35 (m, 2H) , 2.30-2.23 (m, 1H) , 2.15-1.96 (m, 3H) , 1.28-1.26 (m, 3H) , 1.23-1.08 (m, 3H) , 0.86-0.81 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.94, -132.84, -173.98; LC-MS: m/z = 669.1 [M-H] ^-.

Compound 228: ¹H NMR (400 MHz, CD₃OD) δ 7.19-7.15 (m, 1H) , 7.04-6.99 (m, 1H) , 5.47-5.32 (m, 2H) , 4.49-4.37 (m, 2H) , 4.00-3.92 (m, 2H) , 3.81-3.77 (m, 1H) , 3.74-3.70 (m, 1H) , 3.63-3.47 (m, 3H) , 3.25-3.18 (m, 1H) , 2.51-2.37 (m, 2H) , 2.32-2.27 (m, 1H) , 2.15-2.11 (m, 1H) , 2.05-1.96 (m, 2H) , 1.33-1.31 (m, 3H) , 1.23-1.13 (m, 2H) , 1.06-0.94 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -132.86, -174.07; LC-MS: m/z = 669.1 [M-H] ^-.

Compound 229: 2-amino-4- ( (5S) -8-chloro-4- (2, 2-difluoroethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 229)

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.19 (m, 1H) , 7.06-7.02 (m, 1H) , 7.04 (t, J = 57.2 Hz, 1H) , 5.43 (d, J = 53.2 Hz, 1H) , 4.75-4.69 (m, 1H) , 4.54-4.40 (m, 4H) , 4.22-4.21 (m, 1H) , 4.04-4.01 (m, 1H) , 3.69-3.53 (m, 3H) , 3.27-3.24 (m, 1H) , 2.58-2.35 (m, 2H) , 2.30-2.14 (m, 3H) , 2.04-2.01 (m, 1H) , 1.42 (t, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -120.33, -122.68, -125.56, -134.91, -175.60; LC-MS: m/z = 665.2 [M+H] ⁺.

Compound 230 and Compound 231: 2-amino-4- ( (5S, 9S) -8-chloro-4- (2, 2-difluoroethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 230) and 2-amino-4- ( (5S, 9R) -8-chloro-4- (2, 2-difluoroethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 231)

Compound 230 and Compound 231 were obtained by chiral Prep-HPLC separation of Compound 229 on a CHIRALPAK AD-H column. Compound 230 was the first fraction and Compound 231 was the second fraction eluting from the column.

Compound 230: LC-MS: m/z = 665.2 [M+H] ⁺.

Compound 231: LC-MS: m/z = 665.2 [M+H] ⁺.

Compound 232: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2, 2, 2-trifluoroethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 232)

¹H NMR (400 MHz, DMSO-d₆) : δ 8.11 (d, J = 9.6 Hz, 2H) , 7.30-7.24 (m, 1H) , 7.18-7.12 (m, 1H) , 5.56-5.31 (m, 1H) , 5.09-4.98 (m, 1H) , 4.82-4.68 (m, 2H) , 4.49-4.13 (m, 4H) , 3.75-3.42 (m, 2H) , 3.29-2.83 (m, 2H) , 2.39-1.81 (m, 6H) , 1.31-1.27 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -66.55, -116.51, -130.36, -131.69; LC-MS: m/z = 683.2 [M+H] ⁺.

Compound 233 and Compound 234: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2, 2, 2-trifluoroethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 233) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2, 2, 2-trifluoroethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin -9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 234)

Compound 233 and Compound 234 were obtained by chiral Prep-HPLC separation of Compound 232 on a CHIRALPAK AD-H column. Compound 233 was the first fraction and Compound 234 was the second fraction eluting from the column.

Compound 233: ¹H NMR (400 MHz, CD₃OD) : δ 7.24-7.20 (m, 1H) , 7.06-7.01 (m, 1H) , 5.45-5.30 (m, 1H) , 5.21-5.11 (m, 1H) , 4.77-4.73 (m, 1H) , 4.50-4.33 (m, 4H) , 4.29-4.22 (m, 1H) , 3.55-3.36 (m, 3H) , 3.19-3.13 (m, 1H) , 2.49-2.27 (m, 2H) , 2.21-2.07 (m, 3H) , 2.00-1.93 (m, 1H) , 1.39 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -69.34, -118.89, -133.09, -173.82; LC-MS: m/z = 683.2 [M+H] ⁺.

Compound 234: ¹H NMR (400 MHz, CD₃OD) : δ 7.21-7.17 (m, 1H) , 7.05-7.01 (m, 1H) , 5.43-5.30 (m, 1H) , 5.21-5.11 (m, 1H) , 4.75-4.71 (m, 1H) , 4.52-4.42 (m, 3H) , 4.33-4.23 (m, 2H) , 3.55-3.36 (m, 3H) , 3.17-3.11 (m, 1H) , 2.45-2.31 (m, 2H) , 2.23-2.06 (m, 3H) , 1.98-1.89 (m, 1H) , 1.40 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -69.15, -118.84, -132.22, -173.85; LC-MS: m/z = 683.2 [M+H] ⁺.

Compound 235 and Compound 236: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro- 4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 235) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 236)

Compound 235 and Compound 236 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 235 was the first fraction and Compound 236 was the second fraction from the separation of Suzuki coupling products.

Compound 235: ¹H NMR (400 MHz, CD₃OD) : δ 7.22-7.19 (m, 1H) , 7.05-7.01 (m, 1H) , 5.50-5.33 (m, 2H) , 4.74-4.70 (m, 1H) , 4.48 (s, 2H) , 4.37 (d, J = 12.4 Hz, 1H) , 4.32-4.27 (m, 1H) , 3.97-3.92 (m, 1H) , 3.76-3.26 (m, 5H) , 2.58-2.42 (m, 2H) , 2.27-2.17 (m, 3H) , 2.12-1.99 (m, 1H) , 1.38-1.33 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.92, -135.39, -174.27; LC-MS: m/z = 659.3 [M+H] ⁺ _.

Compound 236: ¹H NMR (400 MHz, CD₃OD) : δ 7.21-7.16 (m, 1H) , 7.05-7.01 (m, 1H) , 5.51-5.37 (m, 2H) , 4.73-4.69 (m, 1H) , 4.55 (d, J = 12.0 Hz, 1H) , 4.41-4.37 (m, 2H) , 4.32-4.28 (m, 1H) , 3.98-3.94 (m, 1H) , 3.78-3.55 (m, 4H) , 3.28-3.24 (m, 1H) , 2.56-2.42 (m, 2H) , 2.33-2.16 (m, 3H) , 2.03-1.96 (m, 1H) , 1.37-1.34 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.89, -134.46, -174.24; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 237 and Compound 238: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 237) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -1-hydroxypropan-2-yl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 238)

Compound 237 (Less polar) and Compound 238 (More polar) were obtained from their atropisomeric mixture by Prep-TLC (DCM/MeOH = 10/1) separation.

Compound 237: ¹H NMR (400 MHz, CD₃OD) : δ 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.07-7.00 (m, 1H) , 5.58 (s, 1H) , 5.50-5.34 (m, 1H) , 4.71 (dd, J = 12.4, 5.2 Hz, 1H) , 4.52-4.44 (m, 3H) , 4.38-4.27 (m, 1H) , 3.84-3.77 (m, 2H) , 3.69-3.57 (m, 2H) , 2.66-2.17 (m, 6H) , 2.10-1.93 (m, 2H) , 1.38-1.31 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.94, -135.48, -174.29; LC-MS: m/z = 657.1 [M-H] ^-.

Compound 238: ¹H NMR (400 MHz, CD₃OD) : δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.07-6.99 (m, 1H) , 5.59-5.33 (m, 2H) , 4.70 (dd, J = 12.4, 5.2 Hz, 1H) , 4.49-4.44 (m, 2H) , 4.36-4.27 (m, 2H) , 3.86-3.77 (m, 2H) , 3.66-3.46 (m, 3H) , 3.25-3.13 (m, 1H) , 2.52-1.93 (m, 6H) , 1.40 (d, J = 7.2 Hz, 3H) , 1.30 (d, J = 7.2 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.97, -134.16, -174.10; LC-MS: m/z = 657.1 [M-H] ^-.

Compound 239 and Compound 240: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -2-hydroxypropyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 239) and (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (S) -2-hydroxypropyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 240)

Compound 239 and Compound 240 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 239 was the first fraction and Compound 240 was the second fraction of the separation of Suzuki coupling products.

Compound 239: ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.19 (m, 1H) , 7.05-7.01 (m, 1H) , 5.38 (d, J = 53.2 Hz, 1H) , 4.72-4.67 (m, 1H) , 4.47 (d, J = 12.4 Hz, 1H) , 4.42-4.34 (m, 3H) , 4.21-4.12 (m, 2H) , 3.69-3.64 (m, 1H) , 3.57-3.42 (m, 3H) , 3.21-3.13 (m, 1H) , 2.51-2.29 (m, 2H) , 2.23-2.07 (m, 3H) , 2.02-1.93 (m, 1H) , 1.40 (d, J = 6.8 Hz, 3H) , 1.29 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.00, -133.98, -173.92; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 240: ¹H NMR (400 MHz, CD₃OD) δ 7.20-7.16 (m, 1H) , 7.05-7.00 (m, 1H) , 5.38 (d, J = 53.2 Hz, 1H) , 4.70-4.66 (m, 1H) , 4.47 (d, J = 12.8 Hz, 1H) , 4.43-4.29 (m, 3H) , 4.23-4.18 (m, 2H) , 3.64-3.60 (m, 1H) , 3.55-3.40 (m, 3H) , 3.18-3.11 (m, 1H) , 2.46-2.31 (m, 2H) , 2.27-2.20 (m, 1H) , 2.12-2.05 (m, 2H) , 1.99-1.90 (m, 1H) , 1.40 (d, J = 6.8 Hz, 3H) , 1.29 (d, J = 6.0 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.99, -132.99, -173.90; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 241 and Compound 242: 2-amino-4- ( (5S, 9S) -8-chloro-4- (cyanomethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 241) and 2-amino-4- ( (5S, 9R) -8-chloro-4- (cyanomethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 242)

Compound 241 and Compound 242 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 241 was the first fraction and Compound 242 was the second fraction of separation of Suzuki coupling products.

Compound 241: ¹H NMR (400 MHz, CD₃OD) δ 7.21 (dd, J = 8.4, 5.2 Hz, 1H) , 7.06-7.02 (m, 1H) , 5.51-5.32 (m, 1H) , 4.85-4.68 (m, 3H) , 4.55 (s, 2H) , 4.46 (d, J = 13.2 Hz, 1H) , 4.27-4.21 (m, 1H) , 3.66-3.45 (m, 3H) , 3.25-3.19 (m, 1H) , 2.57-2.33 (m, 2H) , 2.29-2.21 (m, 1H) , 2.19-2.10 (m, 2H) , 2.08-1.97 (m, 1H) , 1.49 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.78, -132.45, -173.87; LC-MS: m/z =640.2 [M+H] ⁺.

Compound 242: ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 2H) , 7.25 (dd, J = 8.4, 5.2 Hz, 1H) , 7.17-7.13 (m, 1H) , 5.57-5.15 (m, 1H) , 5.02-4.78 (m, 1H) , 4.83-4.65 (m, 2H) , 4.33 (d, J = 12.8 Hz, 2H) , 4.30-4.10 (m, 2H) , 3.31-2.71 (m, 4H) , 2.31-1.70 (m, 6H) , 1.38 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) : δ -116.49, -130.09, -172.12; LC-MS: m/z = 640.2 [M+H] ⁺.

Compound 243: 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (methylsulfonyl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 243)

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J = 8.4 Hz, 2H) , 7.29-7.19 (m, 1H) , 7.19-7.07 (m, 1H) , 5.53-5.24 (m, 1H) , 4.76-4.61 (m, 1H) , 4.52-4.06 (m, 5H) , 3.94-3.81 (m, 1H) , 3.78-3.58 (m, 2H) , 3.3-2.8 (m, 7H) , 2.38-2.07 (m, 3H) , 2.02-1.79 (m, 3H) , 1.38-1.28 (m, 3H) . ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.61, -130.72 , -172.01. LC-MS: m/z = 707.2 [M+H] ⁺.

Compound 244 and Compound 245: (S) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (methylsulfonyl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 244) and (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (methylsulfonyl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 245)

Compound 244 (Less polar) and Compound 245 (More polar) were obtained from Compound 243 by Prep-TLC (DCM/MeOH = 10/1) separation.

Compound 244: ¹H NMR (400 MHz, CD₃OD) δ 7.22 (dd, J = 8.4, 5.2 Hz, 1H) , 7.04 (t, J = 9.2 Hz, 1H) , 5.51 (dt, J = 52.4, 3.6 Hz, 1H) , 4.69 (dd, J = 12.8, 4.4 Hz, 1H) , 4.66 (s, 2H) , 4.60-4.54 (m, 1H) , 4.43 (d, J = 12.8 Hz, 1H) , 4.29-4.23 (m, 1H) , 4.09-4.02 (m, 1H) , 3.93-3.90 (m, 1H) , 3.84-3.71 (m, 4H) , 3.43-3.36 (m, 1H) , 3.11 (s, 3H) , 2.73-2.58 (m, 1H) , 2.55-2.46 (m, 1H) , 2.40-2.36 (m, 1H) , 2.31-2.24 (m, 2H) , 2.19-2.09 (m, 1H) , 1.44 (d, J = 6.8 Hz, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) δ -118.77, -133.84, -174.07. LC-MS: m/z = 707.1 [M+H] ⁺.

Compound 245: ¹H NMR (400 MHz, CD₃OD) δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (m, J =9.2 Hz, 1H) , 5.60-5.44 (m, 1H) , 4.69 (dd, J = 12.4, 3.6 Hz, 2H) , 4.64-4.56 (m, 2H) , 4.42 (d, J = 12.8 Hz, 1H) , 4.29-4.23 (m, 1H) , 4.07-4.00 (m, 1H) , 3.97-3.84 (m, 1H) , 3.81-3.66 (m, 4H) , 3.42-3.35 (m, 1H) , 3.11 (s, 3H) , 2.70-2.56 (m, 1H) , 2.52-2.46 (m, 1H) , 2.43-2.39 (m, 1H) , 2.30-2.23 (m, 2H) , 2.15-2.06 (m, 1H) , 1.46 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.73, -133.06, -174.05; LC-MS: m/z = 707.1 [M+H] ⁺.

Compound 246: 2- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) acetamide (Compound 246)

¹H NMR (400 MHz, CD₃OD) : δ 7.24-7.16 (m, 1H) , 7.06-7.00 (m, 1H) , 5.56-5.33 (m, 1H) , 4.71-4.66 (m, 1H) , 4.62-4.54 (m, 2H) , 4.. 48-4.22 (m, 3H) , 4.18-4.07 (m, 1H) , 3.67-3.48 (m, 3H) , 3.28-3.22 (m, 1H) , 2.58-2.33 (m, 2H) , 2.28-2.13 (m, 3H) , 2.08-1.95 (d, J = 54.0 Hz, 1H) , 1.46 (t, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.86, -133.14, -173.85; LC-MS: m/z = 658.2 [M+H] ⁺.

Compound 247: 10-ethyl-4-fluoro-5- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (methylsulfinyl) -8H, 10H-7-oxa-1, 3, 6, 10-tetraazaspiro [cyclohepta [de] naphthalene-9, 1'-cyclopropan] -1 (10a) , 2, 3a, 4, 6-pentaene (Compound 247)

¹H NMR (400 MHz, CD₃OD) δ 7.18 (dd, J = 8.8, 5.2 Hz, 1H) , 7.03 (t, J = 9.2 Hz, 1H) , 5.42 (d, J = 53.2 Hz, 1H) , 4.93 (d, J = 16.0 Hz, 1H) , 4.69 (dd, J = 12.8, 4.0 Hz, 1H) , 4.61 (d, J = 12.8 Hz, 1H) , 4.47 (dd, J = 27.6, 16.0 Hz, 2H) , 4.29 (d, J = 12.0 Hz, 1H) , 4.08-4.05 (m, 1H) , 3.71-3.53 (m, 3H) , 3.21 (s, 3H) , 3.01 (s, 3H) , 2.48-2.38 (m, 2H) , 2.23-1.94 (m, 5H) , 1.46 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.84, -133.43, -174.01; LC-MS: m/z = 686.2 [M+H] ⁺.

Compound 248: 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 248)

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 2H) , 7.20 (d, J = 40.8 Hz, 2H) , 5.59-5.12 (m, 3H) , 4.91-4.71 (m, 1H) , 4.61-3.91 (m, 4H) , 3.81-3.42 (m, 3H) , 3.18-3.06 (m, 1H) , 2.49-2.42 (m, 3H) , 2.37-2.18 (m, 2H) , 2.09-1.87 (m, 4H) , 1.51-1.31 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.56, -130.47, -172.38; LC-MS: m/z = 697.2 [M+H] ⁺.

Compound 249 and Compound 250: (S) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-isopropyl-5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 249) and (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-isopropyl-5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 250)

Compound 249 and Compound 250 were obtained by chiral Prep-HPLC separation of their atropisomeric mixture with Boc protection on a CHIRALPAK AD-H column, followed by the treatment of TFA. Compound 249 was the first fraction and Compound 250 was the second fraction eluting from the column.

Compound 249: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.19 (m, 1H) , 7.05-7.00 (m, 1H) , 5.69-5.62 (m, 1H) , 5.49-5.35 (m, 1H) , 4.74 (dd, J = 5.2 , 12.4, 1H) , 4.47-4.25 (m, 4H) , 3.72-3.51 (m, 3H) , 3.30-3.22 (m, 1H) , 2.60-2.37 (m, 2H) , 2.28-2.18 (m, 3H) , 2.05-1.99 (m, 1H) , 1.38-1.29 (m, 9H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.95, -135.56, -174.28; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 250: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.18 (m, 1H) , 7.05-7.00 (m, 1H) , 5.69-5.62 (m, 1H) , 5.49-5.36 (m, 1H) , 4.74 (dd, J = 5.2 , 12.4, 1H) , 4.56-4.53 (m, 1H) , 4.42-4.27 (m, 3H) , 3.77-3.54 (m, 3H) , 3.30-3.23 (m, 1H) , 2.56-2.42 (m, 2H) , 2.33-2.29 (m, 1H) , 2.22-2.15 (m, 2H) , 2.01-1.94 (m, 1H) , 1.40-1.29 (m, 9H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -134.61, -174.29; LC-MS: m/z = 643.3 [M+H] ⁺.

Compound 251 and Compound 252: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-methoxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 251) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-methoxyethyl) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 252)

Compound 251 and Compound 252 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 251 came from the first fraction and Compound 252 came from the second fraction of separation of Suzuki coupling products.

Compound 251: ¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 24.8 Hz 1H) , 7.03 (d, J = 18.0 Hz, 1H) , 5.41 (d, J = 52.8 Hz, 1H) , 4.66 (d, J = 22.4 Hz, 1H) , 4.45-4.31 (m, 4H) , 4.28-4.21 (m, 1H) , 3.94-3.88 (m, 1H) , 3.84-3.73 (m, 2H) , 3.66-3.48 (m, 3H) , 3.39 (s, 3H) , 3.25 (d, J = 24.0 Hz, 1H) , 2.60-2.45 (m, 1H) , 2.38 (s, 1H) , 2.20-2.11 (m, 3H) , 2.01 (s, 1H) , 1.37 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.87, -134.45, -174.10; LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 252: ¹H NMR (400 MHz, CD₃OD) δ 7.18 (dd, J = 8.4, 5.2 Hz, 1H) , 7.08-6.96 (m, 1H) , 5.40 (d, J = 53.2 Hz, 1H) , 4.71-4.56 (m, 2H) , 4.51-4.20 (m, 5H) , 3.93-3.45 (m, 6H) , 3.39 (s, 3H) , 3.17 (d, J =32.8 Hz, 1H) , 2.56-1.87 (m, 7H) , 1.38 (d, J = 6.8 Hz, 3H) . ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.91, -133.50, -174.04, LC-MS: m/z = 659.2 [M+H] ⁺.

Compound 253: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 253)

Step 1: Synthesis of (S) -2- ( (3, 4-dimethylbenzyl) amino) propan-1-ol (Compound 253-1)

A mixture of (S) -2-aminopropan-1-ol (4.51 g, 60.0 mmol) , 2, 4-dimethoxybenzaldehyde (2.01 g, 12.0 mmol) and sodium triacetoxyborohydride (5.10 g, 24 mmol) in dichloromethane (60 mL) was stirred at 0 ℃ for 10 hours. The mixture was diluted with dichloromethane (150 mL) and washed with water (100 mL) and brine (100 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 20/1) to afford Compound 253-1 (2.97 g, 27%yield) as a light yellow oil.

Step 2: Synthesis of (S) -7-bromo-6-chloro-5- (2- ( (3, 4-dimethylbenzyl) amino) propoxy) -8-fluoro-2- (methylthio) quinazolin-4-ol (Compound 253-2)

To a solution of Compound 253-1 (2.97 g, 13.2 mmol) in dichloromethane (30 mL) at 0 ℃under N₂ atmosphere was added sodium hydride (60 %, 702 mg, 17.6 mmol) and Intermediate 3 (1.50 g, 4.39 mmol) . The mixture was stirred at 40 ℃ for 2 hours, diluted with ethyl acetate (100 mL) and washed with water (80 mL) and brine (80 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 20/1) to afford Compound 253-2 (1.03 g, 46%yield) as a light yellow solid.

Step 3: Synthesis of (S) -9-bromo-8-chloro-4- (3, 4-dimethylbenzyl) -10-fluoro-5-methyl-2- (methylthio) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 253-3)

To a solution of Compound 253-2 (1.03 g, 1.83 mmol) in N, N-dimethylacetamide (10 mL) at 25 ℃ was added N, N-diisopropylethylamine (456 mg, 3.66 mmol) and HATU (1.39 g, 3.66 mmol) . The mixture was stirred at 25 ℃ for 2 hours, diluted with ethyl acetate (50 mL) and washed with water (100 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 30/1) to afford

Compound 253-3 (770 mg, 85%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J = 8.4 Hz, 1H) , 6.48-6.42 (m, 2H) , 5.42 (d, J = 15.2 Hz, 1H) , 4.61 (d, J = 15.2 Hz, 1H) , 4.54 (dd, J = 12.4, 4.4 Hz, 1H) , 4.23 (d, J = 12.8 Hz, 1H) , 4.04-3.98 (m, 1H) , 3.83 (s, 3H) , 3.80 (s, 3H) , 2.46 (s, 3H) , 1.35 (d, J =6.8 Hz, 3H) .

Step 4: Synthesis of (S) -9-bromo-8-chloro-10-fluoro-5-methyl-2- (methylthio) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 253-4)

A solution of Compound 253-3 (720 mg, 1.45 mmol) in trifluoroacetic acid (10 mL) was stirred at 65 ℃ for 12 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (50 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 30/1) to afford Compound 253-4 (521 mg, 95%yield) as a light yellow solid. LC-MS: m/z = 377.9 [M+H] ⁺.

Step 5: Synthesis of tert-butyl- (4- ( (5S, 9R) -8-chloro-10-fluoro-5-methyl-2- (methylthio) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 253-5b)

A mixture of Compound 253-4 (460 mg, 1.32 mmol) , 5-a (1.60 g, 3.96 mmol) , cesium carbonate (1.72g, 5.28 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (267 mg, 0.33 mmol) in toluene (10 mL) was stirred at 100 ℃ for 2 hours under N₂ atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH = 20/1, 5a: R_f = 0.4; 5b: R_f= 0.35) to afford Compound 253-5b (97 mg, 12%yield) as a white solid.

Step 6: Synthesis of tert-butyl- (4- ( (5S, 9R) -8-chloro-10-fluoro-5-methyl-2- (methylsulfinyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 253-6)

To a solution of Compound 253-5b (97 mg, 0.16 mmol) in dichloromethane (2 mL) at 0 ℃ under N₂ atmosphere was added 3-chloroperoxybenzoic acid (36 mg, 0.18 mmol, wt 85%) . The mixture was stirred at 0 ℃ for 1 hour. The reaction was diluted with dichloromethane (10 mL) and washed with sat. NaHCO₃ (4 mL) , water (5 mL) and brine (5 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 253-6 (80 mg, crude) as a brown solid. It was used in the next step without further purification.

Step 7: Synthesis of tert-butyl- (4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 253-7)

To a solution of Compound 253-6 (80 mg, crude) and 4-a (63 mg, 0.40 mmol) in toluene (1.5 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (38 mg, 0.40 mmol) . The mixture was stirred at 0 ℃ for 10 minutes and quenched with water (8 mL) . The aqueous phase was extracted with ethyl acetate (4 mL x2) . The combined organic layers were washed with brine (5 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 20/1) to afford Compound 253-7 (50 mg, 36%yield of two steps) as a light yellow solid. LC-MS: m/z = 701.2 [M+H] ⁺.

Step 8: Synthesis of 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 253)

To a solution of Compound 253-7 (50 mg, 0.07 mmol) in dichloromethane (2 mL) at 0 ℃ was added trifluoroacetic acid (0.5 mL) . The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate (20 mL) , washed with water (8 mL) and brine (8 mL) . The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 253 (6.78 mg, 16%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H) , 7.34-7.27 (m, 2H) , 7.24-7.21 (m, 1H) , 7.15-7.11 (m, 1H) , 5.26 (d, J = 54.0 Hz, 1H) , 4.39-4.29 (m, 1H) , 4.00 (dd, J = 31.2, 10.0 Hz, 2H) , 3.83-3.77 (m, 1H) , 3.37 (s, 1H) , 3.12-3.01 (m, 2H) , 2.85-2.79 (m, 1H) , 2.11-1.97 (m, 3H) , 1.86-1.75 (m, 2H) , 1.55-1.43 (m, 2H) , 1.28 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.69, -130.93, -172.07; LC-MS: m/z = 601.2 [M+H] ⁺.

Compound 254: 4- ( (5S) -4-acetyl-8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -2-amino-7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 254)

Step 1: Synthesis of (5S) -9-bromo-8-chloro-10-fluoro-5-methyl-2- (methylsulfinyl) -5, 6-dihydro-4H-[1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 254-1)

To a solution of Compound 253-4 (200 mg, 0.53 mmol) in dichloromethane (10 mL) at 0 ℃ under N₂ atmosphere was added 3-chloroperoxybenzoic acid (129 mg, 0.63 mmol, wt 85%) . The mixture was stirred at 0 ℃ for 20 minutes and diluted with ethyl acetate (50 mL) . The organic layer was washed with sat. NaHCO₃ (30 mL) , water (30 mL) and brine (50 mL) successively, then it was dried over Na₂SO₄, filtered, and concentrated to afford Compound 254-1 (210 mg, crude) as a yellow oil. It was used in the next step without further purification.

Step 2: Synthesis of (S) -9-bromo-8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline (Compound 254-2)

To a mixture of Compound 254-1 (210 mg, crude) and 4-a (252 mg, 1.58 mmol) in toluene (8 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (152 mg, 1.58 mmol) . The mixture was stirred at 0 ℃ for 30 mins and quenched with water (20 mL) . The aqueous phase was extracted with ethyl acetate (30 mL x2) . The combined organic layers were washed with brine (40 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 15/1) to afford Compound 254-2 (160 mg, 62%yield of two steps) as a yellow oil. LC-MS: m/z = 489.1 [M+H] ⁺.

Step 3: Synthesis of 1- ( (S) -9-bromo-8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethan-1-one (Compound 254-3)

To a solution of Compound 254-2 (160 mg, 0.33 mmol) in dichloromethane (10 mL) at 0 ℃ under N₂ atmosphere was added N, N-diisopropylethylamine (421 mg, 3.27 mmol) and acetyl chloride (128 mg, 1.63 mmol) . The mixture was stirred at 20 ℃ for 16 hours, diluted with dichloromethane (50 mL) , and washed with water (30 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 20/1) to afford Compound 254-3 (120 mg, 69%yield) as a yellow solid. LC-MS: m/z = 531.1 [M+H] ⁺.

Step 4: Synthesis of tert-butyl (4- ( (5S) -4-acetyl-8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 254-4)

A mixture of Compound 254-3 (120 mg, 0.23 mmol) , 5-a (456 mg, 1.13 mmol) , cesium carbonate (222 mg, 0.68 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (78 mg, 0.09 mmol) in toluene (15 mL) was stirred at 100 ℃ for 40 min under N₂ atmosphere. The reaction was cooled to room temperature, diluted with ethyl acetate (70 mL) , washed with water (25 mL) and brine (25 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 15/1) to afford Compound 254-4 (70 mg, 42%yield) as a yellow solid. LC-MS: m/z = 743.2 [M+H] ⁺.

Step 5: Synthesis of 4- ( (5S) -4-acetyl-8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -2-amino-7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 254)

To a solution of Compound 254-4 (70 mg, 0.09 mmol) in dichloromethane (6 mL) was added TFA (2 mL) . The mixture was stirred at 20 ℃ for 3 hours, diluted with dichloromethane (40 mL) and washed with sat. Na₂CO₃ (30 mL) , water (30 mL) and brine (30 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 254 (37 mg, 61%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.27-7.17 (m, 1H) , 7.05 (dd, J = 16.0, 8.8 Hz, 1H) , 5.43-5.23 (m, 2H) , 4.77 (dd, J = 12.8, 6.4 Hz, 1H) , 4.49-4.35 (m, 2H) , 4.01 (dd, J = 24.4, 12.0 Hz, 1H) , 3.45-3.34 (m, 3H) , 3.14-3.07 (m, 1H) , 2.46-2.17 (m, 3H) , 2.11-1.93 (m, 6H) , 1.25 (dd, J = 11.2, 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.46, -131.31, -173.86; LC-MS: m/z = 643.2 [M+H] ⁺.

Compound 255: 2-amino-4- ( (6S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -6-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 255)

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.18 (m, 1H) , 7.04 (t, J = 8.8 Hz, 1H) , 5.57-5.43 (m, 1H) , 4.88-4.83 (m, 1H) , 4.67-4.50 (m, 2H) , 4.21-4.16 (m, 1H) , 4.00-3.72 (m, 8H) , 3.45-3.35 (m, 1H) , 2.66-2.57 (m, 1H) , 2.53-2.36 (m, 2H) , 2.36-2.32 (m, 2H) , 2.15-2.03 (m, 1H) , 1.55-1.53 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.75, -134.29, -174.35; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 256: 2-amino-4- ( (6S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -1-hydroxypropan-2-yl) -6-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 256)

Compound 256 was obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 256 was the second fraction of separation of Suzuki coupling products. ¹H NMR (400 MHz, CD₃OD) : δ 7.19 (dd, J = 8.4, 5.2 Hz, 1H) , 7.08-6.99 (m, 1H) , 5.40 (d, J = 52.8 Hz, 1H) , 5.30-5.21 (m, 1H) , 4.97-4.92 (m, 1H) , 4.46-4.40 (m, 2H) , 3.91 (dd, J = 15.6, 2.4 Hz, 1H) , 3.85-3.75 (m, 2H) , 3.66-3.48 (m, 3H) , 3.46-3.40 (m, 1H) , 3.26-3.19 (m, 1H) , 2.53-2.33 (m, 2H) , 2.29-2.23 (m, 1H) , 2.21-2.11 (m, 2H) , 2.07-1.95 (m, 1H) , 1.49 (d, J = 6.4 Hz, 3H) , 1.28 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.96, -133.51, -174.03; LC-MS: m/z = 657.2 [M-H] ^-.

Compound 257: 2-amino-4- ( (6R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (2-hydroxyethyl) -6-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 257)

¹H NMR (400 MHz, CD₃OD) δ 7.22-7.17 (m, 1H) , 7.06-7.01 (m, 1H) , 5.45 (d, J = 53.2 Hz, 1H) , 4.82-4.75 (m, 1H) , 4.56-4.71 (m, 2H) , 4.18-4.12 (m, 1H) , 3.99-3.58 (m, 8H) , 3.28-3.25 (m, 1H) , 2.59-2.43 (m, 2H) , 2.38-2.20 (m, 3H) , 2.07-1.98 (m, 1H) , 1.54-1.51 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD ) δ -120.43, -135.49, -175.69; LC-MS: m/z = 645.2 [M+H] ⁺.

Compound 258: 4- [ (11R) -3- { [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] methoxy} -8-chloro-6-fluoro-13- [ (2R) -1-hydroxypropan-2-yl] -11-methyl-10-oxa-2, 4, 13-triazatricyclo [7.4.1.0^ {5, 14} ] tetradeca-1, 3, 5, 7, 9 (14) -pentaen-7-yl] -2-amino-7-fluoro-1-benzothiophene-3-carbonitrile (Compound 258)

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H) , 8.08 (s, 2H) , 7.25-7.18 (m, 1H) , 7.17-7.10 (m, 1H) , 5.47-5.18 (m, 1H) , 5.08-4.95 (m, 1H) , 4.86-4.79 (m, 1H) , 4.78-4.69 (m, 1H) , 4.25-3.94 (m, 2H) , 3.86-3.74 (m, 1H) , 3.66-3.52 (m, 2H) , 3.48-3.40 (m, 1H) , 3.24-3.00 (m, 2H) , 2.96-2.81 (m, 1H) , 2.25-1.95 (m, 4H) , 1.89-1.72 (m, 2H) , 1.43 (d, J =6.0 Hz, 3H) , 1.28 (d, J =6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -117.05, -131.17, -172.33; LC-MS: m/z = 657.3 [M-H] ^-.

Compound 259: 2- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-fluorophenol (Compound 259)

¹H NMR (400 MHz, CD₃OD) δ 7.29 (d, J = 23.2 Hz, 1H) , 6.76 (d, J = 8.4 Hz, 1H) , 6.70 (t, J = 8.8 Hz, 1H) , 5.42 (d, J = 52.8 Hz, 1H) , 4.68 (d, J = 17.2 Hz, 1H) , 4.47 (d, J = 33.6 Hz, 2H) , 4.34 (d, J = 12.8 Hz, 1H) , 4.28 (s, 1H) , 4.12 (d, J = 23.6 Hz, 1H) , 3.69-3.50 (m, 4H) , 3.24 (d, J = 24.4 Hz, 1H) , 2.47-2.0 (m, 2H) , 2.15 (s, 3H) , 2.01 (s, 1H) , 1.42 (d, J = 6.4 Hz, 3H) , 1.37 (t, J = 7.2 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -115.50, -174.08; LC-MS: m/z = 275.2 [M/2+H] ⁺.

Compound 260: 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro- [1, 4] dioxepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 260)

Step 1: Synthesis of (R) -1- (trityloxy) propan-2-ol (Compound 260-1)

To a solution of (2R) -propane-1, 2-diol (3.0 g, 39.4 mmol) in dichloromethane (150 mL) was added triethylamine (8.0 g, 78.9 mmol) , triphenylmethyl chloride (12.1 g, 43.4 mmol) and 4-dimethylaminopyridine (193 mg, 1.6 mmol) at 0 ℃. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x2) . The combined organic layers were washed with brine (150 mL) , dried over Na₂SO₄, filtered, and concentrated to afford Compound 260-1 (13.5 g, crude) as a colorless oil. It was used for the next step without further purification.

Step 2: Synthesis of (R) -tert-butyldimethyl ( (1- (trityloxy) propan-2-yl) oxy) silane (Compound 260-2)

To a solution of Compound 260-1 (13.5 g, crude) in dichloromethane (200 mL) was added 1H-imidazole (8.7 g, 127.2 mmol) and tert-butyldimethylsilyl chloride (9.6 g, 63.6 mmol) at 0 ℃. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with dichloromethane (100 mL x2) . The combined organic layers were washed with brine (100 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%-2%) to afford Compound 260-2 (15.2 g, 89.2%yield of two steps) as a white solid. ¹H NMR (400 MHz, CDCl₃) : δ 7.47 (d, J = 7.2 Hz, 6H) , 7.28 (t, J = 7.2 Hz, 6H) , 7.21 (t, J = 7.2 Hz, 3H) , 4.00-3.92 (m, 1H) , 3.12-3.08 (m, 1H) , 2.87-2.84 (m, 1H) , 1.14 (d, J = 6.4 Hz, 3H) , 0.88 (s, 9H) , 0.05 (s, 3H) , 0.04 (s, 3H) .

Step 3: Synthesis of (R) -2- ( (tert-butyldimethylsilyl) oxy) propan-1-ol (Compound 260-3)

To a solution of Compound 260-2 (15.2 g, 35.1 mmol) in dichloromethane (200 mL) was added trifluoroacetic acid (10 mL, 134.2 mmol) dropwise at 0℃ over 5 mins. The mixture was stirred at room temperature for 30 mins. The reaction solution was adjusted to pH = 9 with saturated NaHCO₃ solution and extracted with dichloromethane (100 mL x2) . The combined organic layers were washed with brine (80 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was stirred in methanol (40 mL) and filtered. The filtrate was concentrated and purified by silica gel flash chromatography (EtOAc/PE = 0%-10%) to afford Compound 260-3 (1.8 g, 26.9%yield) as a colorless oil.

Step 4: Synthesis of (R) -7-bromo-5- (2- ( (tert-butyldimethylsilyl) oxy) propoxy) -6-chloro-8-fluoro-2- (methylthio) -quinazolin-4-ol (Compound 260-4)

To a solution of Compound 260-3 (1.1 g, 5.7 mmol) in THF (30 mL) was added sodium hydride (1.1 g, 26.3 mmol, 60%) at 0 ℃. The mixture was stirred at this temperature for 0.5 hour, followed by the addition of Intermediate 3 (1.5 g, 4.4 mmol) to the above solution. The mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with sat. NH₄Cl (30 mL) , extracted with ethyl acetate (30 mL x2) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (PE/EtOAc = 10%-20%) to afford Compound 260-4 (450 mg, 20.0%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) : δ 12.81 (s, 1H) , 4.29-4.25 (m, 1H) , 3.93-3.89 (m, 1H) , 3.72-3.68 (m, 1H) , 2.56 (s, 3H) , 1.25 (d, J = 6.0 Hz, 3H) , 0.84 (s, 9H) , 0.07 (s, 3H) , 0.05 (s, 3H) ; LC-MS: m/z = 511.1 [M+H] ⁺.

Step 5: Synthesis of (R) -7-bromo-6-chloro-8-fluoro-5- (2-hydroxypropoxy) -2- (methylthio) quinazolin-4-ol (Compound 260-5)

To a solution of Compound 260-4 (450 mg, 0.88 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (2.3 g, 8.8 mmol) . The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x2) . The combined organic layers were washed with brine (6 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 10%-50%) to afford Compound 260-5 (320 mg, 91.5%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) : δ 12.86 (s, 1H) , 4.89 (d, J = 4.4 Hz, 1H) , 4.07-4.02 (m, 1H) , 3.89-3.82 (m, 2H) , 2.58 (s, 3H) , 1.16 (d, J = 6.4 Hz, 3H) ; LC-MS: m/z = 397.0 [M+H] ⁺.

Step 6: Synthesis of (S) -9-bromo-8-chloro-10-fluoro-5-methyl-2- (methylthio) -5, 6-dihydro- [1, 4] dioxepino [5, 6, 7-de] quinazoline (Compound 260-6)

To a solution of Compound 260-5 (320 mg, 0.8 mmol) in THF (20 mL) was added triphenylphosphine (839 mg, 3.2 mmol) and diethyl azodicarboxylate (557 mg, 3.2 mmol) at 0℃ under N₂ atmosphere. The mixture was stirred at this temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x2) . The combined organic layers were washed with brine (8 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (DCM/PE = 0%-50%) to afford Compound 260-6 (160 mg, 52.7%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) : δ 5.09-4.94 (m, 1H) , 4.74 (d, J = 13.2 Hz, 1H) , 4.67-4.59 (m, 1H) , 2.57 (s, 3H) , 1.44 (d, J = 6.8 Hz, 3H) ; LC-MS: m/z = 378.9 [M+H] ⁺.

Step 7: Synthesis of tert-butyl (4- ( (S) -8-chloro-10-fluoro-5-methyl-2- (methylthio) -5, 6-dihydro- [1, 4] dioxepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 260-7)

A mixture of Compound 260-6 (100 mg, 0.26 mmol) , 5-a (315 mg, 0.78 mmol) , cesium carbonate (424 mg, 1.3 mmol) and [1, 1'-bis (diphenylphosphine) ferrocene] palladium dichloride dichloromethane complex (32 mg, 0.039 mmol) in toluene (6 mL) was stirred at 100 ℃ for 1 hour under N₂ atmosphere. The mixture was cooled to room temperature, diluted with water (6 mL) and extracted with ethyl acetate (8 mL x2) . The combined organic layers were washed with brine (6 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc/PE = 0%-20%) to afford Compound 260-7 (100 mg, 65.0%yield) as a yellow solid.

Step 8: Synthesis of tert-butyl (4- ( (5S) -8-chloro-10-fluoro-5-methyl-2- (methylsulfinyl) -5, 6-dihydro- [1, 4] dioxepino- [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 260-8)

To a solution of Compound 260-7 (100 mg, 0.17 mmol) in dichloromethane (2 mL) at 0 ℃ under N₂ atmosphere was added 3-chloroperoxybenzoic acid (41 mg, 0.20 mmol, wt. 85%) . The mixture was stirred at 0 ℃ for 10 minutes. The reaction solution was diluted with dichloromethane (10 mL) and washed with sat. NaHCO₃ (6 mL) , water (6 mL) and brine (6 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 260-8 (105 mg, crude) as a yellow solid. It was used for the next step without further purification.

Step 9: Synthesis of tert-butyl (4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro- [1, 4] dioxepino [5, 6, 7-de] quinazolin-9-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 260-9)

To a solution of Compound 260-8 (105 mg, crude) and 4-a (54 mg, 0.34 mmol) in toluene (2 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (33 mg, 0.34 mmol) . The mixture was stirred at 0 ℃ for 10 minutes. The reaction solution was quenched with water (6 mL) and extracted with ethyl acetate (8 mL x2) . The combined organic layers were washed with brine (6 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 14/1) to afford Compound 260-9 (25 mg, 20.9%yield of two steps) as a yellow solid. LC-MS: m/z = 702.2 [M+H] ⁺.

Step 10: Synthesis of 2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro- [1, 4] dioxepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 260)

A mixture of Compound 260-9 (25 mg, 0.036 mmol) in 2, 2, 2-trifluoroacetic acid (0.5 mL) and dichloromethane (1 mL) was stirred at 0 ℃ for 3 hours. The reaction was quenched with sat. NaHCO₃ (6 mL) and extracted with ethyl acetate (10 mL x2) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 260 (12.65 mg, 58.4%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) : δ 7.22-7.18 (m, 1H) , 7.04 (t, J = 8.8 Hz, 1H) , 5.30 (d, J = 54.0 Hz, 1H) , 5.11-5.05 (m, 1H) , 4.71 (d, J = 13.6 Hz, 1H) , 4.60-4.55 (m, 1H) , 4.34-4.26 (m, 2H) , 3.35-3.16 (m, 3H) , 3.13-2.99 (m, 1H) , 2.37-2.12 (m, 3H) , 2.03-1.87 (m, 3H) , 1.56 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.73, -131.18, -173.64; LC-MS: m/z = 602.2 [M+H] ⁺.

Compound 261 and Compound 262: 4- [ (7S) -16- { [ (2R, 7aS) -2-fluoro-hexahydro-1H-pyrrolizin-7a-yl] methoxy} -11-chloro-13-fluoro-9-methyl-2, 9, 15, 17-tetraazatetracyclo [8.7.1.0^ {2, 7} . 0^ {14, 18} ] octadeca-1 (17) , 10 (18) , 11, 13, 15-pentaen-12-yl] -2-amino-7-fluoro-1-benzothiophene-3-carbonitrile (Compound 261) and (S) -2-amino-4- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4-methyl-5, 5a, 6, 7, 8, 9-hexahydro-4H-pyrido [2', 1': 3, 4] [1, 4] diazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 262)

Compound 261 and Compound 262 were obtained by following the procedures described in the synthesis of Compound 32. Compound 261 was the first fraction and Compound 262 was the second fraction of separation of Suzuki coupling product. The atropisomeric configuration was assigned based on the biochemical data.

Compound 261: ¹H NMR (400 MHz, CD₃OD) δ 7.17-7.10 (m, 1H) , 7.03-6.97 (m, 1H) , 5.32 (d, J = 53.6 Hz, 1H) , 4.36 (d, J = 10.8 Hz, 1H) , 4.21 (d, J = 10.8 Hz, 1H) , 3.77-3.62 (m, 2H) , 3.59-3.47 (m, 2H) , 3.44-3.34 (m, 4H) , 3.25 (s, 3H) , 3.08-3.01 (m, 1H) , 2.38-2.14 (m, 3H) , 2.06-1.99 (m, 2H) , 1.96-1.87 (m, 2H) , 1.85-1.44 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.40, -133.27, -173.74. LC-MS: m/z = 652.2 [M-H] ^-.

Compound 262: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.10 (m, 1H) , 7.05-6.96 (m, 1H) , 5.42-5.29 (m, 1H) , 4.45-4.39 (m, 1H) , 4.35-4.27 (m, 1H) , 3.85-3.74 (m, 1H) , 3.63-3.49 (m, 3H) , 3.48-3.34 (m, 6H) , 3.16-3.09 (m, 1H) , 3.02-2.91 (m, 1H) , 2.51-2.37 (m, 1H) , 2.36-2.29 (m, 1H) , 2.23-2.15 (m, 1H) , 2.14-2.02 (m, 3H) , 2.00-1.90 (m, 2H) , 1.86-1.80 (m, 1H) , 1.74-1.68 (m, 1H) , 1.63-1.59 (m, 1H) , 1.50-1.43 (m, 1H); ¹⁹F NMR (377 MHz, CD₃OD) δ -119.42, -133.84, -173.83; LC-MS: m/z = 654.2 [M+H] ⁺.

Compound 263 and Compound 264: 6- ( (5S, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 263) and 6- ( (5R, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 264)

Step 1: Synthesis of (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid (Compound 263-1)

A mixture of 6-bromo-N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (500 mg, 1.17 mmol) , bis (pinacolato) diboron (595 mg, 2.34 mmol) , potassium acetate (290 mg, 2.95 mmol) and PdCl₂ (dppf) (95 mg, 0.12 mmol) in 1, 4-dioxane (40 mL) was stirred at 80 ℃ for 6 hours under N₂ atmosphere. The reaction was diluted with ethyl acetate (50 mL) , washed with water (20 mL x2) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 263-1 (998 mg, crude) as a black solid.

Step 2: Synthesis of (S) -6- (6-chloro-4-fluoro-2- (methylthio) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (Compound 263-2)

A mixture of Compound 263-1 (450 mg, crude) , Compound 27-2 (320 mg, 0.76 mmol) , potassium phosphate tribasic (324.8 mg, 1.53 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (61 mg, 0.075 mmol) in 1, 4-dioxane/H₂O (10 mL/1 mL) was stirred at 80 ℃ for 2 hours under N₂ atmosphere. The mixture was diluted with ethyl acetate (50 mL) , washed with water (20 mL x2) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane = 3%) to afford Compound 263-2 (160 mg, 22%two steps yield) as a yellow solid.

Step 3: Synthesis of 6- ( (8aS) -6-chloro-4-fluoro-2- (methylthio) -8, 8a, 9, 10, 11, 12 hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -5-iodo-N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (Compound 263-3)

A solution of Compound 263-2 (160 mg, 0.23 mmol) , N-iodosuccinimide (263 mg, 1.17 mmol) , and p-toluenesulfonic acid (1.58 mg, 0.01 mmol) in N, N-dimethylacetamide (5 mL) was stirred at 25 ℃ for 16 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x3) . The combined organic layers were washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-20%) to afford Compound 263-3 (130 mg, 69.6%yield) as a white solid.

Step 4: Synthesis of 6- ( (8aS) -6-chloro-4-fluoro-2- (methylthio) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 263-4)

A solution of Compound 263-3 (130 mg, 0.16 mmol) , methyl 2, 2 -difluoro-2- (fluorosulfonyl) acetate (614 mg, 3.2 mmol) and CuI (366 mg, 1.92 mmol) in N, N-dimethylacetamide (5 mL) was stirred at 90 ℃ for 4 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x3) . The combined organic layers were washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-20%) to afford Compound 263-4) (60 mg, 69.6%yield) as a white solid.

Step 5 and 6: Synthesis of 6- ( (8aS) -6-chloro-4-fluoro-2- (methylsulfinyl) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 263-5) and 6- ( (8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 263-6)

To a solution of Compound 263-4 (60 mg, 0.08 mmol) in dichloromethane (6 mL) at 0 ℃ under N₂ atmosphere was added 3-chloroperoxybenzoic acid (16.2 mg, 0.08 mmol, wt 85%) . The mixture was stirred at 25℃ for 0.5 hour. The reaction was diluted with dichloromethane (30 mL) , washed with sat. NaHCO₃ (20 mL x2) , water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford Compound 263-5 as a yellow solid (92 mg, crude) . It was used for the next step without further purification.

To a solution of Compound 264-3 (92 mg, crude) and 4-a (38 mg, 0.24 mmol) in toluene (6 mL) at 0 ℃ under N₂ atmosphere was added sodium tert-butoxide (22 mg, 0.24 mmol) . The mixture was stirred at 25 ℃ for 1 hour, quenched with water (20 mL) and extracted with ethyl acetate (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 15/1) to afford Compound 263-6 (60 mg, 86.7%yield) as a white solid. LC-MS: m/z = 433.2 [1/2M+H] ⁺.

Step 7: Synthesis of 6- ( (5S, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 263) and 6- ( (5R, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 264)

A solution of Compound 263-6 (50 mg, 0.057 mmol) in TFA (9 mL) was stirred at 50 ℃ for 6 hours. The mixture was quenched with aqueous sodium carbonate solution (20 mL) and extracted with dichloromethane (20 mL x2) . The combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford Compound 263 (R_f = 0.5, 12 mg, 33.7%yield) and Compound 264 (R_f = 0.3, 7 mg, 19.6%yield) as a white solid. The configuration of the atropisomers were arbitrarily assigned.

Compound 263: ¹H NMR (400 MHz, CD₃OD) δ 6.58 (s, 1H) , 5.39-5.17 (m, 2H) , 4.50-4.46 (m, 1H) , 4.39-4.34 (m, 1H) , 4.31-4.28 (m, 1H) , 4.23-4.21 (m, 1H) , 4.00-3.91 (m, 1H) , 3.46-3.36 (m, 1H) , 3.31-3.19 (m, 2H) , 3.09-3.02 (m, 2H) , 2.48-2.36 (m, 4H) , 2.31-2.13 (m, 3H) , 2.09-1.98 (m, 3H) , 1.92-1.79 (m, 3H) , 1.76-1.64 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -56.60, -134.85, -173.66; LC-MS: m/z = 625.3 [M+H] ⁺.

Compound 264: ¹H NMR (400 MHz, CD₃OD) δ 6.59 (s, 1H) , 5.40-5.22 (m, 2H) , 4.51-4.39 (m, 2H) , 4.34-4.31 (m, 1H) , 4.24-4.21 (m, 1H) , 3.98-3.93 (m, 1H) , 3.47-3.56 (m, 1H) , 3.27-3.21 (m, 2H) , 3.09-3.03 (m, 2H) , 2.51-2.38 (m, 4H) , 2.33-2.15 (m, 3H) , 2.08-1.991.99 (m, 3H) , 1.95-1.76 (m, 5H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -56.57, -134.88, -173.70; LC-MS: m/z = 625.3 [M+H] ⁺.

Compound 265: 2- ( (S) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-fluorophenol (Compound 265)

¹H NMR (400 MHz, CD₃OD) δ 7.28 (dd, J = 14.8, 6.4 Hz, 1H) , 6.75 (d, J = 8.0 Hz, 1H) , 6.69 (t, J = 8.4 Hz, 1H) , 5.40-5.17 (m, 2H) , 4.47 (dd, J = 2.8, 13.2 Hz, 1H) , 4.40 (dd, J = 13.2, 5.6 Hz, 1H) , 4.28 (dd, J = 33.6, 10.8 Hz, 2H) , 3.99-3.89 (m, 1H) , 3.46-3.33 (m, 1H) , 3.30-3.21 (m, 1H) , 3.12-2.99 (m, 2H) , 2.44-2.22 (m, 2H) , 2.23-2.12 (m, 1H) , 2.09-1.97 (m, 3H) , 1.97-1.54 (m, 7H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -115.48, -130.74, -173.69; LC-MS: m/z = 561.2 [M+H] ⁺.

Compound 267: 2-amino-4- ( (S) -6-chloro-4-fluoro-2- (2-hydroxy-2-methylpropoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 267)

¹H NMR (400 MHz, CD₃OD) δ 7.18 (t, J = 0.8 Hz, 1H) , 7.02 (t, J = 0.8 Hz, 1H) , 5.24 (d, J = 52.4 Hz, 1H) , 4.50 (dd, J = 1.6, 0.4 Hz, 1H) , 4.46 (dd, J = 3.2, 0.8 Hz, 1H) , 4.25 (s, 2H) , 3.90-3.85 (m, 1H) , 3.15-2.98 (m, 1H) , 2.10-1.98 (m, 1H) , 1.97-1.57 (m, 5H) , 1.32 (s, 3H) , 1.28 (s, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -119.08, -131.82; LC-MS: m/z = 572.2 [M+H] ⁺.

Compound 268 and Compound 269: (S) -2-amino-4- ( (S) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 3, 4, 13, 13a-hexahydropyrazino [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 268) and (R) -2-amino-4- ( (S) -11-chloro-9-fluoro-7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1, 2, 3, 4, 13, 13a-hexahydropyrazino [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-10-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 269)

Compound 268 and Compound 269 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 268 was the first fraction and Compound 269 was the second fraction of separation of Suzuki coupling products.

Compound 268: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.16 (m, 1H) , 7.04 (t, J = 8.0 Hz, 1H) , 5.61-5.45 (m, 1H) , 5.35-5.27 (m, 1H) , 4.71 (d, J = 12.4 Hz, 1H) , 4.62-4.58 (m, 3H) , 4.26 (d, J = 12.0 Hz, 1H) , 4.00-3.79 (m, 3H) , 3.54-3.34 (m, 5H) , 3.22-3.12 (m, 1H) , 2.66-2.57 (m, 1H) , 2.56-2.52 (m, 1H) , 2.46-2.38 (m, 1H) , 2.33-2.25 (m, 2H) , 2.13-2.05 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.48, -131.76, -174.31; LC-MS: m/z = 642.2 [M+H] ⁺.

Compound 269: ¹H NMR (400 MHz, CD₃OD) δ 7.25-7.19 (m, 1H) , 7.04 (t, J = 9.2 Hz, 1H) , 5.64-5.45 (m, 1H) , 5.42-5.32 (m, 1H) , 4.69 (s, 2H) , 4.65-4.61 (m, 2H) , 4.42-4.34 (m, 1H) , 4.04-3.81 (m, 3H) , 3.68-3.61 (m, 1H) , 3.59-3.42 (m, 4H) , 3.28-3.22 (m, 1H) , 2.75-2.54 (m, 2H) , 2.44-2.29 (m, 3H) , 2.20-2.12 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.45, -131.36, -174.29; LC-MS: m/z = 642.2 [M+H] ⁺.

Compound 270 and Compound 271: 8- ( (5S, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -5-fluoroquinolin-2-amine (Compound 270) and 8- ( (5R, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -5-fluoroquinolin-2-amine (Compound 271)

Compound 270 and Compound 271 were obtained by chiral Prep-HPLC separation of its atropisomeric mixture on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 270 was the first fraction and Compound 277 was the second fraction eluting from the column.

Compound 270: ¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J = 9.2 Hz, 1H) , 7.40-7.33 (m, 1H) , 7.03 (dd, J = 9.6, 8.0 Hz, 1H) , 6.88 (d, J = 9.2 Hz, 1H) , 5.48-5.33 (m, 1H) , 5.31-5.23 (m, 1H) , 4.56-4.37 (m, 4H) , 4.02-3.96 (m, 1H) , 3.68-3.61 (m, 1H) , 3.57-3.49 (m, 2H) , 3.26-3.17 (m, 1H) , 3.14-3.05 (m, 1H) , 2.47-2.14 (m, 6H) , 2.01-1.70 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -124.36, -132.00, -174.07; LC-MS: m/z = 611.2 [M+H] ⁺.

Compound 271: ¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J = 9.2 Hz, 1H) , 7.41-7.36 (m, 1H) , 7.03 (dd, J = 9.6, 8.0 Hz, 1H) , 6.88 (d, J = 9.2 Hz, 1H) , 5.47-5.31 (m, 1H) , 5.31-5.24 (m, 1H) , 4.57-4.33 (m, 4H) , 4.01-3.92 (m, 1H) , 3.61-3.41 (m, 3H) , 3.22-3.04 (m, 2H) , 2.40-1.81 (m, 10H) , 1.75-1.58 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -124.41, -132.05, -174.04; LC-MS: m/z = 611.2 [M+H] ⁺.

Compound 272 and Compound 273: 8- ( (5S, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -5-fluoroquinolin-2-amine (Compound 272) and 8- ( (5R, 8aS) -6-chloro-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -5-fluoroquinolin-2-amine (Compound 273)

Compound 272 (less polar) and Compound 273 (more polar) were obtained from their atropisomeric mixture by Prep-TLC (DCM/MeOH = 10/1) separation.

Compound 272: ¹H NMR (400 MHz, CD₃OD) δ 6.60 (s, 1H) , 5.51-5.35 (m, 1H) , 5.32-5.25 (m, 1H) , 4.49-4.38 (m, 4H) , 4.00-3.91 (m, 1H) , 3.65-3.48 (m, 3H) , 3.27-3.18 (m, 1H) , 3.08 (td, J = 12.8, 2.4 Hz, 1H) , 2.61-2.46 (m, 1H) , 2.45-2.43 (m, 3H) , 2.42-2.34 (m, 1H) , 2.30-2.24 (m, 1H) , 2.21-2.14 (m, 2H) , 2.05-1.98 (m, 2H) , 1.87-1.72 (m, 3H) , 1.72-1.58 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -56.37, -137.38, -143.79, -173.99; LC-MS: m/z = 609.3 [M+H] ⁺.

Compound 273: ¹H NMR (400 MHz, CD₃OD) δ 6.60 (s, 1H) , 5.49-5.33 (m, 1H) , 5.31-5.25 (m, 1H) , 4.47-4.40 (m, 3H) , 4.36-4.31 (m, 1H) , 3.99-3.90 (m, 1H) , 3.63-3.47 (m, 3H) , 3.23-3.16 (m, 1H) , 3.07 (td, J = 12.8, 2.4 Hz, 1H) , 2.53-2.45 (m, 1H) , 2.44-2.42 (m, 3H) , 2.39-2.34 (m, 1H) , 2.28-2.22 (m, 1H) , 2.15-2.09 (m, 2H) , 2.05-1.97 (m, 2H) , 1.93-1.88 (m, 1H) , 1.86-1.76 (m, 3H) , 1.68-1.61 (m, 1H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -56.22, -137.21, -143.98, -173.92; LC-MS: m/z = 609.3 [M+H] ⁺.

Compound 274: 6- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydro-7-oxa-1, 3, 6, 12a-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-5-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 274)

¹H NMR (400 MHz, CD₃OD) δ 6.59 (s, 1H) , 5.44-5.24 (m, 2H) , 4.49 (d, J = 3.2 Hz, 2H) , 4.37 (d, J = 10.8 Hz, 1H) , 4.28 (d, J = 10.8 Hz, 1H) , 3.98-3.90 (m, 1H) , 3.50-3.43 (m, 1H) , 3.41-3.33 (m, 2H) , 3.15-3.05 (m, 2H) , 2.43 (s, 3H) , 2.37-2.13 (m, 3H) , 2.11-1.71 (m, 8H) , 1.69-1.50 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -55.93, -148.78, -173.75; LC-MS: m/z = 592.3 [M+H] ⁺.

Compound 275: 4- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydro-7-oxa-1, 3, 6, 12a-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalen-5-yl) -6-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 275)

¹H NMR (400 MHz, CD₃OD) δ 6.33 (s, 1H) , 5.46-5.30 (m, 2H) , 4.50 (d, J = 2.8 Hz, 2H) , 4.42 (d, J = 11.2 Hz, 1H) , 4.33 (d, J = 10.8 Hz, 1H) , 3.99-3.94 (m, 1H) , 3.59-3.33 (m, 3H) , 3.21-3.05 (m, 2H) , 2.54 (s, 3H) , 2.51-2.30 (m, 2H) , 2.27-1.71 (m, 9H) , 1.69-1.50 (m, 1H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -55.27, -147.13, -173.80; LC-MS: m/z = 592.2 [M+H] ⁺.

Compound 276 and Compound 277: (S) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 276) and (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 277)

Compound 276 and Compound 277 were obtained by chiral Prep-HPLC separation of Compound 248 on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 276 was the first fraction and Compound 277 was the second fraction eluting from the column.

Compound 276: LC-MS: m/z = 697.2 [M+H] ⁺.

Compound 277: LC-MS: m/z = 697.2 [M+H] ⁺.

Compound 278: 2-amino-4- ( (S) -4- ( (5-amino-1, 3, 4-oxadiazol-2-yl) methyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 278)

LC-MS: m/z = 698.2 [M+H] ⁺.

Compound 279: 6- ( (S) -8-chloro-4-ethyl-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 279)

¹H NMR (400 MHz, CD₃OD) δ 6.59 (s, 1H) , 5.37 (d, J = 54 Hz, 1H) , 4.65-4.58 (m, 1H) , 4.41 (s, 2H) , 4.42-4.05 (m, 6H) , 3.67-3.62 (m, 1H) , 3.47-3.35 (m, 1H) , 2.44 (s, 3H) , 2.40-1.87 (m, 6H) , 1.47-1.32 (m, 6H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -56.66, -147.13, -173.81; LC-MS: m/z = 613.2 [M+H] ⁺.

Compound 280: 2- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) -N-ethyl-N-methylacetamide (Compound 280)

LC-MS: m/z = 700.2 [M+H] ⁺. (Atropisomeric ratio: 1: 1.64 by HPLC analysis)

Compound 281: 2-amino-4- ( (5S) -4- (2- (azetidin-1-yl) -2-oxoethyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 281)

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 1H) , 7.01-6.91 (m, 1H) , 6.39 (brs, 1H) , 6.26 (brs, 1H) , 5.29 (d, J = 52.0 Hz, 1H) , 5.00-3.90 (m, 11H) , 2.49 -1.81 (m, 8H) , 1.51-1.38 (m, 3H) ; ¹⁹F NMR (377 MHz, CDCl₃) -116.43, -129.41/-130.58 (from different atropisomers) , -172.70; LC-MS: m/z = 698.2 [M+H] ⁺. (Atropisomeric ratio: 1: 1.87 by chiral HPLC analysis) .

Compound 282: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 282)

¹H NMR (400 MHz, DMSO-d6) δ 8.10 (br, 2H) , 7.30-7.22 (m, 1H) , 7.17-7.10 (m, 1H) , 5.45 (d, J = 53.2 Hz, 1H) , 4.80-4.72 (m, 2H) , 4.52-4.06 (m, 5H) , 3.75-3.35 (m, 7H) , 3.25-3.05 (m, 1H) , 2.48-2.23 (m, 2H) . 2.20-1.72 (m, 8H) , 1.36-1.30 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -116.66, -130.82/-131.97 (from different atropisomers) , -172.62; LC-MS: m/z = 712.2 [M+H] ⁺. (Atropisomeric ratio: 1: 1.63 by chiral HPLC analysis) .

Compound 283 and Compound 284: 4- ( (5R, 8aS) -4, 6-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -6-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 283) and 4- ( (5S, 8aS) -4, 6-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8, 8a, 9, 10, 11, 12-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-5-yl) -6-methyl-5- (trifluoromethyl) pyridin-2-amine (Compound 284)

Compound 283 (less polar) and Compound 284 (more polar) were obtained by Prep-TLC (DCM/MeOH/= 10/1) separation.

Compound 283: ¹H NMR (400 MHz, CD₃OD) δ 6.29 (s, 1H) , 5.41 (d, J = 53.2 Hz, 1H) , 5.28 (d, J = 12.8 Hz, 1H) , 5.50-5.33 (m, 4H) , 4.00-3.93 (m, 1H) , 3.67-3.43 (m, 3H) , 3.68-3.60 (m, 1H) , 3.58-3.42 (m, 2H) , 3.26-3.16 (m, 1H) , 3.07 (td, J = 12.8, 1.6 Hz, 1H) , 2.55 (s, 3H) , 2.51-2.09 (m, 5H) , 2.05-1.55 (m, 7H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -55.78, 136.09, -143.05, -173.92; LC-MS: m/z = 609.3 [M+H] ⁺.

Compound 284: ¹H NMR (400 MHz, CD₃OD) δ 6.30 (s, 1H) , 5.32 (d, J = 54.4 Hz, 1H) , 5.28 (d, J = 10.8 Hz, 1H) , 4.50-4.37 (m, 2H) , 4.32 (d, J = 10.8 Hz, 1H) , 4.23 (d, J = 10.8 Hz, 1H) , 3.97-3.88 (m, 1H) , 3.50-3.30 (m, 3H) , 3.15-3.00 (m, 2H) , 2.55 (s, 3H) , 3.07 (td, J = 12.8, 1.6 Hz, 1H) , 2.55 (s, 3H) , 2.46-1.71 (m, 12H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -55.77, 135.75, -143.49, -173.70; LC-MS: m/z = 609.2 [M+H] ⁺.

Compound 285: 3- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) -N, N-dimethylpropanamide (Compound 285)

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.15 (m, 1H) , 7.06-7.00 (m, 1H) , 5.43 (d, J = 52.8 Hz, 1H) , 4.77-4.34 (m, 5H) , 4.31-4.20 (m, 1H) , 3.86-3.50 (m, 4H) , 3.30-3.20 (m, 1H) , 3.12 (s, 3H) . 3.00-2.92 (m, 5H) , 2.60-2.33 (m, 1H) , 2.32-2.10 (m, 4H) , 2.07-1.91 (m, 1H) , 1.45-1.36 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -118.82, -133.51/-134.31 (from different atropisomers) , -174.15; LC-MS: m/z = 700.2 [M+H] ⁺. Atropisomeric ratio: 1: 2.42 by HPLC analysis.

Compound 286: 2-amino-4- ( (5S) -8-chloro-4- (2- (dimethylamino) ethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 286)

¹H NMR (400 MHz, CD₃OD) δ 7.27-7.17 (m, 1H) , 7.10-7.02 (m, 1H) , 5.53 (d, J = 52.4 Hz, 1H) , 4.82-4.44 (m, 5H) , 4.32-4.23 (m, 1H) , 4.10-3.64 (m, 5H) , 3.60-3.38 (m, 2H) , 3.20-3.00 (m, 6H) . 2.78-2.39 (m, 3H) , 2.38-2.07 (m, 3H) , 1.50-1.40 (m, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d6) -118.47, -133.91/-134.79 (from different atropisomers) , -174.67; LC-MS: m/z = 672.2 [M+H] ⁺.

Compound 287: 2-amino-4- ( (S) -10-ethyl-4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -9-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-5-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 287)

¹H NMR (400 MHz, CD₃OD) δ 7.45-7.36 (m, 1H) , 7.03 (t, J = 9.2 Hz, 1H) , 5.51-5.36 (m, 1H) , 4.69-4.61 (m, 1H) , 4.55-4.37 (m, 3H) , 4.28-4.15 (m, 2H) , 3.71-3.51 (m, 4H) , 3.29-3.20 (m, 1H) , 2.54-2.15 (m, 5H) , 2.07-1.99 (m, 1H) , 1.41-1.35 (m, 6H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -117.86, -147.17, -173.98; LC-MS: m/z = 596.2 [M+H] ⁺.

Compound 288: 2- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl dimethylcarbamate (Compound 288)

¹H NMR (400 MHz, CD₃OD) δ 7.24-7.13 (m, 1H) , 7.07-6.96 (m, 1H) , 5.41-5.26 (m, 1H) , 4.72-4.39 (m, 7H) , 4.37-4.22 (m, 2H) , 4.21-4.12 (m, 1H) , 3.93-3.82 (m, 1H) , 3.50-3.34 (m, 1H) , 3.15-3.00 (m, 1H) , 2.90 (s, 6H) , 2.30-2.22 (m, 1H) , 2.21-2.09 (m, 2H) , 2.09-1.96 (m, 3H) , 1.41 (t, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.06, -132.90, -173.68; LC-MS: m/z = 716.2 [M+H] ⁺.

Compound 289: methyl (2- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl) (methyl) carbamate (Compound 289)

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.14 (m, 1H) , 7.05-6.98 (m, 1H) , 5.44-5.23 (m, 1H) , 4.69-4.61 (m, 1H) , 4.47-4.19 (m, 4H) , 4.15-3.99 (m, 1H) , 3.88-3.39 (m, 7H) , 3.38-3.31 (m, 2H) , 3.15-2.97 (m, 4H) , 2.46-2.16 (m, 3H) , 2.07-1.86 (m, 3H) , 1.43-1.36 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.07, -132.94, -173.52; LC-MS: m/z = 716.2 [M+H] ⁺.

Compound 290: 2-amino-4- ( (5aS) -3-chloro-1, 11-difluoro-15- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10-methyl-5, 5a, 6, 7-tetrahydro-12H-pyrazolo [5” , 1” : 3', 4'] [1, 4] diazepino [7', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 290)

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.10 (m, 1H) , 7.09-6.94 (m, 1H) , 6.27 (d, J = 7.6 Hz, 1H) , 5.60-5.43 (m, 1H) , 4.83-4.77 (m, 1H) , 4.68-4.35 (m, 7H) , 3.98-3.67 (m, 3H) , 3.35-3.32 (m, 1H) , 2.79-2.16 (m, 7H) , 2.16-1.99 (m, 4H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.70, -131.96, -173.89, -178.56; LC-MS: m/z = 725.2 [M+H] ⁺.

Compound 291 and Compound 292: 2-amino-4- ( (5S, 9S) -4- (2- (azetidin-1-yl) -2-oxoethyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 291) and 2-amino-4- ( (5S, 9R) -4- (2- (azetidin-1-yl) -2-oxoethyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 292)

Compound 291 and Compound 292 were obtained by chiral Prep-HPLC separation of Compound 281 on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 291 was the first fraction and Compound 292 was the second fraction eluting from the column.

Compound 291: LC-MS: m/z = 698.2 [M+H] ⁺.

Compound 292: LC-MS: m/z = 698.2 [M+H] ⁺.

Compound 293: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (2-oxooxazolidin-3-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 293)

¹H NMR (400 MHz, CD₃OD) δ 7.20-7.12 (m, 1H) , 7.06-6.97 (m, 1H) , 5.44-5.25 (m, 1H) , 4.71-4.61 (m, 1H) , 4.51-4.26 (m, 6H) , 4.20-4.10 (m, 1H) , 3.92-3.65 (m, 4H) , 3.62-3.53 (m, 1H) , 3.50-3.32 (m, 2H) , 3.13-3.03 (m, 1H) , 2.46-2.15 (m, 3H) , 2.09-1.89 (m, 3H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.02, -132.55, -173.55; LC-MS: m/z = 714.2 [M+H] ⁺.

Compound 294: 2-amino-7-fluoro-4- ( (S) -4-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -10- ( (S) -1-hydroxypropan-2-yl) -9-methyl-9, 10-dihydro-8H-7-oxa-1, 3, 6, 10-tetraazacyclohepta [de] naphthalen-5-yl) benzo [b] thiophene-3-carbonitrile (Compound 294)

1H NMR (400 MHz, CD3OD) δ 7.43-7.38 (m, 1H) , 7.03 (t, J = 9.2 Hz, 1H) , 5.71-5.54 (m, 1H) , 5.53-5.37 (m, 1H) , 4.70-4.62 (m, 1H) , 4.53-4.36 (m, 4H) , 3.84-3.77 (m, 2H) , 3.75-3.54 (m, 3H) , 3.29-3.19 (m, 1H) , 2.62-2.40 (m, 2H) , 2.33-2.16 (m, 3H) , 2.9-1.99 (m, 1H) , 1.37 (d, J = 7.2 Hz, 3H) , 1.32 (d, J = 6.8 Hz, 3H) ; 19F NMR (377 MHz, CD3OD) δ -117.87, -147.68, -174.05; LC-MS: m/z = 626.2 [M+H] +.

Compound 295 and Compound 296: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 295) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 296)

Compound 295 and Compound 296 were obtained by chiral Prep-HPLC separation of Compound 282 on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 295 was the first fraction and Compound 296 was the second fraction eluting from the column.

Compound 295: LC-MS: m/z = 712.2 [M+H] ⁺.

Compound 296: LC-MS: m/z = 712.2 [M+H] ⁺.

Compound 297 and Compound 298: 3- ( (S) -9- ( (S) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) -N, N-dimethylpropanamide (Compound 297) and 3- ( (S) -9- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) -N, N-dimethylpropanamide (Compound 298)

Compound 297 and Compound 298 were obtained by chiral Prep-HPLC separation of Compound 285 on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 297 was the first fraction and Compound 298 was the second fraction eluting from the column.

Compound 297: LC-MS: m/z = 700.2 [M+H] ⁺.

Compound 298: LC-MS: m/z = 700.2 [M+H] ⁺.

Compound 299 and Compound 300: 2-amino-4- ( (5S, 9S) -8-chloro-4- (2- (dimethylamino) ethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 299) and 2-amino-4- ( (5S, 9R) -8-chloro-4- (2- (dimethylamino) ethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 300)

Compound 299 and Compound 300 were obtained by chiral Prep-HPLC separation of Compound 286 on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 299 was the first fraction and Compound 300 was the second fraction eluting from the column.

Compound 299: ¹H NMR (400 MHz, CD₃OD) δ 7.24-7.18 (m, 1H) , 7.07-7.00 (m, 1H) , 5.48-5.33 (m, 1H) , 4.72-4.65 (m, 1H) , 4.52-4.45 (m, 2H) , 4.44-4.34 (m, 2H) , 4.21-4.11 (m, 1H) , 3.77-3.51 (m, 4H) , 3.28-3.20 (m, 1H) , 3.10-3.00 (m, 1H) , 2.97-2.86 (m, 1H) , 2.58 (s, 6H) , 2.44-2.37 (m, 1H) , 2.27-2.11 (m, 4H) , 2.04-2.00 (m, 1H) , 1.41 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.85, -134.00, -174.03; LC-MS: m/z = 336.7 [M/2+H] ⁺.

Compound 300: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.16 (m, 1H) , 7.07-7.01 (m, 1H) , 5.54-5.36 (m, 1H) , 4.74-4.65 (m, 1H) , 4.64-4.57 (m, 1H) , 4.56-4.38 (m, 3H) , 4.22-4.13 (m, 1H) , 3.85-3.63 (m, 4H) , 3.37-3.32 (m, 1H) , 3.27-3.17 (m, 1H) , 3.14-3.02 (m, 1H) , 2.72 (s, 6H) , 2.60-2.40 (m, 2H) , 2.37-2.28 (m, 1H) , 2.26-2.18 (m, 2H) , 2.06-1.97 (m, 1H) , 1.43 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.71, -133.50, -174.34; LC-MS: m/z = 672.2 [M+H] ⁺.

Compound 301, Compound 302 and Compound 303: 2-amino-4- ( (5S) -8-chloro-4- (1, 1-dioxidotetrahydrothiophen-3-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (isomer 1: Compound 301; isomer 2: Compound 302; isomer 3, Compound 303)

Mixture of Compound 301 (isomer 1) /Compound 302 (isomer 2) and Compound 303 (isomer 3) were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. The mixture of Compound 301 (isomer 1) and Compound 302 (isomer 2) was eluted out as the first fraction and Compound 303 (isomer 3) as the second fraction after the Suzuki coupling step. Compound 301 and Compound 302 were separated by chiral Prep-HPLC separation of their mixture on a UnichiralAD-5H column, followed by further Prep-TLC (DCM/MeOH = 10/1) purification. Compound 301 was the first fraction and Compound 302 was the second fraction. Compound 303 was purified by Prep-TLC (DCM/MeOH = 10/1) purification.

Compound 301 (isomer 1) : ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.17 (m, 1H) , 7.07-7.00 (m, 1H) , 5.44-5.30 (m, 1H) , 4.71-4.62 (m, 1H) , 4.58 (s, 2H) , 4.43-4.34 (m, 2H) , 4.27-4.17 (m, 1H) , 3.97-3.84 (m, 1H) , 3.83-3.71 (m, 1H) , 3.68-3.61 (m, 1H) , 3.52-3.38 (m, 3H) , 3.24-3.13 (m, 2H) , 2.77-2.59 (m, 2H) , 2.43-2.18 (m, 3H) , 2.15-2.04 (m, 2H) , 2.02-1.94 (m, 1H) , 1.45-1.34 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.95, -133.33, -174.62; LC-MS: m/z = 719.1 [M+H] ⁺.

Compound 302 (isomer 2) : LC-MS: m/z = 719.1 [M+H] ⁺.

Compound 303 (isomer 3) : ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.13 (m, 1H) , 7.03 (t, J = 8.0 Hz, 1H) , 5.37-5.31 (m, 1H) , 4.67-4.61 (m, 1H) , 4.54-4.47 (m, 1H) , 4.47-4.40 (m, 1H) , 4.40-4.33 (m, 1H) , 4.24-4.17 (m, 1H) , 3.99-3.85 (m, 2H) , 3.59-3.45 (m, 3H) , 3.25-3.15 (m, 2H) , 2.66-2.55 (m, 2H) , 2.44-2.24 (m, 3H) , 2.15-2.11 (m, 1H) , 2.06-1.97 (m, 2H) , 1.64-1.55 (m, 2H) , 1.44 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.07, -132.54, -173.77; LC-MS: m/z = 719.1 [M+H] ⁺.

Compound 304 and Compound 305: 2-amino-4- ( (5S, 9S) -8-chloro-4- (2- (cyclopropylsulfonyl) ethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 304) and 2-amino-4- ( (5S, 9R) -8-chloro-4- (2- (cyclopropylsulfonyl) ethyl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 305)

Compound 304 (Less polar) and Compound 305 (More polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 304: LC-MS: m/z = 733.2 [M+H] ⁺.

Compound 305: LC-MS: m/z = 733.2 [M+H] ⁺.

Compound 306: (5aS) -1-fluoro-11- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (5- (trifluoromethyl) -1H-indazol-4-yl) -5, 5a, 6, 7, 8, 9-hexahydro-4-oxa-3, 9a, 10, 12-tetraazabenzo [4, 5] cyclohepta [1, 2, 3-de] naphthalene (Compound 306)

Compound 306 was synthesized by following procedures similar for the synthesis of Compound 1 described above. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H) , 7.79 (d, J = 8.8 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 1H) , 5.50-5.32 (m, 2H) , 4.56-4.38 (m, 2H) , 3.87-3.83 (m, 2H) , 3.20-2.95 (m, 2H) , 2.42-2.22 (m, 2H) , 2.10-1.90 (m, 4H) , 1.40-1.20 (m, 6H) , 0.92-0.85 (m, 4H) ; ¹⁹F NMR (376 MHz, DMSO) δ -56.60, -100.01, -142.45; LC-MS: m/z = 601.9 [M+H] ⁺.

Compound 307: (R) -2-amino-4- ( (S) -8-chloro-2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -10-fluoro-4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 307)

¹H NMR (400 MHz, CD₃OD) δ 7.23-7.17 (m, 1H) , 7.07-7.01 (m, 1H) , 4.67-4.61 (m, 1H) , 4.52-4.45 (m, 1H) , 4.44-4.37 (m, 1H) , 4.35-4.27 (m, 1H) , 4.14-4.04 (m, 1H) , 3.41 (s, 3H) , 3.29-3.20 (m, 1H) , 3.15-3.07 (m, 1H) , 2.89 (s, 6H) , 1.43 (d, J = 6.8 Hz, 3H) , 0.95-0.89 (m, 2H) , 0.84-0.75 (m, 2H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.78, -134.35; LC-MS: m/z = 585.2 [M+H] ⁺.

Compound 308 and Compound 309: 2- ( (5S, 9S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl dimethylcarbamate (Compound 308) and 2- ( (5S, 9R) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl dimethylcarbamate (Compound 309)

Compound 308 (less polar) and Compound 309 (more polar) were obtained from the separation of Compound 288 on Prep-TLC (MeOH/DCM = 1/10) .

Compound 308: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.15 (m, 1H) , 7.06-6.99 (m, 1H) , 5.52-5.34 (m, 1H) , 4.72-4.65 (m, 1H) , 4.58-4.36 (m, 6H) , 4.24-4.16 (m, 1H) , 3.90-3.81 (m, 1H) , 3.72-3.46 (m, 3H) , 3.27-3.17 (m, 1H) , 2.91 (s, 6H) , 2.55-2.24 (m, 3H) , 2.20-2.08 (m, 2H) , 2.04-1.93 (m, 1H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.96, -133.77, -173.92; LC-MS: m/z = 716.2 [M+H] ⁺.

Compound 309: ¹H NMR (400 MHz, CD₃OD) δ 7.21-7.15 (m, 1H) , 7.06-6.99 (m, 1H) , 5.48-5.35 (m, 1H) , 4.72-4.65 (m, 1H) , 4.58-4.36 (m, 6H) , 4.24-4.16 (m, 1H) , 3.90-3.81 (m, 1H) , 3.72-3.46 (m, 3H) , 3.27-3.17 (m, 1H) , 2.91 (s, 6H) , 2.55-2.25 (m, 3H) , 2.20-2.08 (m, 2H) , 2.06-1.93 (m, 1H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.89, -133.08, -174.00; LC-MS: m/z = 716.2 [M+H] ⁺.

Compound 310: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-4, 5-dimethyl-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 310)

¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (br, 2H) , 7.29-7.19 (m, 1H) , 7.17-7.08 (m, 1H) , 4.75-4.55 (m, 3H) , 4.30 (d, J = 12.8 Hz, 1H) , 4.16-4.06 (m, 1H) , 3.87-3.34 (m, 5H) , 3.11-2.70 (m, 4H) , 2.30-2.09 (m, 1H) , 2.00-1.76 (m, 3H) , 1.34 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, DMSO-d₆) δ -116.68, -130.61; LC-MS: m/z = 571.1 [M+H] ⁺.

Compound 311: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-4, 5-dimethyl-2- ( (S) -1- ( (S) -1-methylpyrrolidin-2-yl) ethoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 311)

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.14 (m, 1H) , 7.06-6.99 (m, 1H) , 5.42-5.34 (m, 1H) , 4.67-4.60 (m, 1H) , 4.47-4.40 (m, 1H) , 4.14-4.07 (m, 1H) , 3.70-3.57 (m, 2H) , 3.45 (s, 3H) , 3.23-3.14 (m, 1H) , 3.02 (s, 3H) , 2.41-2.32 (m, 1H) , 2.20-2.05 (m, 2H) , 1.99-1.90 (m, 1H) , 1.51 (d, J = 6.4 Hz, 3H) , 1.45 (d, J = 6.4 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.90, -132.68; LC-MS: m/z = 585.2 [M+H] ⁺.

Compound 312: (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 312)

¹H NMR (400 MHz, CD₃OD) δ 7.21-7.13 (m, 1H) , 7.04-6.98 (m, 1H) , 4.64-4.50 (m, 3H) , 4.46-4.40 (m, 1H) , 4.11-3.98 (m, 2H) , 3.51-3.46 (m, 1H) , 3.43 (s, 3H) , 3.31 (s, 3H) , 3.29-3.19 (m, 1H) , 2.68-2.58 (m, 4H) , 2.21-2.16 (m, 1H) , 2.02-1.94 (m, 1H) , 1.44 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.05, -132.62; LC-MS: m/z = 601.2 [M+H] ⁺.

Compound 313 and Compound 314: 2-amino-4- ( (5S, 9S) -4- (3- (azetidin-1-yl) -3-oxopropyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 313) and 2-amino-4- ( (5S, 9R) -4- (3- (azetidin-1-yl) -3-oxopropyl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 314)

Compound 313 (Less polar) and Compound 314 (More polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 313: LC-MS: m/z = 712.2 [M+H] ⁺.

Compound 314: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.17 (m, 1H) , 7.07-7.01 (m, 1H) , 5.52-5.38 (m, 1H) , 4.72-4.56 (m, 2H) , 4.50-4.35 (m, 3H) , 4.31-4.19 (m, 3H) , 4.02 (t, J = 8.0 Hz, 2H) , 3.83-3.59 (m, 4H) , 3.30-3.25 (m, 1H) , 2.79-2.63 (m, 2H) , 2.58-2.41 (m, 2H) , 2.35-2.16 (m, 5H) , 2.06-1.96 (m, 1H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.81, -133.51, -174.18; LC-MS: m/z = 712.2 [M+H] ⁺.

Compound 315 and Compound 316: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 315) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 316)

Compound 315 (Less polar) and Compound 316 (More polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 315: ¹H NMR (400 MHz, CD₃OD) δ 7.23-7.16 (m, 1H) , 7.06-6.98 (m, 1H) , 5.39-5.22 (m, 1H) , 4.68-4.61 (m, 1H) , 4.41-4.27 (m, 3H) , 4.26-4.16 (m, 2H) , 3.90-3.81 (m, 1H) , 3.58-3.48 (m, 2H) , 3.44 (t, J = 6.8 Hz, 2H) , 3.36-3.31 (m, 1H) , 3.27-3.18 (m, 2H) , 3.05-2.91 (m, 3H) , 2.43-2.16 (m, 2H) , 2.15-2.06 (m, 1H) , 2.04-1.93 (m, 4H) , 1.93-1.80 (m, 3H) , 1.40 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.13, -133.17, -173.42; LC-MS: m/z = 726.2 [M+H] ⁺.

Compound 316: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.15 (m, 1H) , 7.07-6.99 (m, 1H) , 5.51-5.33 (m, 1H) , 4.71-4.63 (m, 1H) , 4.58-4.51 (m, 1H) , 4.47-4.33 (m, 3H) , 4.30-4.21 (m, 1H) , 3.87-3.78 (m, 1H) , 3.72-3.48 (m, 5H) , 3.44 (t, J = 6.8 Hz, 2H) , 3.28-3.20 (m, 1H) , 2.99-2.87 (m, 2H) , 2.54-2.33 (m, 2H) , 2.31-2.23 (m, 1H) , 2.20-2.10 (m, 2H) , 2.02-1.86 (m, 5H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.83, -133.35, -174.08; LC-MS: m/z = 726.2 [M+H] ⁺.

Compound 317 and Compound 318: (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (S) -1-methyl-2-oxopyrrolidin-3-yl) -5, 6- dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 317) and (S) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (S) -1-methyl-2-oxopyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 318)

Compound 317 (Less polar) and Compound 318 (More polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 317: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.14 (m, 1H) , 7.07-6.98 (m, 1H) , 5.45-5.26 (m, 1H) , 4.72-4.63 (m, 1H) , 4.52-4.44 (m, 2H) , 4.34-4.26 (m, 2H) , 4.12-4.07 (m, 1H) , 3.72-3.68 (m, 1H) , 3.60-3.36 (m, 4H) , 3.18-3.13 (m, 1H) , 2.91 (s, 3H) , 2.63-2.58 (m, 1H) , 2.55-2.47 (m, 1H) , 2.45-2.35 (m, 1H) , 2.35-2.28 (m, 1H) , 2.24-2.17 (m, 1H) , 2.16-2.04 (m, 2H) , 1.97-1.90 (m, 1H) , 1.52-1.47 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.84, -133.26, -174.19; LC-MS: m/z = 698.2 [M+H] ⁺.

Compound 318: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.19 (m, 1H) , 7.05-7.01 (m, 1H) , 5.46-5.33 (m, 1H) , 4.74-4.69 (m, 1H) , 4.57-4.40 (m, 4H) , 4.12-4.07 (m, 1H) , 3.71-3.54 (m, 5H) , 3.18-3.13 (m, 1H) , 2.91 (s, 3H) , 2.55-2.47 (m, 4H) , 2.45-2.04 (m, 4H) , 1.52-1.47 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.69, -134.50, -174.24; LC-MS: m/z = 698.2 [M+H] ⁺.

Compound 319 and Compound 320: 2-amino-4- ( (5S, 9S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (2-oxooxazolidin-3-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 319) and 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- (2- (2-oxooxazolidin-3-yl) ethyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 320)

Compound 319 and Compound 320 were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 319 eluted out as the first fraction and Compound 320 as the second fraction after the Suzuki coupling step. Both are atropisomers of Compound 293.

Compound 319: ¹H NMR (400 MHz, CD₃OD) δ 7.22-7.18 (m, 1H) , 7.06-6.98 (m, 1H) , 5.30 (d, J = 54 Hz, 1H) , 4.68-4.62 (m, 1H) , 4.51-4.26 (m, 6H) , 4.20-4.10 (m, 1H) , 3.92-3.65 (m, 4H) , 3.62-3.53 (m, 1H) , 3.50-3.32 (m, 2H) , 3.13-3.03 (m, 1H) , 2.46-2.15 (m, 3H) , 2.09-1.89 (m, 3H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.13, -133.09, -173.41; LC-MS: m/z = 714.2 [M+H] ⁺.

Compound 320: ¹H NMR (400 MHz, CD₃OD) δ 7.18-7.14 (m, 1H) , 7.04-6.97 (m, 1H) , 5.31 (d, J = 54 Hz, 1H) , 4.66-4.63 (m, 1H) , 4.48-4.22 (m, 6H) , 4.20-4.10 (m, 1H) , 3.90-3.55 (m, 5H) , 3.50-3.26 (m, 3H) , 3.05-2.98 (m, 1H) , 2.40-2.24 (m, 3H) , 2.09-1.89 (m, 3H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.09, -132.31, -173.41; LC-MS: m/z = 714.2 [M+H] ⁺.

Compound 321: methyl (2- ( (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl) carbamate (Compound 321)

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.14 (m, 1H) , 7.07-6.98 (m, 1H) , 5.35 (d, J = 52 Hz, 1H) , 4.71-4.50 (m, 3H) , 4.47-4.36 (m, 2H) , 4.34-4.20 (m, 2H) , 4.16-4.02 (m, 1H) , 3.64 (s, 3H) , 3.63-3.30 (m, 4H) , 3.17-3.03 (m, 1H) , 2.49-2.13 (m, 3H) , 2.12-1.85 (m, 3H) , 1.39 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.04, -132.56/-132.35 (from different atropisomers) , -173.78; LC-MS: m/z = 702.2 [M+H] ⁺.

Compound 322: 2-amino-4- ( (5S) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (1-methyl-2-oxopyrrolidin-3-yl) methyl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 322)

¹H NMR (400 MHz, CD₃OD) δ 7.25-7.15 (m, 1H) , 7.02 (t, J = 8.8 Hz, 1H) , 5.42 (d, J = 52.8 Hz, 1H) , 4.80-4.63 (m, 2H) , 4.61-4.46 (m, 4H) , 3.74-3.10 (m, 8H) , 2.87-2.85 (m, 3H) , 2.59-1.88 (m, 8H) , 1.42-1.26 (m, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.91, -132.98/-133.92, -173.74/173.92 (from different isomers) ; LC-MS: m/z = 712.2 [M+H] ⁺.

Compound 323 and Compound 324: 2- ( (5S, 9S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl pyrrolidine-1-carboxylate (Compound 323) and 2- ( (5S, 9R) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl pyrrolidine-1-carboxylate (Compound 324)

Compound 323 and Compound 324 were obtained by chiral Prep-HPLC separation of their mixture on a UnichiralAD-5H column, followed by further Prep-HPTLC purification. Compound 323 was the first fraction and Compound 324 was the second fraction.

Compound 323: ¹H NMR (400 MHz, CD₃OD) δ 7.20 (dd, J = 8.2, 5.0 Hz, 1H) , 7.02 (t, J = 8.4 Hz, 1H) , 5.33 (d, J = 52.8 Hz, 1H) , 4.68 (dd, J = 12.8, 4.8 Hz, 1H) , 4.64-4.53 (m, 2H) , 4.51-4.39 (m, 3H) , 4.34 (d, J = 10.8 Hz, 1H) , 4.25 (d, J = 10.8 Hz, 1H) , 4.22-4.14 (m, 1H) , 3.95-3.85 (m, 1H) , 3.49-3.20 (m, 6H) , 3.14-3.02 (m, 1H) , 2.44-2.11 (m, 3H) , 2.07-1.80 (m, 7H) , 1.41 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.07, -133.30, -173.65; LC-MS: m/z = 742.2 [M+H] ⁺.

Compound 324: ¹H NMR (400 MHz, CD₃OD) δ 7.17 (dd, J = 8.2, 5.0 Hz, 1H) , 7.02 (t, J = 8.4 Hz, 1H) , 5.33 (d, J = 52.8 Hz, 1H) , 4.72 (dd, J = 12.8, 4.4 Hz, 1H) , 4.60-4.40 (m, 5H) , 4.33 (d, J = 10.8 Hz, 1H) , 4.25-4.15 (m, 2H) , 3.91-3.81 (m, 1H) , 3.48-3.21 (m, 6H) , 3.10-3.01 (m, 1H) , 2.41-2.14 (m, 3H) , 2.07-1.80 (m, 7H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.07, -132.45, -173.72; LC-MS: m/z = 742.2 [M+H] ⁺.

Compound 325 and Compound 326: 2- ( (5S, 9R) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl acetate (Compound 325) and 2- ( (5S, 9S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -8-chloro-10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro- 1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-4-yl) ethyl acetate (Compound 326)

Compound 325 (less polar) and Compound 326 (more polar) were obtained by Prep-TLC (DCM/MeOH = 10/1) separation of their atropisomeric mixture.

Compound 325: ¹H NMR (400 MHz, CD₃OD) δ 7.18 (dd, J = 8.2, 5.0 Hz, 1H) , 7.02 (t, J = 8.4 Hz, 1H) , 5.41 (d, J = 52.8 Hz, 1H) , 4.70 (dd, J = 12.8, 4.4 Hz, 1H) , 4.57-4.44 (m, 5H) , 4.39-4.36 (m, 1H) , 4.24-4.18 (m, 1H) , 3.89-3.82 (m, 1H) , 3.66-3.48 (m, 3H) , 3.23-3.17 (m, 1H) , 2.52-2.26 (m, 3H) , 2.17-2.07 (m, 5H) , 2.03-1.97 (m, 1H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.91, -133.03, -173.92; LC-MS: m/z = 687.2 [M+H] ⁺.

Compound 326: ¹H NMR (400 MHz, CD₃OD) δ 7.21 (dd, J = 8.6, 5.0 Hz, 1H) , 7.03 (t, J = 8.8 Hz, 1H) , 5.43 (d, J = 52.4 Hz, 1H) , 4.71 (dd, J = 12.8, 4.4 Hz, 1H) , 4.57-4.44 (m, 5H) , 4.39-4.36 (m, 1H) , 4.24-4.18 (m, 1H) , 3.89-3.82 (m, 1H) , 3.66-3.48 (m, 3H) , 3.23-3.17 (m, 1H) , 2.52-2.26 (m, 3H) , 2.17-2.07 (m, 5H) , 2.03-1.97 (m, 1H) , 1.40 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -118.89, -134.07, -174.05; LC-MS: m/z = 687.2 [M+H] ⁺.

Compound 327: (R) -2-amino-4- ( (S) -8-chloro-10-fluoro-2- ( ( (2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 327)

¹H NMR (400 MHz, CD₃OD) δ 7.20-7.14 (m, 1H) , 7.05-6.99 (m, 1H) , 5.33-5.19 (m, 1H) , 4.67-4.53 (m, 3H) , 4.46-4.40 (m, 1H) , 4.12-4.04 (m, 1H) , 3.74-3.60 (m, 1H) , 3.53-3.47 (m, 1H) , 3.44 (s, 3H) , 3.05-2.90 (m, 1H) , 2.75 (s, 3H) , 2.49-2.33 (m, 1H) , 2.22-2.03 (m, 1H) , 1.44 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.00, -132.88, -172.61; LC-MS: m/z = 589.2 [M+H] ⁺.

Compound 328: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-4, 5-dimethyl-2- (piperazin-1-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 328)

¹H NMR (400 MHz, CD₃OD) δ 7.17-7.13 (m, 1H) , 7.02-6.98 (m, 1H) , 4.56-4.52 (m, 1H) , 4.39-4.36 (m, 1H) , 4.01-3.97 (m, 1H) , 3.93-3.90 (m, 4H) , 3.33 (s, 3H) , 2.97 (t, J = 5.2 Hz, 4H) , 1.41 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) δ -119.49, -133.82; LC-MS: m/z = 542.1 [M+H] ⁺.

Compound 329: 2-amino-4- ( (5S, 9R) -8-chloro-10-fluoro-4, 5-dimethyl-2- ( (R) -1- ( (S) -1-methylpyrrolidin-2-yl) ethoxy) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) -7-fluorobenzo [b] thiophene-3-carbonitrile (Compound 329)

¹H NMR (400 MHz, CD₃OD) : δ 7.20 (dd, J = 8.4, 5.2 Hz, 1H) , 7.03 (t, J = 9.2 Hz, 1H) , 5.52 (q, J = 6.4 Hz, 1H) , 4.66 (dd, J = 13.2, 4.4 Hz, 1H) , 4.45 (d, J = 13.2 Hz, 1H) , 4.14-4.08 (m, 1H) , 3.63-3.49 (m, 2H) , 3.44 (s, 3H) , 3.13-3.02 (m, 1H) , 2.97 (s, 3H) , 2.33-2.19 (m, 2H) , 2.16-2.05 (m, 1H) , 2.01-1.89 (m, 1H) , 1.50 (d, J = 6.4 Hz, 3H) , 1.44 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD) : δ -118.75, -134.73; LC-MS: m/z = 585.2 [M+H] ⁺.

Compound 330: 2-amino-7-fluoro-4- ( (2S, 5aS) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 330)

Step 1: Synthesis of tert-butyl (4- ( (2R, 5aS) -3-chloro-1-fluoro-12- (methylsulfinyl) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 330-1)

To a solution of Compound 112-1 (505 mg, 0.80 mmol) in dichloromethane (5 mL) at 0 ℃ under N₂ atmosphere was added 3-chloroperoxybenzoic acid (163 mg, 0.80 mmol, wt 85%) . After stirring at 0 ℃ for 20 minutes, the mixture was diluted with ethyl acetate (100 mL) and washed with sat. Na₂SO₃ (50 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane = 25%-35%) to afford Compound 330-1 (385 mg, 74.5%yield) as a yellow solid.

Step 2: Synthesis of tert-butyl (4- ( (2R, 5aS) -3-chloro-1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) -3-cyano-7-fluorobenzo [b] thiophen-2-yl) carbamate (Compound 330-2)

To a solution of Compound 330-1 (385 mg, 0.73 mmol) and 4-a (349 mg, 2.19 mmol) in tetrahydrofuran (4 mL) at 0 ℃ under N₂ atmosphere was added lithium bis (trimethylsilyl) amide (3.7 mL, 1 mol/L) . The mixture was stirred at 25 ℃ for 1 hour and quenched with water (50 mL) . The aqueous phase was extracted with ethyl acetate (50 mL x2) . The combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol = 10/1) to afford Compound 330-2 (293 mg, 62.6%yield) as a brown solid.

Step 3: Synthesis of tert-butyl (3-cyano-7-fluoro-4- ( (2S, 5aS) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophen-2-yl) carbamate (Compound 330-3)

A mixture of Compound 330-2 (150 mg, 0.20 mmol) , methylboronic acid (60 mg, 1.00 mmol) , cesium carbonate (652 mg, 2.00 mmol) and RuPhos Pd G3 (50 mg, 0.06 mmol) in toluene (4 mL) was stirred at 120 ℃ for 1 hour under N₂ atmosphere under microwave irradiation. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) , washed with water (50 mL) and brine (50 mL) successively. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to afford

Compound 330-3 (109 mg, crude) as a yellow solid. It was used for the next step without further purification. LC-MS: m/z = 721.3 [M+H] ⁺.

Step 4: Synthesis of 2-amino-7-fluoro-4- ( (2S, 5aS) -1-fluoro-12- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -3-methyl-5, 5a, 6, 7, 8, 9-hexahydropyrido [2', 1': 3, 4] [1, 4] oxazepino [5, 6, 7-de] quinazolin-2-yl) benzo [b] thiophene-3-carbonitrile (Compound 330)

To a solution of Compound 330-3 (83 mg, crude) in dichloromethane (1.5 mL) at 0 ℃ was added trifluoroacetic acid (1.5 mL) under N₂ atmosphere. The mixture was stirred at 0 ℃ for 2 hours. Then, it was diluted with ethyl acetate (50 mL) , washed with water (50 mL) and brine (50 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol = 9/1) to afford Compound 330 (21 mg, 28.1%yield) as a yellow solid. ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.17-7.10 (m, 1H) , 7.07-7.00 (m, 1H) , 5.47 (d, J = 63.2 Hz, 1H) , 5.24 (d, J = 13.2 Hz, 1H) , 4.65-4.58 (m, 1H) , 4.50-4.42 (m, 2H) , 4.38-4.30 (m, 1H) , 3.99-3.90 (m, 1H) , 3.80-3.61 (m, 4H) , 3.11-3.00 (m, 1H) , 2.55-2.49 (m, 1H) , 2.48-2.43 (m, 1H) , 2.42-2.32 (m, 1H) , 2.27-2.19 (m, 2H) , 2.03-1.58 (m, 10H) ; ¹⁹F NMR (377 MHz, CD₃OD-d₄) δ -119.37, -136.44, -174.43. LC-MS: m/z = 621.1 [M+H] ⁺.

Compound 331: (5S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 331)

LC-MS: m/z = 606.2 [M+H] ⁺.

Compound 332: 2-amino-7-fluoro-4- ( (5S, 9S) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5, 8-trimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) benzo [b] thiophene-3-carbonitrile (Compound 332)

¹H NMR (400 MHz, CD₃OD-d₄) δ 7.11 (dd, J = 8.2, 5.0 Hz, 1H) , 7.00 (t, J = 8.6 Hz, 1H) , 5.30 (d, J = 52.8 Hz, 1H) , 4.53 (dd, J = 12.8, 4.4 Hz, 1H) , 4.36 (d, J = 12.8 Hz, 1H) , 4.31 (d, J = 10.4 Hz, 1H) , 4.19 (d, J = 10.4 Hz, 1H) , 4.03-3.98 (m, 1H) , 3.40 (s, 3H) , 3.30-3.12 (m, 3H) , 3.06-2.96 (m, 1H) , 2.40-2.10 (m, 5H) , 2.07-1.93 (m, 4H) , 1.42 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD-d₄) δ -119.82, -135.24, -173.60. LC-MS: m/z = 595.2 [M+H] ⁺.

Compound 333 and Compound 334: (S) -9- ( (R) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 333) and (S) -9- ( (S) -2-amino-3-cyano-7- fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 334)

Compound 333 and Compound 334 were obtained by Prep-HPLC separation of their atropisomeric mixture. Compound 333 was the first fraction. Compound 334 was the second fraction.

Compound 333: LC-MS: m/z = 580.2 [M+H] ⁺.

Compound 334: LC-MS: m/z = 580.2 [M+H] ⁺.

Compound 335: (S) -2-amino-7-fluoro-4- ( (S) -10-fluoro-2- ( ( (2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4, 5, 8-trimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) benzo [b] thiophene-3-carbonitrile (Compound 335)

LC-MS: m/z = 569.2 [M+H] ⁺.

Compound 336: (S) -9- ( (S) -2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5-methyl-4- ( (S) -1-methyl-2-oxopyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 336)

LC-MS: m/z = 689.2 [M+H] ⁺.

Compound 337: (S) -2-amino-7-fluoro-4- ( (S) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dimethyl-4- ( (S) -1-methyl-2-oxopyrrolidin-3-yl) -5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazolin-9-yl) benzo [b] thiophene-3-carbonitrile (Compound 337)

LC-MS: m/z = 678.2 [M+H] ⁺.

Compound 338 and Compound 339: (5S, 9R) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 338) and (5S, 9S) -9- (2-amino-3-cyano-7-fluorobenzo [b] thiophen-4-yl) -10-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4, 5-dimethyl-5, 6-dihydro-4H- [1, 4] oxazepino [5, 6, 7-de] quinazoline-8-carbonitrile (Compound 339)

Compound 338 and Compound 339 were the atropisomers of Compound 331. Both were obtained by following the procedures described in the synthesis of Compound 111 and Compound 128. Compound 338 was synthesized from the first fraction of Suzuki coupling products after column chromatography. Compound 339 was synthesized from the second fraction of Suzuki coupling products after column chromatography.

Compound 338: ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.32 (dd, J = 8.4, 5.2 Hz, 1H) , 7.06 (t, J = 8.6 Hz, 1H) , 5.30 (d, J = 54.4 Hz, 1H) , 4.72 (dd, J = 12.8, 4.4 Hz, 1H) , 4.50 (d, J = 13.2 Hz, 1H) , 4.43 (d, J = 11.2 Hz, 1H) , 4.35 (d, J = 11.2 Hz, 1H) , 4.20-4.12 (m, 1H) , 3.56-3.35 (m, 6H) , 3.19-3.08 (m, 1H) , 2.51-2.14 (m, 3H) , 2.46-2.32 (m, 3H) , 1.41 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD-d₄) δ -117.91, -134.04, -173.82; LC-MS: m/z = 606.2 [M+H] ⁺.

Compound 339: ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.28 (dd, J = 8.2, 5.0 Hz, 1H) , 7.05 (t, J = 8.8 Hz, 1H) , 5.30 (d, J = 53.2 Hz, 1H) , 4.71 (dd, J = 13.2, 4.4 Hz, 1H) , 4.50 (d, J = 12.4 Hz, 1H) , 4.47 (d, J = 11.2 Hz, 1H) , 4.34 (d, J = 11.2 Hz, 1H) , 4.20-4.12 (m, 1H) , 3.66-3.35 (m, 6H) , 3.19-3.08 (m, 1H) , 2.50-1.87 (m, 6H) , 1.41 (d, J = 6.8 Hz, 3H) ; ¹⁹F NMR (377 MHz, CD₃OD-d₄) δ -117.82, -133.32, -173.88; LC-MS: m/z = 606.2 [M+H] ⁺.

The following compounds or a pharmaceutically acceptable salt thereof can be synthesized using similar chemistry and procedure as described above:

The following compounds or a pharmaceutically acceptable salt thereof can also be synthesized using similar chemistry and procedure as described above:

The following compounds or a pharmaceutically acceptable salt thereof can also be synthesized using similar chemistry and procedure as described above.

Example 3: In vitro TR-FRET GDP-KRAS binding assay.

This example illustrates the exemplary compounds of the present invention bind to GDP-form KRAS G12D and capable of displacing a labeled tracer ligand occupying the KRAS G12D^GDP binding site.

The ability of a compound to bind to KRAS G12D was measured using a TR-FRET assay. Biotinylated GDP-loaded recombinant human KRAS G12D (His-Avi-KRAS 1-185, produced by ChemPartner) is incubated with a customed Cy5 labelled tracer, europium labelled streptavidin and a series of compound (1%DMSO final) in buffer (50 mM HEPES, 5 mM MgCl₂, 0.05‰Tween20, and 1mM DTT) . The Em665/620 fluorescence signal is read out after an hour incubation using the PE EnVision instrument. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .

Example 4: GTP-KRAS^G12D/RAF1 binding assay.

This example illustrates the exemplary compounds of the present application’s inhibitory effect of the interactions between GTP bound KRAS^G12D and RAF1 protein.

The interaction between Tag1-RAF1 and Tag2-KRAS G12D (GTP bound KRAS^G12D) is detected by using anti-Tag1-Eu and anti-Tag2-XL665, when the antibodies are brought into close proximity due to RAF1 and GTP-KRAS^G12D binding, fluorescent resonance energy transfer (FRET) occurs. This specific FRET signal is directly proportional to the extent of GTP-KRAS^G12D/RAF1 interaction. GTP-KRAS^G12D/RAF1 inhibition by small molecules will lead to a reduction in signal because of compound blocking the interaction.

The inhibitory efficacy was measured using a TR-FRET assay. The RAF1 protein and GTP-KRAS^G12D and a series of compound (1%DMSO final) was incubated for 20 mins. The Em665/620 fluorescence signal was read out after 2 hours after anti-EU and anti-XL665 addition using the PE EnVision instrument. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data was normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max was the Em665/620 value containing enzyme-positive wells, Min was the Em665/620 value of the enzyme-free negative wells, Sample was the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC₅₀ was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .

Example 5: Cell Based p-ERK Assay.

This Example illustrates that exemplary compounds disclosed herein inhibit the intracellular phosphorylation of ERK downstream of KRAS G12D.

This experiment directly tested the inhibition of compounds on KRAS G12D at the cellular level by detesting the endogenous phosphorylation level of ERK1/2. After activation of the RAS-RAF-MEK pathway, ERK1/2 were phosphorylated, after cells lysis, 2 different specific antibodies (one labeled with Eu3+-Cryptate (donor) and the other with D2 (acceptor) to recognize phosphorylated ERK1/2 (Thr202/Tyr204) site and the ERK1/2 protein itself, respectively. When phosphorylation occurs, the two dyes are approached by a light source (laser or flashlight) to excite fluorescence resonance energy transfer (FRET) from the donor to the acceptor, which emits a fluorescence wavelength (665 nm) at a specific location. The specific signal is proportional to the level of phospho-ERK1/2 (Thr202/Tyr204) .

Procedures: PK-59 cells expressing KRAS G12D mutation (ECACC, Cat. No. 95090715) were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37℃ for 3 days. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 2 hours or 24 hours, remove the supernatant, add 1*lysate to lyse the cells, transfer the lysate to a new assay plate, add the mixed antibody solution (Cisbio, Cat. No. 64AERPEH) was incubated overnight at room temperature. The microplate was placed on the EnVision instrument to read the Em665/620 fluorescence signal. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC₅₀ was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .

Example 6: Cell based 3D CTG assay

This Example illustrates that exemplary compounds disclosed herein inhibit the cellar proliferation.

The 3D CTG assay is a homogeneous method to determine the number of viable cells in 3D cell culture based on quantitation of the ATP present. The CTG luminescence value is proportional to ATP, which is proportional to the number of living cells.

Procedures: PK-59 cells expressing KRAS G12D mutation (COBIOER, Cat. No. CBP61184) were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37 ℃ 5%CO₂ overnight. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 168 hours, add the CTG detection buffer (Promega, Cat. No. G9681) mixing well. The microplate was placed on the EnVision instrument to read the luminescence signal. According to the formula Inh %=100- (Sample-Min) / (Max-Min) *100%, the data is normalized to obtain the activity inhibition rate Inh %of each concentration point (wherein Max is the value containing DMSO wells, Min is the value of the cell-free negative wells, Sample is the value of the compound-treated sample wells) , enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, IC50 was calculated with Graphpad Prism based on the four-parameter fitting formula Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) .

3D CTG assays can be carried out with cells with different KRAS mutations, such as GP2D (G12D) , NCI-H358 (G12C) , A549 (G12S) , NCI-H727 (G12V) and MKN1 (WT amplified) .

The IC₅₀ data were listed in Table 1 below: “++++” represents IC₅₀ < 300 nM, “+++” represents 300 nM ≤ IC₅₀ < 1 μM, “++” represents 1 μM ≤ IC₅₀ < 5 μM, “+” represents IC₅₀ ≥ 5 μM.

Table 1: IC₅₀ for exemplified compounds

Table 2 below shows 7-day CTG data against different KRAS mutants. The IC₅₀ data were listed in the table below: “++++” represents IC₅₀ < 300 nM, “+++” represents 300 nM ≤ IC₅₀ < 1 μM, “++” represents 1 μM ≤ IC₅₀ < 5 μM, “+” represents IC₅₀ ≥ 5 μM.

Table 2: CTG data against KRAS mutants for exemplified compounds

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

Q¹, Q², and Q³ are independently selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN;

R¹ is selected from L-5-12 membered heterocyclyl and L-C_3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyl and C_3-8 cycloalkyl is optionally substituted with one or more W;

L is selected from -CH₂-, -CH (CH₃) -, CH₂-CH₂-, and a bond;

R² and R⁴ are independently selected from H, C_1-6 alkyl optionally substituted with one or more W, C_3-6 cycloalkyl optionally substituted with one or more W, and 4-8 membered heterocyclyl optionally substituted with one or more W; or R² and R⁴, together with the atoms to which they are attached, form a 4-12 membered heterocyclyl or a 9-12 membered fused bi-cyclic heteroaryl, each of which is optionally substituted with one or more W;

R³ is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;

X is selected from O, S and NR⁵;

Y is selected from a bond and -O-;

Z is selected from (CR⁶R⁷) _n;

n is 1 or 2;

R⁵, R⁶, and R⁷ are independently selected from H and C_1-6 alkyl; and

W is independently selected from OH, CN, halo, C_2-4 alkenyl, C_2-4 alkynyl, -NR⁸R⁹, =NR⁸, oxo, -OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, NR¹⁰C (O) OR¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, phenyl, C_3-8 cycloalkyl, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, S (O) ₂-C_3-8 cycloalkyl, C_1-6 alkylidene, and C_1-6 alkyl, wherein each of the 4-6 membered heterocyclyl, 5 or 6 membered heteroaryl, phenyl, C_3-8 cycloalkyl, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, S (O) ₂-C_3-8 cycloalkyl, C_1-6 alkylidene, and C_1-6 alkyl is optionally substituted with one or more groups selected from F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, -OC (O) NR⁸R⁹, and oxo;

R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl; and

R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl,

provided that when (1) Q¹ is N, Q² and Q³ are independently selected from CH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, and C-CN, and (2) R² and R⁴, together with the atoms to which they are attached, form a 5-9 membered heterocyclyl optionally substituted with one or more W, then the 5-9 membered heterocyclyl contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R⁴ is attached.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein Q¹ is N, one of Q² and Q³ is N, the other is not.
The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein Q¹ is N, Q² is N, and Q³ is not N.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-3, wherein Q¹ is N, Q² is N, and Q³ is C-H or C-F.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein Q¹ is N, Q² is selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is not N.
The compound or a pharmaceutically acceptable salt thereof of claim 5, wherein, Q¹ is N, Q² is selected from N, CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is C-H or C-F.
The compound or a pharmaceutically acceptable salt thereof of claim 5 or 6, wherein Q¹ is N, Q² is selected from CH, C-CF₃, C-OH, C-Cl, C-F, C-CH₃, C-CH (CH₃) ₂, C-cyclopropyl, C-OCH₃, C-SCF₃, C-OCF₃, and C-CN, and Q³ is C-H or C-F.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-7, wherein R³ is phenyl or naphthyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-7, wherein R³ is pyridinyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-7, wherein R³ is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 10, wherein R³ is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more groups selected from F, Cl, methyl, ethyl, ethenyl, ethynyl, CF₃, cyclopropyl, iso-propyl, -NH₂, -CN, and OH.
The compound or a pharmaceutically acceptable salt thereof of claim 11, wherein R³ is selected from
The compound or a pharmaceutically acceptable salt thereof of claim 12, wherein R³ is selected from
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-13, wherein Y is O.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14, wherein X is O.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-15, wherein Z is CH₂, CH (CH₃) or CH₂CH₂.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-16, wherein R¹ is selected from -L-fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen, and -L-4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen, each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen and 4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen is optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 17, wherein each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen and 4-7 membered monocyclic heterocyclyl comprising at least one heteroatom selected from nitrogen and oxygen is optionally substituted with one or more group selected from F, C_1-6 alkoxy, OH, C_1-3 alkylidene optionally substituted with 1-5 F, and C_1-3 alkyl optionally substituted with -OC (O) NR⁸R⁹ or –NR⁸R⁹, with R⁸ and R⁹ independently being selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 18, wherein R⁸ and R⁹ are methyl or R⁸ and R⁹, together with the nitrogen to which they are attached, form a morpholine.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-16, wherein R¹ is L-C_3-8 cycloalkyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 20, wherein R¹ is L-C_3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -OC (O) NR⁸R⁹ or –NR⁸R⁹, with R⁸ and R⁹ independently being selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of any of claim 21, wherein R¹ is L-C_3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -O (CO) N (CH₃) ₂, -O (CO) -morpholine, -N (CH₃) ₂, or morpholine.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-22, wherein R¹ is
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-23, wherein L is a bond, CH₂ or CH (CH₃) .
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² is selected from H, 4-8 membered heterocyclyl optionally substituted with one or more substituent selected from methyl and ethyl, C_3-6 cycloalkyl optionally substituted with one or more substituent selected from OH, -NR⁸R⁹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, and oxo, and C_1-6 alkyl optionally substituted with one or more substituent selected from OH, NR⁸R⁹, -NR¹⁰C (O) R¹¹, -S (O) ₂-C_1-6 alkyl, and 4 or 5 membered heterocyclyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 25, wherein R² is selected from H, methyl, ethyl, - (CH₂) ₂OH, - (CH₂) ₃OH, - (CH₂) ₂NH₂, - (CH₂) ₂NHC (O) CH₃,
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² is H or a C_1-6 alkyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 27, wherein R² is a C_1-6 alkyl optionally substituted with one or more substituent selected from halo, CN, OH, oxo, =NR⁸, -NR⁸R⁹, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, , -NR¹⁰C (O) OR¹¹, C_1-6 alkoxy, -S (O) ₂-C_1-6 alkyl, -S (O) ₂-C_3-8 cycloalkyl, C_3-8 cycloalkyl, 5 or 6 membered heteroaryl, and 4 or 5 membered heterocyclyl, wherein the C_1-6 alkoxy, C_3-8 cycloalkyl, S (O) ₂-C_3-8 cycloalkyl , 5 or 6 membered heteroaryl and 4 or 5 membered heterocyclyl are optionally and independently substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 27 or 28, wherein R² selected from H, methyl, ethyl, isopropyl, -C (O) CH₃, - (CH₂) ₂OH, - (CH₂) ₂OCH₃, -CH₂CN, -CH₂CH₂SO₂CH₃, -CH₂C (O) N (CH₃) ₂, -CH₂CH₂C (O) N (CH₃) _2, -CH₂CH₂OC (O) N (CH₃) _2, -CH₂CH₂N (CH₃) C (O) OCH_3, -CH₂CH₂NHC (O) OCH_3, -CH₂C (O) N (CH₃) (CH₂CH₃) , -CH₂CH₂N (CH₃) _2, -CH (CH₃) CH₂NHCH₃, -CH₂CH₂OC (O) CH₃, - (CH₂) ₃OH, - (CH₂) ₂NH_2, - (CH₂) ₂F, -CH₂CHF₂, -CH₂CF₃, - (CH₂) ₂NHC (O) CH₃, -CH₂C (O) NH₂, - (CH₂) ₂C (O) NH₂, -C (NH) NH₂, -C (NH) CH₃, -CH (CH₃) CH₂NHCH₃, -CH (CH₂CH₃) CH₂NHCH₃, -CH (CH₂OH) CH₂NHCH₃, -CH (CH₂OH) CH₂OH,
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² is a 4-8 membered heterocyclyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 30, wherein R² is a 4-8 membered heterocyclyl optionally substituted with one or more substituent selected from oxo, methyl and ethyl, each of the methyl and ethyl is optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1- ₆ alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 31, wherein R² is selected from
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² is a C_3-6 cycloalkyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 33, wherein R² is a C_3-6 cycloalkyl optionally substituted with one or more substituent selected from F, Cl, OH, CN, -NR⁸R⁹, and C_1-6 alkyl optionally substituted with one or more group selected from OH, F, Cl, C_1-6 alkoxy, -NR⁸R⁹, -OC (O) NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 34, wherein R² is selected from cyclopropanyl, cyclobutanyl,
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-35, wherein R⁴ is selected from H, C_1-6 alkyl optionally substituted with one or more group selected from OH and NH₂, and 4-6 membered heterocyclyl optionally substituted with one or more group selected from methyl and ethyl.
The compound or a pharmaceutically acceptable salt thereof of claim 36, wherein R⁴ is selected from H, methyl, ethyl, -CH (CH₃) ₂, -CH (OH) CH₃, -C (OH) (CH₃) _2, -CH₂NH₂, -CHCH₃NH₂, -C (CH₃) ₂NH₂,
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-35, wherein R⁴ is H or a C_1-6 alkyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 38, wherein R⁴ is a C_1-6 alkyl optionally substituted with one or more group selected from halo, oxo, OH and -NR⁸R⁹, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 38 or 39, wherein R⁴ is selected from H, methyl, ethyl, -CH (CH₃) ₂, -CH₂OH, -CH₂CH₂OH, -CH (OH) CH₃, -C (OH) (CH₃) _2, -CH₂NH₂, -CHCH₃NH₂, -C (CH₃) ₂NH₂, -C (O) NH₂, and CF₃.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² and R⁴, together with the atoms to which they are attached, form a 4-9 membered heterocyclyl optionally substituted with one or more W, in which the 4-9 membered heterocyclyl contains only one heteroatom, wherein the only one heteroatom is the nitrogen to which R⁴ is attached.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² and R⁴, together with the atoms to which they are attached, form a 4-7 membered monocyclic heterocyclyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² and R⁴, together with the atoms to which they are attached, form a 8-12 membered fused, bridged, or spiro bicyclic heterocyclyl optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of any of claims 41-43, wherein R² and R⁴, together with the atoms to which they are attached, form a heterocyclyl selected from each of which is optionally substituted with one or more group selected from OH, F, Cl, CN, NH₂, oxo, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkoxy, -NR⁸R⁹, and oxo wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 44, wherein R² and R⁴, together with the atoms to which they are attached, form a heterocyclyl selected from
The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24, wherein R² and R⁴, together with the atoms to which they are attached, form a 9-12 membered fused bi-cyclic heteroaryl, which is optionally substituted with one or more W.
The compound or a pharmaceutically acceptable salt thereof of claim 46, wherein the 9-12 membered fused bi-cyclic heteroaryl has one ring as being aromatic and the other non-aromatic.
The compound or a pharmaceutically acceptable salt thereof of claim 47, wherein the 9-12 membered fused bi-cyclic heteroaryl has the ring containing N attached to R⁴ as being non-aromatic and the other aromatic.
The compound or a pharmaceutically acceptable salt thereof of claim 48, wherein R² and R⁴, together with the atoms to which they are attached, formwhich is optionally substituted with one or more group selected from OH, F, Cl, CN, NH₂, oxo, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, and C_1-6 alkyl optionally substituted with one or more groups selected from OH, F, Cl, C_1-6 alkyl, C_1-6 alkoxy, -NR⁸R⁹, and oxo, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ and R¹¹ are independently selected from H and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 49, wherein R² and R⁴, together with the atoms to which they are attached, form
The compound or a pharmaceutically acceptable salt thereof of claim 45, wherein R² and R⁴, together with the atoms to which they are attached, formwhich is optionally substituted with two groups selected from C_1-6 alkyl optionally substituted with 1-5 F or Cl, OH, F, Cl, CN, OC (O) NR⁸R⁹, -C (O) NR⁸R⁹, -NR¹⁰C (O) R¹¹, -NR¹⁰C (O) NR⁸R⁹, -S (O) ₂NR⁸NR⁹, -NR¹⁰S (O) ₂R¹¹, wherein R⁸ and R⁹ are independently selected from H and C_1-6 alkyl, or R⁸ and R⁹, together with the nitrogen to which they are attached, independently form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, and C_1-6 alkyl, and R¹⁰ are independently selected from H and C_1-6 alkyl.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from Compound 1-339 or a pharmaceutically acceptable salt thereof.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from

or a pharmaceutically acceptable salt thereof.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from

or a pharmaceutically acceptable salt thereof.
The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from: or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of any of claims 1-55 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
A method of inhibiting KRAS G12D activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 56.
A method of inhibiting KRAS activity comprising contacting KRAS with the compound or a pharmaceutically acceptable salt thereof of any of claims 1-55 or the composition of claim 56 to inhibit the activity of the KRAS.
The method of claim 57 or 58, wherein the KRAS is wild type or KRAS mutant selected from KRAS G12C, G12D, G12V G12S, G12R, G12A, G13D, G13C, G13A, and G13V.
The method of claim 57 or 58, wherein the KRAS is KRAS G12D.
A method of treating a disease or disorder associated with KRAS mutation in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a composition of claim 56.
The method of claim 61, wherein the disease or disorder is cancer.
A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition of claim 56, wherein the cancer comprises cancer cells having KRAS mutation.
The method of any of claims 61-63, wherein the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G12R, KRAS G12A, KRAS G13D, KRAS G13C, KRAS G13A, and KRAS G13V.
The method of claim 64, wherein the KRAS mutation is KRAS G12D.
The method of any of claims 62-65, wherein the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, lung cancer, small intestine cancer, sarcoma, leukemia, melanoma, lymphoma, cholangiocarcinoma, appendiceal cancer, multiple myeloma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, eosophageal cancer, gastroesophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, glioblastoma, and renal cancer.
The method of any of claims 57-66, further comprising administering to the subject in need thereof an additional known anti-cancer agent.