Substituted pyrido [4,3-d]pyrimidines as KRAS modulators

This application is a continuation of U.S. application Ser. No. 19/015,403, filed Jan. 9, 2025, which is a continuation of PCT/US2024/047282, filed Sep. 18, 2024, which claims the benefit of U.S. Patent Application No. 63/583,975, filed on Sep. 20, 2023; U.S. Patent Application No. 63/584,247, filed on Sep. 21, 2023; U.S. Patent Application No. 63/611,382, filed on Dec. 18, 2023; U.S. Patent Application No. 63/636,328, filed on Apr. 19, 2024; and U.S. Patent Application No. 63/671,340, filed on Jul. 15, 2024, all of which are hereby incorporated by reference in their entirety.

KRAS (Kirsten rat sarcoma viral oncogene homologue) is an oncoprotein that is a part of the RAS/MAPK pathway, and relays signals from outside of the cell to the cell's nucleus. KRAS protein is a GTPase and involved in cellular signaling such as regulation of cell proliferation. KRAS can activate cellular signaling pathways including, but not limited to, the mitogen-activated protein kinase (MAPK) pathway. KRAS was previously considered un-targetable, but recent studies have shown that targeting codon 12 can lead to therapeutic effects. There remains an unmet need to identify and develop novel compounds for KRAS inhibition.

Provided herein are inhibitors of KRAS, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of cancer and neoplastic disease.

One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , C—Cl, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C2-C6 alkenyl), or C-(optionally substituted C3-C6 carbocyclyl); X 3 is N, C—H, C—F, C—Cl, C—CN, or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H, —OH, —CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, or C 1 -C6 cycloalkylalkyl.

One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , or C—Cl; X 3 is N, C—H, C—F, C—Cl, C—CN, or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo [5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C 1 -C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

One embodiment provides a compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , or C—Cl; X 3 is N, C—H, C—F, C—Cl or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R′ is L-G, wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (c) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-S-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 1 is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

One embodiment provides a compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, or C—Cl; X 3 is N, C—H, C—F, C—Cl or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo [5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H or optionally substituted C1-C4 alkoxy.

One embodiment provides a compound having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, or C—Cl; X 3 is N, C—H, C—F, or C—Cl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl selected from:

(a) optionally substituted azabicyclo[4.1.0]heptane; (b) optionally substituted oxazabicyclo[4.1.0]heptane; (c) optionally substituted azabicyclo[5.1.0]octane; (d) optionally substituted oxazabicyclo[5.1.0]octane; (c) optionally substituted azabicyclo[6.1.0]nonane; (f) optionally substituted oxazabicyclo[6.1.0]nonane; or (g) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; and

R 4 is selected from H or optionally substituted C 1 -C4 alkoxy.

One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ia), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ib), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ic), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (Id), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ia), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ib), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ic), or pharmaceutically acceptable salt or solvate thereof. One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Id), or pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ia), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ib), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ic), wherein the KRAS protein is contacted in an in vitro setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Id), wherein the KRAS protein is contacted in an in vitro setting.

One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ia), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ib), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Ic), wherein the KRAS protein is contacted in an in vivo setting. One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (Id), wherein the KRAS protein is contacted in an in vivo setting.

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 provides additional structures of compounds of Formula (I);

FIG. 2 provides additional structures of compounds of Formula (I);

FIG. 3 provides additional structures of compounds of Formula (I);

FIG. 4 provides additional structures of compounds of Formula (I);

FIG. 5 provides additional structures of compounds of Formula (I);

FIG. 6 provides additional structures of compounds of Formula (I);

FIG. 7 provides additional structures of compounds of Formula (I);

FIG. 8 provides additional structures of compounds of Formula (I);

FIG. 9 provides additional structures of compounds of Formula (I);

FIG. 10 provides additional structures of compounds of Formula (I);

FIG. 11 provides additional structures of compounds of Formula (I);

FIG. 12 provides additional structures of compounds of Formula (I);

FIG. 13 provides additional structures of compounds of Formula (I);

FIG. 14 provides additional structures of compounds of Formula (I);

FIG. 15 provides additional structures of compounds of Formula (I);

FIG. 16 provides additional structures of compounds of Formula (I);

FIG. 17 provides additional structures of compounds of Formula (I);

FIG. 18 provides additional structures of compounds of Formula (I);

FIG. 19 provides additional structures of compounds of Formula (I);

FIG. 20 provides additional structures of compounds of Formula (I);

FIG. 21 provides additional structures of compounds of Formula (I);

FIG. 22 provides additional structures of compounds of Formula (I);

FIG. 23 provides additional structures of compounds of Formula (I);

FIG. 24 provides additional structures of compounds of Formula (I);

FIG. 25 provides additional structures of compounds of Formula (I); and

FIG. 26 provides additional structures of compounds of Formula (I).

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH 2 radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO 2 radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH 2 radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR 3 , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R 3 )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O)OR a (where tis 1 or 2), —S(O) t R a (where t is 1 or 2) and —S(O)N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, oxo or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a —CF 3 group.

“Alkoxy” refers to a radical bonded through an oxygen atom of the formula-O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R 3 ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O)R a (where t is 1 or 2), —S(O) t OR a (where tis 1 or 2), —S(O)R a (where t is 1 or 2) and —S(O)IN(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O)OR a (where t is 1 or 2), —S(O)R a (where t is 1 or 2) and —S(O) t N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O)OR a (where t is 1 or 2), —S(O)R a (where t is 1 or 2) and —S(O)N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R a )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O)OR a (where t is 1 or 2), —S(O) t R a (where t is 1 or 2) and —S(O)N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 C 8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR a , —SR a , —OC(O)—R a , —N(R a ) 2 , —C(O)R a , —C(O)OR a , —C(O)N(R a ) 2 , —N(R 3 )C(O)OR a , —OC(O)—N(R a ) 2 , —N(R a )C(O)R a , —N(R a )S(O) t R a (where t is 1 or 2), —S(O)OR a (where t is 1 or 2), —S(O): R a (where t is 1 or 2) and —S(O) t N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a ) 2 , —R b —O—R c —C(O)N(R a ) 2 , —R b —N(R a )C(O)OR a , —R b —N(R a )C(O)R a , —R b —N(R a )S(O)R a (where t is 1 or 2), —R b —S(O)R a (where t is 1 or 2), —R b —S(O)OR a (where t is 1 or 2) and —R b —S(O) t N(R a ) 2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each RD is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Re is a straight or branched alkylene or alkenylene chain, and where each of the R a , R b , or Re substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula-Re-aryl where Re is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkenyl” refers to a radical of the formula-Rd-aryl where Re is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula-Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R c -aryl where R o is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a ) 2 , —R b —O—R c —C(O)N(R a ) 2 , —R b —N(R 3 )C(O)OR a , —R b —N(R a )C(O)R a , —R b —N(R a )S(O) t R a (where t is 1 or 2), —R b —S(O) t R a (where t is 1 or 2), —R b —S(O) t OR a (where t is 1 or 2) and —R b —S(O)N(R a ) 2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each RD is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Re is a straight or branched alkylene or alkenylene chain, and where each of the R a , R b , or Re substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula-Re-carbocyclyl where Re is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula-R°-carbocyclyl where Re is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R e -carbocyclyl where Re is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritbianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a ) 2 , —R b —O—R c —C(O)N(R a ) 2 , —R b —N(R a )C(O)OR a , —R b —N(R a )C(O)R a , —R b —N(R a )S(O) t R a (where t is 1 or 2), —R b —S(O): R a (where t is 1 or 2), —R b —S(O)OR a (where t is 1 or 2) and —R b —S(O) t N(R a ) 2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where each of the R a , R b , or R c substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula-Re-heterocyclyl where Re is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R c -heterocyclyl where Re is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta [1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo [3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta [d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta [d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta [d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a, 7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1//-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a ) 2 , —R b —N(R a ) 2 , —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a ) 2 , —R b —O—R c —C(O)N(R a ) 2 , —R b —N(R a )C(O)OR a , —R b —N(R a )C(O)R a , —R b —N(R a )S(O) t R a (where t is 1 or 2), —R b —S(O)R a (where t is 1 or 2), —R b —S(O)OR a (where t is 1 or 2) and —R b —S(O) t N(R a ) 2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R′ is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Re is a straight or branched alkylene or alkenylene chain, and where each of the R a , R b , or Re substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula-Re-heteroaryl, where Re is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R e -heteroaryl, where Re is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in, for example, U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can, in some instances, improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C.). Isotopic substitution with 2 H, 1 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 33 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated. In some embodiments, isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

In certain embodiments, the compounds disclosed herein have some or all of the H atoms replaced with 2 H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6 (10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2), 9-32.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d 3 (CD 3 I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD 3 I is illustrated, by way of example only, in the reaction schemes below.

Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD 4 ), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD 4 is illustrated, by way of example only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the KRAS inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and, aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

“Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

KRAS Protein and Function

RAS mutation is frequent in cancer, with approximately 19% of patients with cancer harboring RAS mutations (I.A. Prior et al., Cancer Res 2020; 80: 2969-74). Ras proteins are important for activating signaling networks for controlling cell differentiation, proliferation, and survival, encoded by three genes HRAS, KRAS, and NRAS. The three genes share significant sequence homology and largely overlapping functions. Activation of RAS is facilitated by guanine nucleotide exchange factors (GEF), and activation causes conformational changes.

The KRAS gene encodes two highly related protein isoforms, KRAS-4A and KRAS-4B, which comprise of 189 and 188 amino acids. KRAS generally refers to KRAS-4B, because of the high level of mRNA encoding KRAS-4B in cells. KRAS has two major domains, the catalytic G domain and a hypervariable region (HVR).

KRAS G domain is the basis of biological function of GTPase proteins. The G domain comprises 6 beta-strands of the protein core, surrounded by five alpha-helices, and comprises residues 1-166. The G domain also consists of other regions: switch I, switch II, and the P loop. KRAS-GTP binding alters the conformation of the switches I and II in the G domain. When activated, KRAS binds to its downstream molecules as monomers or dimers to mediate series of signaling cascades. KRAS also has a flexible C-terminal, the hypervariable region (HVR), which is important for localizing KRAS to the membrane.

The RAS family comprises three isoforms, but about 85% of RAS-related cancers are caused by mutations in the KRAS isoform. The mutations in KRAS isoform occurs most frequently in solid tumors such as colorectal carcinoma, lung adenocarcinoma, and pancreatic ductal carcinoma. Further, nearly 80% of KRAS mutant tumors are located within codon 12, with the most common mutations being p.G12D, p.G12V, and p.G12C.

KRAS protein functions as a molecular switch in growth factor signaling pathways by regulating proliferation by alternating between a GDP-bound inactive form and a GTP-bound active form. The GTP-bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form. Many growth factors such as but not limited to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGF) can activate KRAS proteins through intermediary molecules after activating receptor tyrosine kinases. Upstream regulation can promote binding of GTP and KRAS, converting KRAS from an inactive to an active state. Molecules upstream of KRAS mainly mediate the activation or inactivation of KRAS by regulating guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386). Another molecule in KRAS activation is Src homology phosphatase 2 (SHP2) which plays a role in KRAS activation. SHP2 is a common signaling regulatory that mediates receptor tyrosine kinases signals to KRAS-ERK signaling, and dephosphorylation substrates of SHP2 have been shown to promote KRAS activation.

The RAF-MEK-ERK pathway is a downstream target of KRAS signaling. Another pathway KRAS is involved in is the PI3K-AKT-mTOR pathway (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).

KRAS was previously considered to be an undruggable protein, but recently there have been advances in targeting codon 12, and specifically in G12C inhibitors. Many efforts have been focused on indirectly targeting KRAS, so there remains an unmet need of targeting KRAS, which the compounds provided herein fulfill. With the discovery of a new allosteric site of KRAS, G12C, several covalently binding inhibitors of KRAS have emerged and are under clinical investigation. However, KRAS inhibition is a complex issue with a lack of understanding of the underlying principles, and there still remains an unmet need for new inhibitors which target other KRAS mutations such as, but not limited to G12D and G12V.

KRAS mutations are frequently found in colorectal cancer, pancreatic cancer, and non-small cell lung cancer (M.H. Hofmann et al., Cancer Discov 2022; 12: 924-37). The KRAS allelic distribution varies between the tumor types, with G12C mutations in 13.6% of lung adenocarcinomas, whereas the G12D and G12V mutations are most common in colorectal and pancreatic cancer. The G12D, G12V, and G12C mutations are the three most frequent allele mutations. KRAS mutations, especially at codon 12, is strongly associated with cellular KRAS dependency, indicating that KRAS acts as an oncogenic driver.

Prior Art Small Molecules Inhibitors

There have been advances for KRAS G12C inhibitors, such as sotorasib (AMG510) and adagrasib (MRTX849). Sotorasib is the first to be approved by the US Food and Drug Administration (FDA). Both inhibitors rely on the interaction with the nucleophilic cysteine 12 in the GDP state and occupy the switch II pocket.

NMR studies have shown that MRTX849 can engage mutant KRAS proteins lacking the nucleophilic mutant cysteine 12, but that the engagement is selected for inactive GDP-loaded state of KRAS protein. AMG510 exhibits weak binding and relies on irreversible reaction of the mutant cysteine 12 for KRAS (G12C) inhibitory activity (J.D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

AMG510 and additional KRAS inhibitors are described in Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors (B.A Lanman et al., J. Med. Chem. 2020, 63, 52-65).

Novel Compounds Inhibiting KRAS

In one aspect, provided herein are KRAS inhibitory compounds.

One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , C—Cl, C-(optionally substituted C1-C6 alkyl), C-(optionally substituted C2-C6 alkenyl), or C-(optionally substituted C3-C6 carbocyclyl); X 3 is N, C—H, C—F, C—Cl, C—CN, or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane, (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H, —OH, —CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, or C1-C6 cycloalkylalkyl.

One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , or C—Cl; X 3 is N, C—H, C—F, C—Cl, C—CN, or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C 1 -C 4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkylalkyl, cyano, or halogen.

One embodiment provides a compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, C—CH 3 , or C—Cl; X 3 is N, C—H, C—F, C—Cl or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C 1 -C 4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo [5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (i) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 cycloalkyl, C1-C6 cycloalkylalkyl, cyano, or halogen.

One embodiment provides a compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate, thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, or C—Cl; X 3 is N, C—H, C—F, C—Cl or C—CF 3 ; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl substituent selected from the group consisting of:

(a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; (s) optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and (t) optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl; and

R 4 is selected from H or optionally substituted C1-C4 alkoxy.

One embodiment provides a compound having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

X 1 is N or C—CN; X 2 is N, C—H, C—F, or C—Cl; X 3 is N, C—H, C—F, or C—Cl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; R 1 is L-G; wherein L is optionally substituted C1-C4 alkylene,

and G is an optionally substituted 5- to 10-membered heterocyclyl;

—N(R 2 )R 3 form an optionally substituted heterocyclyl selected from:

(a) optionally substituted azabicyclo[4.1.0]heptane; (b) optionally substituted oxazabicyclo[4.1.0]heptane; (c) optionally substituted azabicyclo[5.1.0]octane; (d) optionally substituted oxazabicyclo[5.1.0]octane; (e) optionally substituted azabicyclo[6.1.0]nonane; (f) optionally substituted oxazabicyclo[6.1.0]nonane; or (g) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; and

R 4 is selected from H or optionally substituted C1-C4 alkoxy.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is N.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is C—CN.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is N.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C—CH 3.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C-(optionally substituted C1-C6 alkyl).

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C-(optionally substituted C2-C6 alkenyl).

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C-(optionally substituted C3-C6 carbocyclyl).

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X 2 is C—H, C—F, or C—Cl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X 3 is N.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C—F.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, X 3 is C—CF 3.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted aryl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted aryl is an optionally substituted phenyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an —OH group at the meta-position.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an —NH 2 group at the meta-position.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is a 2,3,5-trisubstituted phenyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the 2,3,5-trisubstituted phenyl is substituted with a 3-hydroxy group.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 1-naphthyl is further substituted at the 8-position.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein År is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a):

wherein:

R 12 is hydrogen, deuterium, or F; R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a monocyclic optionally substituted heteroaryl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 2-pyridinyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl is

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 2-pyridinyl is

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the monocyclic optionally substituted heteroaryl is an optionally substituted 4-pyridinyl. In some embodiments, the optionally substituted 4-pyridinyl is:

In some embodiments, the optionally substituted 4-pyridinyl is:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.

In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

In some embodiments, the bicyclic optionally substituted heteroaryl is selected from:

In some embodiments, the bicyclic optionally substituted heteroaryl is:

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b1):

wherein:

R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b2):

wherein:

R 12 is hydrogen, deuterium, or F; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b3):

wherein:

R 12 is hydrogen, deuterium, or F; R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b4):

wherein:

R 12 is hydrogen, deuterium, or F; R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b5):

wherein:

R 12 is hydrogen, deuterium, or F; R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is described by Formula (b6):

wherein:

R 12 is hydrogen, deuterium, or F; R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 14 is hydrogen, deuterium, F, C 1 , or Br; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

In some embodiments, the bicyclic optionally substituted heteroaryl is is described by Formula (b8):

wherein:

R 13 is hydrogen, deuterium, —OH, —NH 2 , Cl, —CN, —OCONHMe, —NHCO 2 Me; R 15 is hydrogen, deuterium, F, C 1 , or Br; R 16 is hydrogen, deuterium, F, Cl, Br, —CN, or —CH 3 ; R 17 is hydrogen, deuterium, F, C 1 , or —CN; and R 18 is hydrogen, deuterium, —CH 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CH═CH 2 , —C═CH, —OCHF 2 , —OCF 3 , —CH 2 F, —CHF 2 , —CF 3 , —CN, Cl, F, —OCH 3 , —OCD 3 , —OCH 2 F, or —OCD 2 F.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1-C4 alkylene.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C 1 alkylene.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (c):

wherein,

each R 20 -R 30 is independently selected from hydrogen or deuterium.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (d):

wherein,

R 31 is selected from hydrogen, F, Cl, —CN, —OH, or optionally substituted C1-C4 alkyl;

R 32 is hydrogen, deuterium or optionally substituted C1-C4 alkyl; and

R 33 is hydrogen, deuterium, F, or optionally substituted C1-C4 alkyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R′ is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form an optionally substituted heterocyclyl selected from:

(a) optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl; (b) optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl; (c) optionally substituted 2-azabicyclo[5.1.0]octan-2-yl; (d) optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl (e) optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl; (f) optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl; (g) optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl; (h) optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (i) optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl (i) optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl; (k) optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl; (l) optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl; (m) optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl; (n) optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl; or (o) optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.

In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl. In some embodiments, the optionally substituted 2-azabicyclo[5.1.0]octan-2-yl is substituted with an oxo group. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl. In some embodiments, —N (R 2 )R 3 form an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl. In some embodiments, —N(R 2 )R 3 form an optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl. In some embodiments, N (R 2 )R 3 form an optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl. In some embodiments, the optionally substituted heterocyclyl is optionally substituted with a group selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the group is chloro. In some embodiments, the group is fluoro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluor or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[4.1.0]heptane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[3.1.0]hexane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted azabicyclo[6.1.0]nonane heterocyclyl has a structure selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form an optionally substituted azabicyclo[4.1.0]heptane heterocyclyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form an optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form an optionally substituted azabicyclo[6.1.0]nonane heterocyclyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form an optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein —N(R 2 )R 3 form a group selected from:

optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl.

In some embodiments, the group is optionally substituted with a halogen.

In some embodiments, N (R 2 )R 3 form a group selected from:

In some embodiments, —N(R 2 )R 3 form a group selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H. In some embodiments, R 4 is optionally substituted C 1 -C 4 alkoxy. In some embodiments, R 4 is-OCH 3 . In some embodiments, R 4 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 is selected from optionally substituted C 1 -C 6 cycloalkyl or C 1 -C 6 cycloalkylalkyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is halogen. In some embodiments, R 4 is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkylalkyl, cyano, or halogen.

Another embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is H, and Rè is:

In some embodiments, X 1 and X 3 are N, and X 2 is C—F.

In some embodiments, Ar is selected from:

In some embodiments, Ar is selected from:

In some embodiments, Ar is selected from:

In some embodiments, Ar is selected from:

In some embodiments, Ar is selected from:

In some embodiments, Ar is selected from:

wherein Z is selected from the group consisting of halogen, cyano, and hydroxyl. In some embodiments, the halogen is fluoro or chloro.

One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.

One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in any one of FIGS. 1 - 26 .

Preparation of Compounds

The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Comwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCl America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the KRAS inhibitory compound described herein is administered as a pure chemical. In other embodiments, the KRAS inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one KRAS inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the KRAS inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the KRAS inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

In some embodiments, the KRAS inhibitory compound as described by Formula (I), Formula (Ia), or Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

The dose of the composition comprising at least one KRAS inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.

Methods of Treatment

One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. One embodiment provides a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides a use of a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides the use wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. One embodiment provides the method of treating cancer wherein the cancer is lung adenocarcinoma.

One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. One embodiment provides the use wherein the cancer is lung adenocarcinoma.

Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Table 1. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vitro setting.

Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

I. Chemical Synthesis

In some embodiments, the KRAS inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

ACN acetonitrile ° C. degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH 2 Cl 2 ) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli M molar M + parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THE tetrahydrofuran TPP Triphenylphosphine

To an ice-cooled mixture of 1,4-oxazepane (20 g, 197.73 mmol) and K 2 CO3 (54.65 g, 395.45 mmol) in THF (200 mL) under nitrogen atmosphere was added Cbz-C 1 (40.47 g, 237.27 mmol) dropwise at room temperature. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with saturated aq. NaHCO 3 (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 35% EA in PE to afford the title compound (44 g, 94% yield) as a colorless oil. MS: m/z=236.05 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.39-7.29 (m, 5H), 5.15 (s, 2H), 3.75-3.56 (m, 8H), 1.93-1.79 (m, 2H).

To a solution of benzyl 1,4-oxazepane-4-carboxylate (40 g, 170.00 mmol) in MeOH (200 mL) was added tetraethylammonium tosylate (25.62 g, 85.00 mmol) at room temperature. The reaction mixture was electrolysis with C(+) I C(−) electrodes at constant current 200 mA. The resulting mixture was stirred at 20° C. for 72 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford a mixture of the title compounds (37 g, 82.03%) as a light-yellow oil. 1 H NMR (400 MHz, Chloroform-d) § 7.39-7.31 (m, 5H), 5.53-5.09 (m, 3H), 4.12-3.20 (m, 9H), 2.72-2.22 (m, 1H), 2.12-1.24 (m, 1H).

Step 3: Benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2H-1,4-oxazepine-4-carboxylate

To an ice-cooled solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate and benzyl 5-methoxy-1,4-oxazepane-4-carboxylate (8.3 g, 31.28 mmol) in DCM (830 mL) were added DIEA (4.85 g, 37.54 mmol) and TMSOTf (8.34 g, 37.54 mmol 1.2) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 0.5 hour. The solid was filtered out, and the filter cake was washed with hexane (1660 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, cluted with 42% EA in PE to afford two peaks. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 1, 2.18 g, 29% yield) as a yellow solid. 1 H NMR (400 MHz, Chloroform-d) § 7.40-7.29 (m, SH), 5.96-5.74 (m, 2H), 5.18 (s, 2H), 4.11-4.07 (m, 2H), 3.84-3.87 (m, 2H), 2.04-1.94 (m, 2H). The second eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 2, 2.52 g, 34% yield) as a yellow solid. 1 H NMR (400 MHZ, Chloroform-d) § 7.42-7.28 (m, 5H), 5.26-4.85 (m, 4H), 4.22-4.20 (m, 2H), 3.93-3.70 (m, 4H).

To a solution of Intermediate 1 (2.18 g, 9.35 mmol) in DCM (25 mL) was added ZnEt2 (24.93 mL, 24.93 mmol, 1 M in n-hexane) at room temperature. The mixture was stirred at room temperature for 0.5 hours. A solution of diiodomethane (10.02 g, 37.40 mmol) in DCM (12 mL) was added to the mixture dropwise in an ice bath, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into cold saturated aq. NH 4 Cl (100 mL), extracted with DCM (3×100 mL), washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 40% EA in PE to afford the title compound (1.8 g, 77% yield) as a yellow oil. MS: m/z=248.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) § 7.38-7.28 (m, 5H), 5.29-5.07 (m, 2H), 4.18-3.92 (m, 2H), 3.69-3.63 (m, 1H), 3.42-3.39 (m, 1H), 3.16-3.10 (m, 1H), 2.45-2.40 (m, 1H), 1.91-1.74 (m, 2H), 1.46-1.10 (m, 2H).

To an ice-cooled solution of benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (4 g, 16.17 mmol) in MeOH (200 mL) was added Pd/C(1.3 g, 10 wt %) under nitrogen atmosphere. The resulting mixture was stirred in an ice bath for 40 min under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound (1.55 g, crude used through) as a light yellow oil.

To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.46 g, 13.70 mmol) and 2-oxa-6-azabicyclo[5.1.0]octane (1.55 g, crude) in DCM (40 mL) was added DIEA (5.31 g, 41.11 mmol) dropwise at −40° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at −40° C. The mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (Intermediate 3, 4 g, crude) as a light-yellow solid. MS: m/z=329.00, 331.00 [M+H] +.

Step 1: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane

To a stirred solution of Intermediate 3 (4 g, crude) in DMSO (40 mL) under nitrogen atmosphere were added KF (2.47 g, 42.53 mmol) and Intermediate 17 (3.13 g, 19.44 mmol) at room temperature. The resulting mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl/MeOH (10: 1) to afford the title compound (1.5 g, 20% yield for three steps) as a light yellow solid. MS: m/z=454.15 [M+H].

Step 2: (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-ď2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane & (1S,7R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane

The mixture of 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane (1.5 g, 3.30 mmol) was separated by Prep-SFC with the following conditions: Column: JW-Lux Cellulose-3, 4.6 x 50 mm, 3 um; Mobile Phase A: CO2; Mobile Phase B: MeOH; Flow rate: 100 mL/min; Gradient: isocratic 15% B; Back Pressure (bar): 100; RT1: 5.13 min; RT2: 7.47 min. The first eluting peak (RT1: 5.13 min) was concentrated and lyophilized to give the title compound (Intermediate 4, 495 mg, 33% yield) as a light yellow solid 1 H NMR (400 MHZ, Chloroform-d) δ 9.10 (s, 1H), 5.36-5.23 (m, 1H), 4.68-4.65 (m, 1H), 4.02-3.99 (m, 1H), 3.78-3.72 (m, 2H), 3.55-3.49 (m, 1H), 3.36-3.22 (m, 3H), 3.13-2.99 (m, 2H), 2.43-2.17 (m, 4H), 1.99-1.70 (m, 4H), 1.39-1.33 (m, 1H), 0.79-0.75 (m, 1H). The second eluting peak (RT2: 7.47 min) was concentrated and lyophilized to give the title compound (Intermediate 5, 510 mg, 34% yield) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 5.35-5.22 (m, 1H), 4.68-4.65 (m, 1H), 4.03-4.00 (m, 1H), 3.78-3.72 (m, 2H), 3.55-3.49 (m, 1H), 3.31-3.18 (m, 3H), 3.14-3.09 (m, 1H), 3.02-2.96 (m, 1H), 2.44-2.15 (m, 4H), 1.99-1.87 (m, 4H), 1.39-1.29 (m, 1H), 0.79-0.75 (m, 1H).

To a solution of tert-butyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (1 g, 5.07 mmol), benzyl (triethyl) ammonium chloride (23 mg, 101 umol) in CHCl 3 (12 mL) was added a solution of NaOH (661 mg, 16.5 mmol) in H 2 O (1.3 mL). The mixture was stirred at 35° C. for 16 h under N 2 atmosphere. The mixture was diluted with H 2 O (20 mL) and extracted with CH 2 C 12 (10 mL×3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜3% of EtOAc in petroleum ether) to give the title compound (0.87 g, 88% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d) δ 4.07-3.81 (m, 2H), 3.02-2.82 (m, 2H), 2.35-2.25 (m, 2H), 1.87-1.74 (m, 2H), 1.67-1.60 (m, 2H), 1.44 (s, 9H).

To a suspension of sodium debris (1.7 g, 76 mmol) in THF (15 mL) was degassed and purged with N2 three times. A solution of tert-butyl 8,8-dichloro-4-azabicyclo[5.1.0]octane-4-carboxylate (330 mg, 1.18 mmol) in MeOH (6 mL) and THF (6 mL) was added dropwise to the mixture at 25° C. to 40° C. under N 2 . The reaction mixture was stirred at 25° C. for 2 h under N 2 atmosphere. The reaction mixture was quenched slowly with sat. NH 4 Cl aq. (50 mL) at 0° C. and extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturate brine (80 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜4% of EtOAc in petroleum ether) to give the title compound (204 mg, 82% yield) as a colorless oil. 1 H NMR (400 MHZ, Chloroform-d) δ 3.52 (s, 2H), 3.22-3.13 (m, 2H), 2.21 (s, 2H), 1.43 (s, 9H), 1.41-1.31 (m, 2H), 1.00-0.89 (m, 2H), 0.68-0.61 (m, 1H), 0.25-0.19 (m, 1H)

To a solution of tert-butyl 4-azabicyclo[5.1.0]octane-4-carboxylate (204 mg, 965 umol) in HCl (2M in EtOAc, 4 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (143 mg, crude, HCl) as a white solid, which was used in the next step without further purification.

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (245 mg, 969 umol), DIPEA (674.80 μL, 3.87 mmol) in CH 2 Cl 2 (5 mL) was added 4-azabicyclo[5.1.0]octane (143 mg, 969 umol, HCl) at −40° C. under N 2 atmosphere. The reaction mixture was stirred at −40° C. for 0.5 h under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the compound title compound (Intermediate 6, 253 mg, crude) as a yellow solid, which was used in the next step without further purification. MS: m/z=327.0 [M+H] +.

To a solution of azepan-2-one (40 g, 353 mmol) and (Boc) 2 O (84.9 g, 389 mmol) in dry THF (400 mL) was added DMAP (47.5 g, 389 mmol). The mixture was stirred at 25° C. for 3 h. TLC indicated that azepan-2-one was consumed completely and one new spot formed (PE/EA=3: 1, Rr=0.5, color developing reagent: ninhydrin). The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜30% EtOAc in Petroleum ether) to give the title compound (75 g, 99% yield) as an off-white oil. 1 H NMR (400 MHz, CDCL) δ 3.76 (s, 2H), 2.67-2.60 (m, 2H), 1.80-1.68 (m, 6H), 1.51 (s, 9H).

To a solution of tert-butyl 2-oxoazepane-1-carboxylate (68 g, 319 mmol) in THF (1500 mL) were added dropwise TMEDA (44.5 g, 383 mmol) and LDA (2 M, 191 mL) at −78° C. under N 2 . The mixture was stirred at this temperature for 2 h. Diphenyl phosphorochloridate (103 g, 383 mmol) was added dropwise at −78° C. under N 2 . The resulting mixture was stirred at −78° C. for 3 h. TLC indicated that tert-butyl 2-oxoazepane-1-carboxylate was consumed completely and one new spot formed (PE/EA=5: 1, Rr=0.76, color developing reagent: ninhydrin). The reaction mixture was diluted with sat. NH 4 Cl ag. (500 ml) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (cluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (85 g, 60% yield) as a yellow oil. 1 H NMR (400 MHZ, CDCl 3 ) δ 7.41-7.28 (m, 4H), 7.27-7.15 (m, 6H), 5.42 (t, J=2.8, 6.4 Hz, 1H), 3.93-3.07 (m, 2H), 2.14-1.99 (m, 2H), 1.73 (dd, J=5.6, 11.2 Hz, 2H), 1.58-1.48 (m, 2H), 1.41 (s, 9H).

To a solution of tert-butyl 7-((diphenoxyphosphoryl)oxy)-2,3,4,5-tetrahydro-1/-azepine-1-carboxylate (58 g, 130 mmol) in DME (600 mL) were added triphenylphosphane (2.73 g, 10.4 mmol) and Pd (OAc) 2 (1.17 g, 5.21 mmol) at 25° C. under N 2 . TEA (39.5 g, 391 mmol) and formic acid (5.99 g, 130 mmol) in DME (400 mL) were added dropwise to the mixture at 25° C. under N 2 . The mixture was stirred at 84° C. for 40 min under N 2 . TLC indicated one new spot formed (PE/EA=5: 1, R (=0.81, color developing reagent: ninhydrin). The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (Intermediate 7, 20 g, 78% yield) as an off-white oil. 1 H NMR (400 MHZ, CDCl 3 ) δ 6.65-6.26 (m, 1H), 5.05-4.81 (m, 1H), 3.61 (s, 2H), 2.22-2.07 (m, 2H), 1.77-1.63 (m, 4H), 1.45 (s, 9H).

To a solution of Intermediate 7 (160 mg, 760 μmol) in CH 2 Cl 2 (3 mL) was added diethylzinc (1 M in n-hexane, 1.52 mL). The mixture was stirred at 0° C. for 0.5 h under N 2 . A solution of CH 2 I 2 (815 mg, 3.04 mmol) in CH 2 Cl 2 (1.5 mL) was added to the mixture dropwise at 0° C. under N 2 . The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with sat NH 4 Cl aq (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (120 mg, 75% yield) as a colorless oil. 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 3.86-3.72 (m, 1H), 2.92-2.76 (m, 2H), 2.22-2.11 (m, 1H), 1.72-1.58 (m, 2H), 1.38 (s, 11H), 0.99-0.88 (m, 3H), 0.55 (d, J=3.2 Hz, 1H)

To a solution of tert-butyl 2-azabicyclo[5.1.0]octane-2-carboxylate (120 mg, 568 μmol) in CH 2 Cl 2 (2 mL) was added TFA (2 mL) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (100 mg, TFA salt) as a yellow oil, which was used in the next step without further purification.

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (228 mg, 899 μmol) in CH 2 Cl 2 (2 mL) were added DIPEA (581 g, 783 μL) and 2-azabicyclo[5.1.0]octane (100 mg, 899 μmol) at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH 2 Cl 2 (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (Intermediate 8, 150 mg, crude) as a yellow oil, which was used in the next step without further purification. MS: m/z=327.0 [M+H] +.

To a solution of Intermediate 7 (100 mg, 507 μmol) in THF (2 mL) were added Nal (760 mg, 5.07 mmol) and trimethyl (trifluoromethyl) silane (721 mg, 5.07 mmol). The mixture was stirred at 55° C. for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (120 mg, 96% yield) as a colorless oil. 1 H NMR (400 MHZ, Chloroform-d) δ 4.01 (d, J=11.2 Hz, 1H), 3.08-2.77 (m, 2H), 2.12-1.95 (m, 1H), 1.88-1.69 (m, 3H), 1.60-1.52 (m, 3H), 1.49-1.43 (m, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −127.71, −128.14, −149.06, −149.49.

To a solution of tert-butyl 8,8-difluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (600 mg, 2.43 mmol) in CH 2 Cl 2 (15 mL) was added TFA (15 mL) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (600 mg, TFA, salt) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHZ, Chloroform-d) δ 9.89-9.38 (m, 2H), 3.67 (d,)=13.2 Hz, 1H), 3.41 (t, J=10.0 Hz, 1H), 3.11 (t, J=12.8 Hz, 1H), 2.39-2.26 (m, 1H), 2.20-2.00 (m, 3H), 1.99-1.84 (m, 1H), 1.76-1.51 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −126.76, −127.22, −148.98, −149.44.

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (580 mg, 2.30 mmol) in CH 2 Cl 2 (10 mL) were added DIPEA (1.48 g, 2 mL) and 8,8-difluoro-2-azabicyclo[5.1.0]octane (600 mg, 2.30 mmol) at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH 2 Cl 2 (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (1 g, crude) as a yellow solid, which was used into the next step without further purification. MS: m/z=363.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) & 9.20 (s, 1H), 4.54 (d, J=13.6 Hz, 1H), 3.86 (t, J=10.4 Hz, 1H), 3.44-3.33 (m, 1H), 2.33-2.15 (m, 2H), 2.07-2.04 (m, 1H), 1.90-1.84 (m, 1H), 1.68-1.51 (m, 2H), 1.50-1.46 (m, 1H),

Step 4: 7-Chloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy)pyrido[4,3-d]pyrimidine

To a solution of 2,7-dichloro-4-(8,8-difluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoropyrido[4,3-d]pyrimidine (1 g, 2.75 mmol) in 1,4-dioxane (10 mL) were added DIPEA (1.07 g, 1.44 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methanol (1.10 g, 6.88 mmol). The mixture was stirred at 110° C. for 16 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 9, 880 mg, 62% yield over 3 steps) as a yellow solid. MS: m/z=486.2 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.11 (s, 1H), 5.39-5.17 (m, 1H), 4.38-4.24 (m, 2H), 4.20-4.07 (m, 2H), 3.23-2.97 (m, 3H), 2.86-2.77 (m, 1H), 2.36-2.27 (m, 1H), 2.18-2.09 (m, 2H), 2.06-1.95 (m, 3H), 1.95-1.68 (m, 6H), 1.64-1.53 (m, 1H), 1.40-1.29 (m, 1H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ−125.11, −136.40, −138.02, −145.97, −172.16.

To a solution of NaH (3.82 g, 95.4 mmol, 60% purity) in DMF (65 mL) was added tert-butyl allylcarbamate (10 g, 63.6 mmol) in DMF (135 mL) dropwise at 0° C. under N 2 . The mixture was stirred at 25° C. for 30 minutes, and 4-bromobut-1-ene (11.38 g, 76.3 mmol) in DMF (135 mL) was added dropwise to the mixture at 0° C. The reaction mixture was warmed to 25° C. and stirred at 25° C. for 0.5 h. The reaction mixture was quenched with sat. NH 4 Cl aq. (100 mL) at 0° C., warmed to 25° C. and stirred at 25° C. for 30 min. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (400 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜5% of EtOAc in petroleum ether) to give the title compound (15.6 g, 98% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ 5.93-5.68 (m, 2H), 5.17-4.92 (m, 4H), 3.80 (s, 2H), 3.17 (s, 2H), 2.03 (q, J=6.8 Hz, 2H), 1.65-1.57 (m, 2H), 1.45 (s, 9H).

To a solution of tert-butyl allyl (but-3-en-1-yl) carbamate (10 g, 44.4 mmol) in CH 2 Cl 2 (1500 mL) was added Grubb's II (3.77 g, 4.44 mmol) at 40° C. under N 2 . The mixture was stirred at 40° C. for 2 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜10% of EtOAc in petroleum ether) to give the title compound (7.1 g, 81% yield) as a brown oil. 1 H NMR (400 MHz, Chloroform-d) δ 5.83-5.63 (m, 2H), 3.98-3.78 (m, 1H), 3.57-3.37 (m, 4H), 2.37-2.14 (m, 4H), 1.47-1.44 (m, 9H).

To a solution of tert-butyl 2,3,4,7-tetrahydro-1/-azepine-1-carboxylate (500 mg, 2.53 mmol) and BnNEtsCl (16 mg, 50.7 μmol) in CHCls (10 mL) was added a solution of NaOH (1.27 g, 31.7 mmol) in H 2 O (2.43 mL) dropwise at 25° C. The reaction mixture was stirred at 45° C. for 16 h. The mixture was diluted with sat. NH 4 Cl aq. (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜7% of EtOAc in petroleum ether) to give the title compound (780 mg, 60% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ 4.09-3.76 (m, 2H), 3.03-2.79 (m, 2H), 2.40-2.20 (m, 2H), 1.88-1.75 (m, 2H), 1.73-1.58 (m, 2H), 1.44 (s, 9H).

To a suspension of sodium debris (1.56 g, 67.9 mmol) in THF (10 mL) was addded a solution of ter-butyl 8,8-dichloro-3-azabicyclo[5.1.0]octane-3-carboxylate (250 mg, 892 μmol) in MeOH (1 mL) dropwise at 0° C. under N 2 atmosphere. During the addition, the temperature was controlled between 0° C. and 25° C. The mixture was stirred at 25° C. for 3 h under N 2 atmosphere. MeOH was slowly added dropwise until the sodium metal disappearred completely while the temperature was controlled between 25° C. and 40° C. The reaction mixture was quenched with sat. NH 4 Cl aq. (50 mL) slowly at 0° C. and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜6% of EtOAc in petroleum ether) to give the title compound (130 mg, 69% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ 3.69-3.40 (m, 2H), 3.28-3.10 (m, 2H), 2.26-2.16 (m, 2H), 1.49-1.39 (m, 11H), 1.02-0.90 (m, 2H), 0.71-0.60 (m, 1H), 0.22 (q, J=5.2 Hz, 1H).

To a solution of tert-butyl 3-azabicyclo[5.1.0]octane-3-carboxylate (130 mg, 615 μmol) in CH 2 Cl 2 (3 mL) was added TFA (0.5 mL, 6.73 mmol). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (138 mg, TFA salt) as a yellow gum.

To solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (139 mg, 550 μmol, 0.9 eq) and DIPEA (320 μL, 1.83 mmol) in CH 2 Cl 2 (5 mL) at −40° C. was added 3-azabicyclo[5.1.0]octane (138 mg, 612 μmol, TFA salt). The mixture was stirred at −40° C. for 15 min. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (Intermediate 10, 170 mg, 62% yield over 2 steps) as a yellow solid. MS: m/z=326.8 [M+H] +.

To a solution of NaOEt (7.93 g, 117 mmol) in CH 2 Cl 2 (50 mL) was added dropwise a solution of tert-butyl 2,3,4,5-tetrahydro-1/-azepine-1-carboxylate (10 g, 50.7 mmol) and ethyl 2,2-dibromo-2-fluoroacetate (26.8 g, 101 mmol) in CH 2 Cl 2 (50 mL) at 0° C. under N 2 . The reaction mixture was stirred at 25° C. for 12 h. TLC indicated one new spot formed (PE/EA=5: 1, Rf=0.60, color developing reagent: ninhydrin). The residue was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (9 g, 58% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 4.02-3.79 (m, 1H), 3.03-2.82 (m, 2H), 2.29-2.07 (m, 1H), 1.84-1.69 (m, 3H), 1.58-1.42 (m, 12H). 19 F. NMR (376 MHZ, CDCl 3 )-127.11, −157.44.

Step 2: tert-Butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)

To a suspension of sodium debris (8.59 g, 374 mmol) in THF (40 mL) was added a solution of tert-butyl 8-bromo-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (4 g, 13 mmol) in THF (20 mL) and MeOH (20 mL) at 25° C. under N 2 atmosphere. During the addition, the temperature was controlled between 25° C. and 40° C. Then the suspension was stirred at 25° C. for 3 h. MeOH was added dropwise till the sodium metal disappeared completely while the temperature was controlled between 25° C. and 40° C. TLC indicated two spots formed (PB: EA=10: 1, Rt=0.60 with FNMR=-205 and R. 0.55 with FNMR=-232, color developing reagent: ninhydrin). The reaction mixture was quenched slowly with sat. NHACl aq. (200 mL) at 0° C. and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in Petroleum ether) to give the title compound (trans mixture) (Intermediate 11, 1.2 g, 40% yield) as an off-white oil and the title compound (cis mixture) (Intermediate 12, 900 mg, 30% yield) as an off-white oil. Spectra for Intermediate 11: 1 H NMR (400 MHZ, CDCl 3 ) δ=4.44 (s, 1H), 3.97 (s, 1H), 2.81 (dd, J=9.2, 18.8 Hz, 2H), 2.37-2.20 (m, 1H), 1.76-1.66 (m, 2H), 1.58-1.39 (m, 12H), 1.13-0.95 (m, 1H). 19 F. NMR (376 MHz, CDCl 3 ) δ −205.16. Spectra for Intermediate 12: 1 H NMR (400 MHZ, CDCL) δ 4.59-4.23 (m, 1H), 3.95 (s, 1H), 3.02-2.83 (m, 1H), 2.42 (s, 1H), 1.95-1.86 (m, 1H) 1.84-1.67 (m, 3H), 1.63-1.54 (m, 2H), 1.45 (s, 9H), 1.14-1.03 (m, 1H). 19 F NMR (376 MHz, CDCl 3 ) δ −233.29.

To a solution of fert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) (500 mg, 568 μmol) in CH 2 Cl (5 mL) was added TFA (S mL) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The residue was concentrated under reduced pressure to give the title compound (500 mg, TFA salt) as a yellow oil, which was used in the next step without further purification.

Step 2: 2,7-Dichloro-8-fluoro-4-((1R,7S,8R)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (586 mg, 2.32 mmol) in CH 2 Cl 2 (5 mL) were added DIPEA (1.5 g, 2.02 mL) and 8-fluoro-2-azabicyclo[5.1.0]octane TFA salt (trans mixture) (500 mg, 2.32 mmol, TFA salt) at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH 2 Cl (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was separated by SFC(column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B %: 40%, isocratic elution mode) to give the title compound (Intermediate 13, 200 mg, 25% yield, SFC peak 1: 1.126 min) as a yellow solid and the title compound (Intermediate 14, 200 mg, 25% yield, SFC peak 2: 1.546 min) as a yellow solid. Spectra for Intermediate 13: MS: m/z=345.0 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 9.31 (s, 1H), 4.60 (d, J=13.6 Hz, 1H), 4.23-3.94 (m, 1H), 3.76-3.62 (m, 1H), 3.42-3.28 (m, 1H), 2.49-2.35 (m, 1H), 2.12-1.90 (m, 3H), 1.85-1.72 (m, 1H), 1.64-1.59 (m, 1H), 1.12-0.94 (m, 1H). 19 F NMR. (376 MHz, Chloroform-d) δ-132.27, −203.94, −203.97. Spectra for Intermediate 14: MS: m/z=345.0 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 9.30 (s, 1H), 4.60 (d, J=13.6 Hz, 1H), 4.23-3.97 (m, 1H), 3.79-3.61 (m, 1H), 3.44-3.27 (m, 1H), 2.48-2.36 (m, 1H), 2.14-1.89 (m, 3H), 1.85-1.72 (m, 1H), 1.66-1.58 (m, 1H), 1.13-0.94 (m, 1H) 19 F NMR (376 MHz, Chloroform-d) δ-132.29, −203.891, −203.951.

To a solution of tert-butyl 8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture) (500 mg, 2.18 mmol) in CH 2 Cl 2 (5 mL) was added TFA (486 μL, 6.54 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (cis mixture, TFA salt) (280 mg, TFA salt) as a colorless oil, which was used in the next step without further purification.

Step 2: 2,7-Dichloro-8-fluoro-4-((1S,7R,8R)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1R,7S,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (547 mg, 2.17 mmol) in CH 2 Cl (10 mL) were added DIPEA (2.27 mL, 13.0 mmol) and 8-fluoro-2-azabicyclo[5.1.0]octane TFA salt (cis mixture) (280 mg, 2.17 mmol, TFA salt) at −40° C. under N 2 . The mixture was stirred at −40° C. for 0.5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in Petroleum ether) to give a mixture. The mixture was separated by SFC: DAICEL CHIRALPAK IK (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -i-PrOH (0.1% NH 3 H 2 O)]; B %: 40%, isocratic elution mode) to give the title compound (Intermediate 15, 150 mg, 20% yield over 2 steps, SFC Peak1: 1.898 min) as a white solid and the title compound (Intermediate 16, 150 mg, 20% yield over 2 steps, SFC Peak2: 2.263 min) as a white solid. Spectra for Intermediate 15: MS: m/z=344.8 [M+H] + . 1 H NMR (400 MHI 2 , Dimethylsulfoxide-d6) § 9.62 (s, 1H), 5.10-4.82 (m, 1H), 4.41 (d,)=13.2 Hz, 1H), 3.68-3.60 (m, 1H), 3.46 (t, J=12.4 Hz, 1H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H), 1.68-1.56 (m, 2H), 1.36-1.21 (m, 1H). Spectra for Intermediate 16: MS: m/z=344.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.62 (s, 1H), 5.06-4.85 (m, 1H), 4.41 (d, J=13.2 Hz, 1H), 3.70-3.61 (m, 1H), 3.46 (t,)=12.4 Hz, 1H), 2.03-1.94 (m, 2H), 1.86-1.77 (m, 2H), 1.67-1.57 (m, 2H), 1.32-1.22 (m, 1H).

To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methanol (500 mg, 3.141 mmol) and RuCls.H 2 O (35.40 mg, 0.157 mmol) in CC14 (4 mL), MeCN (4 mL) and H 2 O (6 mL) under nitrogen atmosphere was added NaIO 4 (2686.99 mg, 12.564 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 (25% AcOH)/MeOH (5: 1) to afford the title compound (200 mg, 36% yield) as a brown-yellow semi-solid. MS: m/z=174.10 [M+H] +.

To an ice-cooled solution of (2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-carboxylic acid (200 mg, 1.155 mmol) in Me-THF (2 mL) under nitrogen atmosphere was added LiAlD 4 (2.43 mL, 2.425 mmol, 1M in THF) dropwise. The ice bath was removed, and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was cooled and quenched with MeOH (5 mL) in an ice bath. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 1-20% methanol in dichloromethane to afford the title compound (Intermediate 17, 100 mg, 53% yield) as a yellow oil. MS: m/z=162.15 [M+H] +.

To an ice cooled mixture of (3,4-difluorophenyl) acetic acid (7 g, 40.667 mmol), DMAP (5.47 g, 44.734 mmol) and Meldrum's acid (5.86 g, 40.667 mmol) in DCM (71.79 mL) under nitrogen atmosphere was added DCC(9.23 g, 44.734 mmol) dropwise. The reaction mixture was stirred at 0° C. with an ice bath for 16 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (3×100 mL). The resulting mixture was washed with 1 M NaHSO 4 (3×100 mL) and brine (3×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (8 g, crude used through) as a yellow oil. MS: m/z=297.10 [M−H] +.

A solution 5-(2-(3,4-difluorophenyl) acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8 g, crude) in 1-BuOH (80 mL) under nitrogen atmosphere was heated at 88° C. for 5 hours. The resulting mixture was cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-15% EA in PE to afford the title compound (7 g, 65% yield for two steps) as a light-yellow oil. MS: m/z=269.05 [M−H] − . 1H NMR (300 MHz, Chloroform-d) δ 7.26-7.00 (m, 2H), 6.93-6.91 (m, 1H), 3.80 (s, 2H), 3.40 (s, 2H), 1.47 (s, 9H).

To an ice cooled solution of tert-butyl 4-(3,4-difluorophenyl)-3-oxobutanoate (7 g, 25.899 mmol) in DCM (70 mL) under nitrogen atmosphere was added TFA (70 mL, 863.994 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was co-evaporated with toluene (70 mL×6) to give the title compound (6 g, crude used through) as a yellow solid. MS: m/z=213.00 [M−H]

A solution of 4-(3,4-difluorophenyl)-3-oxobutanoic acid (6 g, crude) in CF 3 SO 3 H (180 mL) under nitrogen atmosphere was stirred at room temperature for 16 hours. The resulting mixture was diluted with EtOAc (800 mL), washed with water (4×300 mL) and brine (400 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-50% EA in PE to afford the title compound (1.7 g, 34% yield for two steps) as a black oil. MS: m/z=195.10 [M−H] − . 1 H NMR (400 MHZ, DMSO-d6) δ 10.35 (s, 1H), 9.71 (s, 1H), 7.78-7.72 (m, 1H), 7.63-7.58 (m, 1H), 6.62-6.53 (m, 2H).

To a stirred solution of 6,7-difluoronaphthalene-1,3-diol (520 mg, 2.65 mmol) and (2-bromoethynyl)triisopropylsilane (761.91 mg, 2.91 mmol) in 1,4-dioxane (6 mL) under nitrogen atmosphere were added [Ru (p-cymene)Cl 2]2 (162.34 mg, 0.26 mmol) and KOAc (520.35 mg, 5.30 mmol) at room temperature. The resulting mixture was heated at 110° C. for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-50% EA in PE to afford the title compound (600 mg, 60% yield) as a brown solid. MS: m/z=377.00 [M+H] +.

Step 6: 6,7-Difluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diyl bis(trifluoromethanesulfonate)

To a stirred solution of 6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diol (1.8 g, 4.781 mmol) in DCM (18 mL) were added DIEA (3.7 g, 28.686 mmol) and Tf2O (4.4 g, 14.343 mmol) at −40° C. under nitrogen atmosphere. The resulting mixture was stirred at −40° C. for 3 hours. The resulting mixture was quenched with aq. NaHCO 3 (50 mL), extracted with CH 2 Cl (3×100 mL), washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to afford the title compound (3 g, crude used through) as a brown oil. MS: m/z=638.95 [M−H] −.

Step 7: 3-((Diphenylmethylene)amino)-6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate

To a stirred mixture of 6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (3 g, crude), Pd2 (dba): (428.83 mg, 0.468 mmol), XantPhos (812.90 mg, 1.405 mmol) and Cs2CO 3 (3051.55 mg, 9.366 mmol) in toluene (30 mL) under nitrogen atmosphere was added diphenylmethanimine (933.59 mg, 5.151 mmol) at room temperature. The resulting mixture was heated at 100° C. for 2 hours. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (3 g, 93% yield for two steps) as a yellow oil. MS: m/z=672.20 [M+H] +.

Step 8: N-(6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-yl)-1,1-diphenylmethanimine

To a stirred solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (2 g, 2.977 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (B2Pin2, 1.512 g, 5.954 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere were added KOAc (876.53 mg, 8.931 mmol) and Pd (dppf)C 12 .CH 2 Cl 2 (12.13 mg, 0.015 mmol) at room temperature. The reaction mixture was heated at 110° C. for 3 hours. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, cluted with 0-20% EA in PE to afford the title compound (Intermediate 18, 1.2 g, 62% yield) as a yellow solid. MS: m/z=650.65 [M+H] + . 1 H NMR (400 MHZ, DMSO-d 6 ) δ 7.86-7.83 (m, 1H), 7.70-7.68 (m, 2H), 7.59-7.55 (m, 1H), 7.51-7.48 (m, 2H), 7.31-7.29 (m, 4H), 7.19-7.17 (m, 2H), 7.09-7.08 (m, 1H), 1.27 (s, 12H), 1.13-1.07 (m, 21H).

To a solution of 7-fluoronaphthalene-1,3-diol (50 g, 281 mmol) and 2-bromoethynyl (triisopropyl) silane (77 g, 295 mmol) in 1,4-dioxane (334 mL) were added KOAc (55.1 g, 561 mmol) and dichlororuthenium: 1-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol). The mixture was stirred at 110° C. for 2 h under N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜5% of EtOAc in petroleum ether) to give the title compound (70 g, 194 mmol, 69% yield) as a brown solid. MS: m/z=359.1 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 9.15 (s, 1H), 7.59 (dd, J=5.6, 9.2 Hz, 1H), 7.17 (t, J=8.8 Hz, 1H), 6.77-6.62 (m, 2H), 1.21-1.15 (m, 21H). 19 F NMR (376 MHz, Chloroform-d) δ −112.51.

To a solution of 7-fluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diol (140 g, 390 mmol) and DIPEA (408 mL, 2.34 mol) in CH 2 Cl 2 (3.5 L) was added Tf2O (258 ml, 1.56 mol) dropwise under N 2 atmosphere at 0° C. The mixture was stirred at 0° C. under N 2 atmosphere for 2 h. The reaction mixture was partitioned between CH 2 Cl 2 (500 mL) and H 2 O (2 L). The organic phase was separated, washed with brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜3% of EtOAc in petroleum ether) to give the title compound (218 g, 340 mmol, 87% yield) as a brown solid. 1 H NMR (400 MHZ, Chloroform-d) δ 7.87 (dd, J=5.2, 9.2 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.54-7.47 (m, 2H), 1.26-1.21 (m, 3H), 1.19-1.15 (m, 18H)

Step 3: 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate

A mixture of 7-fluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diylbis (trifluoromethanesulfonate) (94 g, 151 mmol), diphenylmethanimine (54.7 g, 302 mmol, 50.7 mL), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (17.5 g, 30.2 mmol), Pd2 (dba) 3 (6.91 g, 7.55 mmol) and Cs2CO 3 (148 g, 453 mmol) in toluene (1800 mL) was degassed, purged with N 2 three times, and stirred at 100° C. under N 2 atmosphere for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0˜3% of EtOAc in petroleum ether) to give the crude product (80 g) as a brown solid. The crude was triturated with MeOH (150 mL) at 25° C. for 20 min and filtered. The filter cake was dried under reduced pressure to give the title compound (70 g, 94.2 mmol, 62% yield) as a yellow solid. MS: m/z=654.3 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J=8.0 Hz, 2H), 7.57-7.51 (m, 2H), 7.48-7.41 (m, 2H), 7.27 (s, 2H), 7.26-7.19 (m, 2H), 7.17-7.01 (m, 4H), 1.22-1.13 (m, 21H). 19 F NMR (376 MHz, Dimethylsulfoxide-d6) δ −71.40, −104.22.

Step 4: N-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-yl)-1,1-diphenylmethanimine & 6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-amine

A mixture of 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (50 g, 76.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (39 g, 153 mmol), KOAc (30 g, 306 mmol), and Pd (dppf)Cl 2 (11.2 g, 15.3 mmol) in 1,4-dioxane (600 mL) was degassed, purged with N 2 three times, and stirred at 100° C. under N 2 atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Bluent: 0˜100% of EtOAc in petroleum ether) to give the title compound (Intermediate 19, 9 g, 14.3 mmol, 19% yield) as a yellow solid and the title compound (Intermediate 20, 10 g, 21.4 mmol, 28% yield) as a brown oil. Spectra for Intermediate 19: MS: m/z=632.4 [M+H] + . H NMR (400 MHZ, Dimethylsulfoxide-d6) δ 7.86-7.79 (m, 1H), 7.72-7.67 (m, 2H), 7.60-7.53 (m, 1H), 7.53-7.47 (m, 2H), 7.42 (t, J=9.2 Hz, 1H), 7.34-7.27 (m, 4H), 7.22-7.16 (m, 2H), 7.14-7.10 (m, 1H), 1.27 (s, 12H), 1.14-1.08 (m, 21H), 19 F. NMR (376 MHz, Dimethylsulfoxide-d6) δ −106.71. Spectra for Intermediate 20: MS: m/z=468.3 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.67-7.57 (m, 1H), 7.27 (t, J=9.0 Hz, 1H), 7.23-7.17 (m, 1H), 6.89 (d, J=2.4 Hz, 1H), 5.48 (s, 2H), 1.33 (s, 12H), 1.17-1.11 (m, 21H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ-112.20.

Step 1: Benzyl 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate To a stirred mixture of Intermediate 2 (5 g, 21.43 mmol) and Nal (1.61 g, 10.71 mmol) in THE (50 mL) was added trimethyl (trifluoromethyl) silane (12.19 g, 85.74 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was heated at 65° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (5.1 g, 83% yield) as a light yellow solid. MS: m/z=284.00 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) § 7.42-7.30 (m, 5H), 5.18 (s, 2H), 4.35-4.29 (m, 1H), 4.16 (d, J=14.4 Hz, 1H), 3.97 (d, J=12.8 Hz, 1H), 3.60-3.48 (m, 2H), 3.30-3.23 (m, 2H), 2.28-2.17 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −125.47-−126.24 (m, IF), −147.36-−148.73 (m, 1F).

A solution of benzyl 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.3 g, 8.11 mmol) in 33 wt % HBr in AcOH (23 mL) was stirred in an ice bath for 1 hour under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3×50 mL) to afford the compound (1.5 g, crude used through) as a light yellow solid.

Step 3: 2-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.54 g, 10.05 mmol) and 8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (1.5 g, crude) in DCM (40 mL) was added DIEA (3.90 g, 30.17 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (1: 1) to afford the title compound (1.9 g, 51% yield) as a light yellow solid. MS: m/z=365.05, 367.05 [M+H].

Step 4: 2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 2-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane (1.9 g, 5.20 mmol) in DMSO (40 mL) was added KF (604.61 mg, 10.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (1: 1) to afford the title compound (1.6 g, 88% yield) as a light yellow solid. MS: m/z=349.10 [M+H] +.

Step 5: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane

To an ice-cooled stirred mixture of Intermediate 17 (443.86 mg, 2.75 mmol) in THF (8 mL) was added NaH (110.12 mg, 2.75 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. The mixture was stirred an an ice bath for 30 min. To the above mixture was added 2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane (800 mg, 2.29 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aq. NH 4 Cl (50 mL) in an ice bath and extracted with CH 2 Cl 2 (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 CL/MeOH (10: 1) to afford the title compound (480 mg, 42% yield) as a light yellow solid. MS: m/z=490.35 [M+H] +.

Step 6: (1R,7R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-dz) pyrido[4,3-d]pyrimidin-4-yl)-8,8-difluoro-5-oxa-2-azabicyclo[5.1.0]octane (480 mg, 0.98 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF 2×25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH 3 -MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 30% B; Detector: UV 220 & 254 nm; RT1: 8.655 min; RT2: 11.221 min. The first eluting peak (RT1: 8.655 min) was concentrated and lyophilized to give the title compound (Intermediate 21, 180 mg, 37% yield, structure tentatively assigned) as a light yellow solid. MS: m/z=490.15 [M+H] + . The second eluting peak (RT2: 11.221 min) was concentrated and lyophilized to give the title compound (Intermediate 22, 90 mg, 18% yield, structure tentatively assigned) as a light yellow solid. MS: m/z=490.15 [M+H] +.

To an ice-cooled solution of Intermediate 1 (5.0 g, 21.45 mmol) and TBAI (1.62 g, 4.40 mmol) in DCM (50 mL) were added 50% aq. NaOH (50 mL) and dibromofluoromethane (12.35 g, 64.35 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with iced water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-30% EA in PE to afford the title compound (2.6 g, 35% yield) as an off-white semi-solid. MS: m/z=361.10, 363.10 [M+NH 4 ] +.

Step 2: Benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (trans mixture) and benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (cis mixture)

To a stirred mixture of benzyl 8-bromo-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (2.6 g, 7.58 mmol) in EtOH (25 mL) under nitrogen atmosphere were added NH 4 Cl (2.10 g, 68.22 mmol) and Zn (2.53 g, 68.22 mmol) at room temperature. The reaction mixture was stirred at 10° C. for 16 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% EA in PE to afford two mixtures. The first eluting peak was collected and concentrated under reduced pressure to give the title compound (trans mixture, F-NMR=−211) (233 mg, 12% yield) as an off-white semi-solid. 1 H-NMR (400 MHZ, Chloroform-d) δ 7.32-7.24 (m, 5H), 5.16-5.12 (m, 2H), 4.66-4.55 (m, 1H), 4.10-3.65 (m, 4H), 3.00-2.90 (m, 1H), 2.87-2.80 (m, 1H), 1.79-1.48 (m, 2H). 19 F. NMR (376 MHz, Chloroform-d) δ −211.30 (s, IF). The second eluting peak was collected and concentrated under reduced pressure to give the title compound (cis mixture, F-NMR=−239) (1.0 g, 50% yield) as an off-white semi-solid. 19 F NMR (376 MHZ, Chloroform-d) δ −239.8 (s, IF)

A solution of benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (trans mixture) (233 mg, 1.78 mmol) in 33 wt % HBr in AcOH (2 mL) was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3×8 mL) to afford the title compound (trans mixture, HBr salt) (Intermediate 23, 130 mg, crude used through) as a brown solid. MS: m/z=132.10 [M+H] + . 1 H NMR (300 MHZ, Deuterium Oxide) δ 5.13-4.93 (m, 1H), 4.14-3.97 (m, 2H), 3.80-3.72 (m, 1H), 3.48-3.38 (m, 1H), 3.33-3.24 (m, 2H), 1.94-1.88 (m, 2H). 19 F NMR (282 MHz, Deuterium Oxide) δ −211.86 (s, IF).

A solution of benzyl 8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (cis mixture) (1.00 g, 7.63 mmol) in 33 wt % HBr in AcOH (10 mL) was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3×20 mL) to afford the title compound (cis mixture) (Intermediate 24, 600 mg, HBr salt, crude used through) as a brown solid. MS: m/z=132.10 [M+H] + . 1 H NMR (300 MHZ, Deuterium Oxide) δ 4.85-4.65 (m, 1H), 4.14-3.86 (m, 2H), 3.65-3.35 (m, 3H), 2.94-2.89 (m, 1H), 2.16-1.99 (m, 2H). 19 F. NMR (282 MHz, Deuterium Oxide) δ −240.77 (s, 1F)

Step 1: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture)

A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (481 mg, 1.90 mmol) and 4A molecular sieves in DCM (34 mL) was stirred at room temperature for 30 min, and then DIEA (738.77 mg, 5.71 mmol) and Intermediate 24 (340 mg, crude) were added at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EA (5: 1) to afford the title compound (cis mixture) (530 mg, 80% yield) as a light yellow solid. MS: m/z=347.00, 349.00 [M+H] +.

Step 2: 6-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture)

To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture) (460 mg, 1.32 mmol) in DMSO (28 mL) was added KF (153.97 mg, 2.65 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EA (5: 1) to afford the title compound (cis mixture) (180 mg, 41% yield) as a light yellow solid. MS: m/z=330.65 [M+H] +.

Step 3: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture)

To an ice-cooled stirred mixture of Intermediate 17 (105.30 mg, 0.65 mmol) in THF (18 mL) was added NaH (26.12 mg, 0.65 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring in an ice bath for 30 min, Intermediate 17 (cis mixture) (180 mg, 0.54 mmol) was added to the above mixture. The ice bath was removed, and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. aq. NH 4 Cl (100 mL), extracted with CH 2 Cl 2 (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (cis mixture) (100 mg, 38% yield) as a light yellow solid. MS: m/z=471.80 [M+H] +.

Step 4: (1S,7R,8R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane & (1R,75,8S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5/f)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 0.21 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ 250×20 mm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH 3 -MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 30%; Detector: UV 220 & 254 nm; RT1: 10.147 min; RT2: 15.476 min. The first eluting peak (RT1: 10.147 min) was concentrated and lyophilized to give the title compound (Intermediate 25, 40 mg, 40% yield) as a light yellow solid. MS: m/z=472.20 [M+H] + . The second eluting peak (RT2: 15.476 min) was concentrated and lyophilized to give the title compound (Intermediate 26, 40 mg, 40% yield) as a light yellow solid. MS: m/z=472.20 [M+H] +.

Step 1: 6-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture)

A solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (260 mg, 1.03 mmol) and 4A molecular sieves in DCM (13 mL) was stirred at room temperature for 30 min, and then DIEA (399.34 mg, 3.09 mmol) and Intermediate 23 (trans mixture) (130 mg, crude) were added at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EA (5: 1) to afford the title compound (trans mixture) (160 mg, 44% yield) as a light yellow solid. MS: m/z=346.95, 348.95 [M+H] +.

Step 2: 6-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture)

To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture) (250 mg, 0.72 mmol) in DMSO (25 mL) was added KF (83.68 mg, 1.44 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EA (5: 1) to afford the title compound (trans mixture) (100 mg, 41% yield) as a light yellow solid. MS: m/z=331.00 [M+H] +.

Step 3: 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture)

To an ice-cooled stirred mixture of Intermediate 17 (58.50 mg, 0.36 mmol) in THF (9 mL) was added NaH (14.51 mg, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring with an ice bath for 30 min, 6-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture) (100 mg, 0.30 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for an hour. The resulting mixture was quenched with sat. aq. NH 4 Cl (50 mL) and extracted with CH 2 Cl 2 (3×50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (trans mixture) (65 mg, 45% yield) as a light yellow solid. MS: m/z=472.10 [M+H] +.

Step 3: (1S,7R,8S)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane & (1R,7S,8R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane

6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (SH)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octane (trans mixture) (65 mg, 0.14 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH 3 -MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 25; Wave Length: 220/254 nm; RT1: 14.707 min; RT2: 18.946 min. The first eluting peak (RT1: 14.707 min) was concentrated and lyophilized to give the title compound (Intermediate 27, 26 mg, 40% yield) as a light yellow solid. The second eluting peak (RT2: 18.946 min) was concentrated and lyophilized to give the title compound (Intermediate 28, 27 mg, 41% yield) as a light yellow solid.

To an ice-cooled solution of 1,4-oxazepan-5-one (30 g, 260.57 mmol) in DMF (300 mL) was added NaH (12.51 g, 312.68 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring with an ice bath for 15 min, PMBCl (44.89 g, 286.63 mmol) was added dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was quenched with sat. aq. NH 4 Cl (1000 mL) and extracted with EA (4×800 mL). The combined organic layers were washed with brine (800 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 4% MeOH in DCM to the title compound (52 g, 84% yield) as a colorless oil. 1H-NMR (300 MHz, DMSO-d 6 ) δ7.21-7.16 (m, 2H), 6.91-6.86 (m, 2H), 4.44 (s, 2H), 3.73 (s, 3H), 3.66-3.63 (m, 2H), 3.50-3.38 (m, 4H), 2.73-2.67 (m, 2H).

To an ice-cooled solution of 4-[(4-methoxyphenyl)methyl]-1,4-oxazepan-5-one (24 g, 102.00 mmol) in THF (240 mL) under nitrogen atmosphere was added LiAlD 4 (306.01 mL, 306.01 mmol, 1 M in THF) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (11.6 mL), 15% aq. NaOH (34.8 mL) and water (11.6 mL) with an ice bath. The resulting mixture was stirred at room temperature for 15 min, then filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 3% MeOH in DCM to afford the title compound (18.9 g, 82% yield) as a colorless oil. 1H-NMR (400 MHZ, Chloroform-d) § 7.26-7.24 (m, 2H), 6.88-6.84 (m, 2H), 3.83-3.76 (m, 5H), 3.74-3.70 (m, 2H), 3.60 (s, 2H), 2.68-2.63 (m, 2H), 1.89-1.86 (m, 2H).

To an ice-cooled solution of 4-(4-methoxybenzyl)-1,4-oxazepane-5,5-d 2 (18.9 g, 84.63 mmol) in DCE (380 mL) under nitrogen atmosphere was added 1-chloroethyl carbonochloridate (30.25 g, 211.59 mmol). The ice bath was removed, and the reaction mixture was heated at 85° C. for 16 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (190 mL) and heated at 65° C. for 3 hours. The resulting mixture was cooled to room temperature and HCl (4 N in 1,4-dioxane, 21.16 mL, 84.64 mmol) was added. The resulting mixture was concentrated under reduced pressure. The residue was triturated with Et20 (3×50 mL) to afford the title compound (11.2 g, crude) as a yellow solid.

To an ice-cooled mixture of 1,4-oxazepane-5,5-d 2 hydrochloride (10 g, 71.62 mmol) and K 2 CO 3 (27.77 g, 214.87 mmol) in THF (100 mL) under nitrogen atmosphere was added Cbz-C 1 (14.66 g, 85.95 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with H 2 O (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 35% EA in PE to afford benzyl 1,4-oxazepane-4-carboxylate-5,5-d 2 (13 g, 76% yield) as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.37-7.29 (m, 5H), 5.15 (s, 2H), 3.81-3.69 (m, 4H), 3.62-3.56 (m, 2H), 1.93-1.86 (m, 2H).

Step 5: Benzyl 3-methoxy-1,4-oxazepane-4-carboxylate-5,5-d 2 & benzyl 5-methoxy-1,4-oxazepane-4-carboxylate-5-d

To a solution of benzyl 1,4-oxazepane-4-carboxylate-5,5-d 2 (13 g, 54.78 mmol) in MeOH (150 mL) was added tetraethylammonium tosylate (8.26 g, 27.39 mmol) at room temperature. The reaction mixture was electrolyzed at room temperature for 20 hours using C(+)/C(−) electrodes at constant current 200 mA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford the title compounds (12 g, 82% yield) as a light-yellow oil. 1H-NMR (400 MHZ, Chloroform-d) δ crude H-NMR showed two isomers.

To an ice-cooled solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate-5,5-d 2 & benzyl 5-methoxy-1,4-oxazepane-4-carboxylate-5-d (11.7 g, 43.76 mmol) in DCM (120 mL) were added DIEA (5.26 g, 40.66 mmol) and TMSOTf (8.34 g, 37.54 mmol) under nitrogen atmosphere. The resulting mixture was stirred in an ice bath for 30 min, quenched with saturated aq. NaHCO 3 (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE to afford two isomers. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (5.0 g, 48% yield) as a yellow oil. 1 H NMR (300 MHz, Chloroform-d) δ 7.41-7.29 (m, 5H), 5.94-5.74 (m, 2H), 5.18 (s, 2H), 4.10-4.07 (m, 2H), 2.04-1.96 (m, 2H).

To a solution of benzyl 6,7-dihydro-1,4-oxazepine-4 (5/)-carboxylate-5,5-d 2 (5.0 g, 21.25 mmol) in DCM (50 mL) was added ZnEt2 (53.13 mL, 53.13 mmol, 1 M in n-hexane) at room temperature. After stirring at room temperature for 0.5 hour, a solution of CH 2 I 2 (22.77 g, 85.00 mmol) in DCM (12 mL) was added to the mixture dropwise with an ice bath. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into cold sat. aq. NH 4 Cl (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 35% EA in PE to afford the title compound (4.0 g, 75% yield) as a yellow oil. MS: m/z=250.10 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) 6 7.39-7.29 (m, 5H), 5.20-5.10 (m, 2H), 3.97-3.92 (m, 1H), 3.69-3.63 (m, 1H), 3.43-3.39 (m, 1H), 2.45-2.42 (m, 1H), 1.91-1.64 (m, 2H), 1.26-1.10 (m, 2H).

To an ice-cooled solution of benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate-5,5-d 2 (2 g, 8.02 mmol) in MeOH (100 mL) was added Pd/C(667 mg, 10 wt %) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 40 min under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound (580 mg, crude used through) as a light yellow oil.

To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.27 g, 5.03 mmol) and 2-oxa-6-azabicyclo[5.1.0]octane-5,5-d 2 (580 mg, crude) in DCM (13 mL) was added DIEA (1.95 g, 15.10 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was quenched with 10% citric solution (50 mL) and extracted with DCM (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (1.1 g, crude used through) as a light yellow solid. MS: m/z=331.10, 333.10 [M+H].

Step 10: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-ď2

To a stirred solution of 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d 2 (1.1 g, 3.32 mmol) in DMSO (11 mL) under nitrogen atmosphere were added KF (675.40 mg, 11.62 mmol) and Intermediate 17 (856.79 mg, 5.31 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (60 mL), and extracted with DCM (3×60 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (670 mg, 29% yield for two steps) as a light yellow solid. MS: m/z=456.30 [M+H] +.

Step 11: (1S,7R)-6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d 2 & (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-da

6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane-5,5-d 2 (900 mg, 1.97 mmol) was separated by Prep-SFC with the following conditions: Column: Enantiocel C 9 -5, 30×250 mm, 5.0 μm; Mobile Phase A: CO 2 , Mobile Phase B: IPA; Flow rate: 100 mL/min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 3.9 min; RT2: 6.4 min; Sample Solvent: MeOH: DCM=2: 1. The first eluting peak (RT1: 3.9 min) was concentrated and lyophilized to give the title compound (Intermediate 29, 350 mg, 38% yield) as a light yellow solid. MS: m/z=456.30 [M+H] + . The second eluting peak (RT2: 6.4 min) was concentrated and lyophilized to give the title compound (Intermediate 30, 350 mg, 38% yield) as a light yellow solid. MS: m/z=456.30 [M+H] +.

To an ice-cooled solution of Intermediate 2 (2.0 g, 8.58 mmol) and TBAI (0.65 g, 1.76 mmol) in DCM (10 mL) under nitrogen atmosphere were added 33 wt % aq. NaOH solution (20 mL) and dibromofluoromethane (4.94 g, 25.74 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with iced water (50 mL), extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-30% EA in PE to afford the title compound (2.4 g, 82% yield) as an off-white semi-solid. MS: m/z=361.10, 363.10 [M+NH 4 ] +.

Step 2 & 3: Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)

To a stirred mixture of benzyl 8-bromo-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.4 g, 7.00 mmol) in EtOH (25 mL) under nitrogen atmosphere were added NH 4 Cl (3.37 g, 63.00 mmol) and Zn (4.12 g, 63.00 mmol) at room temperature. The reaction mixture was heated at 70° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% EA in PE to afford two mixtures. The first eluting mixtures were collected and concentrated under reduced pressure to give the title compound (trans mixture) (Intermediate 31, 700 mg, 38% yield) as an off-white semi-solid. MS: m/z=283.20 [M+NH 4] + . 1 H NMR (300 MHz, Chloroform-d) & 7.39-7.32 (m, 5H), 5.30-5.21 (m, 2H), 4.72-4.52 (m, 1H), 4.41-4.35 (m, 1H), 4.06-4.01 (m, 1H), 3.85-3.80 (m, 1H), 3.49-3.30 (m, 1H), 3.25-3.14 (m, 3H), 2.05-1.92 (m, 1H). 19 F NMR (282 MHz, Chloroform-d) δ −207.85 (s, 1F). The second eluting mixtures were collected and concentrated under reduced pressure to give the title compound (cis mixture) (Intermediate 32, 360 mg, 19% yield) as a yellow oil. MS: m/z=283.20 [M+NH 4 ] + . 1 H NMR (300 MHz, Chloroform-d) δ 7.38-7.30 (m, 5H), 5.15 (s, 2H), 4.67-4.46 (m, 1H), 4.33-4.26 (m, 1H), 4.19-4.14 (m, 1H) 4.02-3.91 (m, 1H), 3.69-3.55 (m, 2H), 3.37-3.29 (m, 1H), 2.74-2.72 (m, 1H)1.64-1.51 (m, 1H). 19 F NMR (282 MHz, Chloroform-d) δ −232.23 (s, 1F).

Intermediate 31 (trans mixture) (2.6 g, 9.81 mmol) in 33 wt % HBr in AcOH (26 mL) under nitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was trituration with hexane (3×50 mL) to afford the title compound (trans mixture, HBr salt) (1.9 g, crude used through) as a light yellow solid.

Step 2: 2-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

To a stirred solution of 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture) (600 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1154.94 mg, 4.57 mmol) in DCM (11 mL) was added DIEA (1773.88 mg, 13.72 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL.), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, cluted with CH 2 Cl 2 /EA (5: 1) to afford the title compound (trans mixture) (800 mg, 50% yield) as a light yellow solid. MS: m/z=347.10, 349.10 [M+H].

Step 3: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

To a stirred solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (800 mg, 2.30 mmol) in DMSO (8 mL) under nitrogen atmosphere were added KF (468.59 mg, 8.06 mmol) and Intermediate 17 (594.43 mg, 3.68 mmol) at room temperature. The resulting mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (trans mixture) (400 mg, 36% yield) as a light yellow solid. MS: m/z=472.25 [M+H] +.

Step 4: (1R,7R,8R)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (400 mg, 0.84 mmol) was separated by Prep-SFC with the following conditions: Column: (S, S)-Whelk-O 1 5 μm Kromasil, 3×25 cm, 5 μm; Mobile Phase A: CO 2 ; Mobile Phase B: MeCN: MeOH=1: 1 (1% 2 M NH 3 -MeOH); Flow rate: 100 mL/min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 3.3 min; RT2: 6.1 min, Sample Solvent: MeOH. The first eluting peak (RT1: 3.3 min) was concentrated and lyophilized to give the title compound (Intermediate 33, 150 mg, 37%) as a light yellow solid. MS: m/z=472.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 5.41-5.16 (m, 1H), 4.69-4.55 (m, 1H), 4.50-4.21 (m, 2H), 4.03-3.79 (m, 3H), 3.70-3.55 (m, 1H), 3.33-3.15 (m, 3H), 3.05-2.94 (m, 1H), 2.40-1.74 (m, 8H). 19 F. NMR (376 MHz, CDCl 3 ) δ −134.22 (s, IF), —173.15 (s, IF), —207.66 (s, IF). The second eluting peak (RT2: 6.1 min) was concentrated and lyophilized to give the title compound (Intermediate 34, 200 mg, 50%) as a light yellow solid. MS: m/z=472.10 [M+H] + : 1 H NMR (400 MHZ, Chloroform-d) δ 9.22 (s, 1H), 5.37-5.16 (m, 1H), 4.68-4.58 (m, 1H), 4.49-4.22 (m, 2H), 4.02-3.81 (m, 3H), 3.71-3.57 (m, 1H), 3.31-3.12 (m, 3H), 3.05-2.91 (m, 1H), 2.40-1.77 (m, 8H). 19 F. NMR (376 MHz, CDCl 3 ) δ −134.20 (s, IF), —173.11 (s, IF), —207.61 (s, IF).

A solution of Intermediate 32 (600 mg, 2.26 mmol) in 33 wt % HBr in AcOH (6 mL) under nitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane (3×50 mL) to afford the title compound (cis mixture, HBr salt) (470 mg, crude used through) as a light yellow solid.

Step 2: 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture)

To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (866.20 mg, 3.43 mmol) and 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (cis mixture) (450 mg, crude) in DCM (18 mL) was added DIEA (1.33 g, 10.29 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (1: 1) to afford the title compound (cis mixture) (260 mg, 21% yield) as a light yellow solid. MS: m/z=347.05, 349.05 [M+H] +.

Step 3: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture)

To a stirred solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) (250 mg, 0.72 mmol) in DMSO (2.5 mL) under nitrogen atmosphere were added KF (146.43 mg, 2.52 mmol) and Intermediate 17 (185.76 mg, 1.15 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (20 mL), extracted with DCM (3×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford 2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 29% yield) as a light yellow solid. MS: m/z=472.30 [M+H] +.

Step 4: (1R, 7R,8S)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (IS, 7S,8R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (cis mixture) (100 mg, 0.21 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH 3 -MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 20%; Detector: UV 220 & 254 nm; RT1: 14.255 min; RT2: 16.335 min. The first eluting peak (RT1: 14.225 min) was concentrated and lyophilized to give the title compound (Intermediate 35, 35 mg, 35% yield) as a light yellow solid. MS: m/z=471.85 [M+H] + . The second eluting peak (RT2: 16.335 min) was concentrated and lyophilized to give the title compound (Intermediate 36, 35 mg, 35% yield) as a light yellow solid. MS: m/z=471.80 [M+H] +.

Step 1: 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane To a mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2 g, 7.92 mmol) and 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (1.07 g, 7.92 mmol) in DCM (40 mL) under nitrogen atmosphere was added DIEA (3.07 g, 23.76 mmol) dropwise at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with water (150 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to afford the title compound (2 g, 80% yield) as a yellow solid. MS: m/z=314.95, 316.95 [M+H] +.

Step 2: 5-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane To a stirred solution of 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane (2 g, 6.34 mmol) in DMSO (40 mL) under nitrogen atmosphere was added KF (0.66 g, 11.42 mmol) at room temperature. The reaction mixture was heated at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (300 mL), and washed with brine (3×80 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to afford the title compound (1.5 g, 79% yield) as a yellow solid. MS: m/z=299.00 [M+H] +.

Step 3: 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane

To an ice-cooled solution of Intermediate 17 (0.97 g, 6.02 mmol) in THF (40 mL) under nitrogen atmosphere was added NaHI (0.24 g, 6.02 mmol, 60% dispersion in mineral oil). After stirring in an ice bath for 0.5 hours, 5-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane (1.5 g, 5.02 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aq. NH 4 Cl (100 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by RP-Flash directly with the following conditions: Column, C 18 , Mobile phase A: 5 mM aq. NH 4 HCO3; Mobile phase B: MeCN; Gradient: 5% B-95% B in 40 min, 57% B hold 3 mins; Flow rate: 40 mL/min; Detector UV: 254 & 210 nm. The collected fractions were combined, concentrated and then lyophilized overnight to give the title compound (500 mg, 22% yield) as a yellow solid. MS: m/z=440.25 [M+H] +.

Step 4: (1R,6S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane. & (15,6R)-5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (SH)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane (500 mg, 1.13 mmol) was separated by Prep-Chiral-HPLC with following conditions: Column: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile Phase A: MTBE (0.5% 2 M NH 3 -MeOH)-HPLC; Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 30%; Detected: UV 220 & 254 nm; RT1: 7.032 min; RT2: 8.72 min. The first eluting isomer (RT1: 7.032 min) was concentrated and lyophilized overnight to give the title compound (Intermediate 37, 150 mg, 30% yield) as a yellow lyophilized powder. MS: m/z=440.20 [M+H] + . The second eluting isomer (RT2: 8.72 min) was concentrated and lyophilized overnight to give the title compound (Intermediate 38, 190 mg, 38% yield) as a yellow lyophilized powder. MS: m/z=440.15 [M+H] +.

Step 1: 6-(2,7-Dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane

To a stirred solution of 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (1.0 g, 3.54 mmol, refer to Intermediate 132 for detail procedures) and 2-oxa-6-azabicyclo[5.1.0]octane (0.40 g, 3.54 mmol, refer to Intermediate 3 for detail procedures) in DCM (20 mL) was added DIEA (0.92 g, 7.08 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric acid solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (0.9 g, crude used through) as a light yellow solid. MS: m/z=359.10, 361.10 [M+H] +.

Step 2: 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane

To a stirred solution of 6-(2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane (0.9 g, crude) in DMSO (9 mL) under nitrogen atmosphere were added KF (0.51 g, 8.77 mmol) and Intermediate 17 (0.65 g, 4.01 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (30 mL), extracted with DCM (3×30 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (440 mg, 25% yield for two steps) as a light yellow solid. MS: m/z=484.20 [M+H] +.

Step 3: (1R,7S)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane & (1S,7R)-6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azabicyclo[5.1.0]octane (440 mg, 0.81 mmol) was separated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRALPAK IF 2×25 cm, 5 μm; Mobile Phase A: Hexane (0.5% 2 M NH 3 -McOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 30% B; Detector: UV 220 nm & 254 nm; RTI: 10.889 min; RT2: 14.542 min. The first eluting peak (RT1: 10.889 min) was concentrated and lyophilized to give the title compound (Intermediate 39, 120 mg, 30% yield) as an off-white solid. MS: m/z=484.25 [M+H] + . The second eluting peak (RT2: 14.542 min) was concentrated and lyophilized to give the title compound (Intermediate 40, 120 mg, 30% yield) as an off-white solid. MS: m/z=484.2 [M+H] +.

To an ice-cooled mixture of morpholine (5 g, 57.39 mmol) and K 2 CO 3 (23.80 g, 172.17 mmol) in THF (50 mL) under nitrogen atmosphere was added CbzCl (11.75 g, 68.86 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with sat. aq. NaHCO 3 (500 mL) and extracted with EA (3×300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 35% EA in PE to afford the title compound (11 g, 86% yield) as a colorless oil. 1H-NMR (400 MHz, Chloroform-d) δ 7.39-7.31 (m, 5H), 5.15 (s, 2H), 3.66-3.49 (m, 8H).

To a solution of benzyl morpholine-4-carboxylate (10 g, 45.19 mmol) in MeOH (200 mL) was added tetraethylammonium tosylate (6.81 g, 22.59 mmol) at room temperature. The reaction mixture was electrolyzed at 20° C. for 28 hours using C(+)/C(−) electrodes at constant current 200 mA. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted 35% EA in PE to afford the title compound (8 g, 70% yield) as a light-yellow oil. 1H-NMR (400 MHz, Chloroform-d) $7.40-7.32 (m, 5H), 5.34-5.04 (m, 3H), 4.20-3.16 (m, 10H).

To an ice-cooled solution of benzyl 3-methoxymorpholine-4-carboxylate (8 g, 31.83 mmol) in DCM (90 mL) were added DIEA (5.35 g, 41.38 mmol) and TMSOTf (8.49 g, 38.20 mmol) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 0.5 hour. The resulting mixture was diluted with hexane (200 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE to afford the title compound (5 g, 71% yield). 1 H-NMR (400 MHZ, Chloroform-d) δ 7.57-7.32 (m, SH), 6.34-6.20 (m, 1H), 6.03-5.75 (m, 1H), 5.19 (d, J=4.0 Hz, 2H), 4.10-4.02 (m, 2H), 3.84-3.73 (m, 2H).

Step 4: Benzyl 7-bromo-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate To an ice-cooled solution of benzyl 2,3-dihydro-4/7-1,4-oxazine-4-carboxylate (5 g, 22.80 mmol) in DCM (15 mL) were added NaOH (25 mL, 50% aq.) and dibromofluoromethane (13124.32 mg, 68.41 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 38% EA in PE to afford the title compound (6 g, 79% yield) as a yellow oil. 1H-NMR (300 MHz, Chloroform-d) δ 7.45-7.33 (m, 5H), 5.31-5.19 (m, 2H), 4.26-3.79 (m, 2H), 3.75-3.60 (m, 1H), 3.50-3.29 (m, 3H).

Step 5: Benzyl-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (trans mixture) & benzyl 7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (cis mixture)

To a stirred solution of benzyl 7-bromo-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (5 g, 15.14 mmol) and NH 4 Cl (7290.71 mg, 136.29 mmol) in EtOH (23 mL) was added Zn (8911.32 mg, 136.29 mmol) at room temperature. The reaction mixture was stirred at 10° C. for 20 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 43% EA in PE to give two mixtures. The first eluting peak was concentrated to give the title compound (trans mixture) (Intermediate 41, 2.02 g, 53% yield) as a light yellow oil. JH NMR (400 MHZ, Chloroform-d) δ 7.42-7.31 (m, 5H), 5.28-5.16 (m, 2H), 4.59-4.43 (m, 1H), 4.06-3.96 (m, 1H), 3.73-3.61 (m, 2H), 3.34-3.19 (m, 3H). 19 F.-NMR (376 MHz, Chloroform-d) à-215.72-˜216.69 (m, F). The second eluting peak was concentrated to give the title compound (cis mixture) (Intermediate 42, 1.28 g, 33% yield) as a yellow oil. JH-NMR (400 MHz, Chloroform-d) δ 7.40-7.32 (m, 5H), 5.30-5.17 (m, 2H), 4.45-4.19 (m, 1H), 3.94-3.79 (m, 1H), 3.70-3.30 (m, 4H), 2.90-2.80 (m, 1H). 19 F-NMR (376 MHz, Chloroform-d) δ −240.93-−242.11 (m, 1F)

To an ice-cooled solution of Intermediate 41 (2.0 g, 7.96 mmol) in MeOH (100 mL) was added Pd/C(771.01 mg, 10% wt) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 40 min under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to afford the title compound (trans mixture) (750 mg, 80% yield, assumed 100% purity) as a light yellow oil.

Step 2: 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture)

To a stirred solution of 7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) (750 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1616.57 mg, 6.40 mmol) in DCM (16 mL) was added DIEA (2482.91 mg, 19.21 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (1: 1) to afford the title compound (trans mixture) (1.1 g, 51% yield) as a light yellow solid. MS: m/z=332.65 [M+H] +.

Step 2: 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture)

To a stirred solution of 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) (1.1 g, 3.30 mmol) in DMSO (11 mL) under nitrogen atmosphere were added KF (671.45 mg, 11.55 mmol) and Intermediate 17 (532.36 mg, 3.30 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (80 mL), and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (trans mixture) (600 mg, 39% yield) as a light yellow solid. MS: m/z=457.80 [M+H] +.

Step 3: (IS,6R, 7S)-5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5/)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane & (1R,65,7R)-5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-LH-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane 5-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-7-fluoro-2-oxa-5-azabicyclo[4.1.0]heptane (trans mixture) (600 mg, 1.31 mmol) was separated by Prep-SFC Column: CHIRAL ART Cellulose-SJ, 3×25 cm, 5 μm, Mobile Phase A: CO 2 ; Mobile Phase B: IPA (0.1% DEA); Flow rate: 100 mL/min; Gradient: isocratic 45% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 2.8 min; RT2: 4.7 min. The first eluting peak (RT1: 2.8 min) was concentrated and lyophilized to give the title compound (Intermediate 43, 110 mg, 18% yield) as a light yellow solid. MS: m/z=458.20 [M+H] + . The second eluting peak (RT2: 4.7 min) was concentrated and lyophilized to give the title compound (Intermediate 44, 110 mg, 18% yield) as a light yellow solid. MS: m/z=458.20 [M+H] +.

To a stirred solution of 1-bromo-2,4,5-trifluorobenzene (1.0 g, 4.74 mmol) in anhydrous EtzO (10 mL) was added n-BuLi (2.5 M in n-hexane, 2.27 mL, 5.69 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 0.5 hours. To the above mixture was added furan (3.2 g, 47.40 mmol) at −78° C., then stirred at −78° C. for 2 hours and additional 16 hours at room temperature. The resulting mixture was quenched with water (20 mL), extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with EA/PE (1/5) to afford the title compound (300 mg, 34% yield) as a yellow oil. MS: m/z=180.95 [M+H] + . 1 H NMR (300 MHz, CD 3 CN) δ 7.21-7.13 (m, 2H), 7.05-7.03 (m, 2H), 5.70-5.69 (m, 2H). 19 F NMR (282 MHz, CD 3 CN) 6 -144.99 (s, 2F).

To an ice-cooled solution of 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene (1.3 g, 7.22 mmol) in anhydrous DCM (15 mL) was added boron trifluoride diethyl etherate (1.07 g, 7.58 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by RP-Flash with the following conditions: column: C-18; Mobile phase A: Water; Mobile phase B: MeCN; Gradient: 10% B to 50% B in 20 min; Detector: UV 254 nm. The collected fractions were combined, concentrated, and then lyophilized overnight to afford the title compound (1.0 g, 76% yield) as a light yellow solid. MS: m/z=179.04 [M−H] + . JH NMR (400 MHZ, Chloroform-d) δ 7.96-7.91 (m, 1H), 7.54-7.52 (m, 1H), 7.36-7.37 (m, 2H), 6.80-6.78 (m, 1H), 5.24 (bs, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −136.83-−137.48 (m, 2F).

To a stirred solution of 6,7-difluoronaphthalen-1-ol (1.0 g, 5.55 mmol) in anhydrous 1,4-dioxane (10 mL) were added dichloro (p-cymene) ruthenium (II) dimer (336.80 mg, 0.55 mmol), (2-bromoethynyl)triisopropylsilane (1.52 g, 5.83 mmol) and KOAc (1.08 g, 11.10 mmol) at room temperature under argon atmosphere. The reaction mixture was heated at 110° C. for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with EA/PE (1/5) to afford the title compound (1.3 g, 65% yield) as a light yellow solid. MS: m/z=359.10 [M−H] + , 1 H NMR (300 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.55-7.49 (m, 1H), 7.41-7.38 (m, 1H), 7.35-7.27 (m, 1H), 7.00-6.97 (m, 1H), 1.29-1.16 (m, 21H). 19 F. NMR (282 MHZ, Chloroform-d) δ −131.53-−131.67 (m, 1F), −137.55-−137.63 (m, 1F).

To a stirred solution of 6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-ol (1.57 g, 4.36 mmol) in DCM (16 mL) were added N-ethyl-N-isopropylpropan-2-amine (2.25 g, 17.44 mmol) and trifluoromethanesulfonic anhydride (1.84 g, 6.54 mmol) at −40° C. under argon atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was quenched with saturated aq. NaHCO 3 (80 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford the title compound (1.6 g, 0.65 mmol, 76% yield) as a light yellow solid. 1 H NMR (300 MHz, Chloroform-d) δ 7.79-7.76 (m, 1H), 7.62-7.46 (m, 3H), 1.25-1.15 (m, 21H). 19 F. NMR (282 MHZ, Chloroform-d) δ −71.20 (s, 3F), −124.63-−124.71 (d, 1F), −134.16-−134.24 (d, 1F).

Step 5: ((2,3-Difluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl)triisopropylsilane

To a stirred mixture of 6,7-difluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (2.2 g, 4.46 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.40 g, 13.39 mmol) in 1,4-dioxane (44 mL) were added Pd (dppf)C 12 ·CH 2 Cl 2 (363.83 mg, 0.44 mmol) and KOAc (1.75 g, 17.86 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 110° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford the title compound (Intermediate 45,1.2 g, 57% yield) as a light yellow solid. 1 H NMR (400 MHZ, Chloroform-d) δ 7.78-7.74 (m, 2H), 7.54-7.42 (m, 2H), 1.43 (s, 12H), 1.27-1.13 (m, 21H).

To a stirred solution of 7-bromo-2,3-dihydro-1/-inden-1-one (3.5 g, 16.58 mmol) and TBAB (534.5 mg, 1.65 mmol) in toluene (40 mL) was added (bromodifluoromethyl)trimethylsilane (10.1 g, 49.74 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 110° C. for 16 hours. To the above solution was added TBAF (1 M in THE, 3.31 mL, 3.31 mmol) at room temperature, and then the mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with H 2 O (50 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (5: 1) to afford the title compound (2.8 g, 70% yield) as an off-white solid. MS: m/z=238.65, 240.65 [M−H] + . 1H NMR (300 MHz, DMSO-d 6 ) δ 10.11-10.10 (m, 1H), 7.90-7.86 (m, 1H), 7.78-7.75 (m, 1H), 7.54-7.45 (m, 2H), 7.30-7.24 (m, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) δ −135.81-−136.21 (m, 1 F).

To a solution of 8-bromo-2-fluoronaphthalen-1-ol (1.5 g, 6.22 mmol) in acetone (20 mL) were added K 2 CO 3 (1.28 g, 9.33 mmol) and iodomethane-d 3 (1.35 g, 9.33 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (5: 1) to afford the title compound (1.5 g, 93% yield) as a yellow semi-solid. 1 H NMR (300 MHZ, DMSO-d 6 ) δ 8.02-7.99 (m, 1H), 7.90-7.83 (m, 2H), 7.65-7.58 (m, 1H), 7.39-7.34 (m, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) õ-129.64 (s, 1F).

To a stirred solution of 8-bromo-2-fluoro-1-(methoxy-d 3 ) naphthalene (500 mg, 1.93 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (983.86 mg, 3.87 mmol) in 1,4-dioxane (5 mL) were added Pd (dppf)Cl 2 .DCM (155.16 mg, 0.19 mmol) and KOAc (570.29 mg, 5.811 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (7: 1) to afford the title compound (Intermediate 46, 510 mg, 86% yield) as a yellow solid. 3H NMR (300 MHz, DMSO-d 6 ) δ 7.96-7.93 (m, 1H), 7.74-7.69 (m, 1H), 7.54-7.45 (m, 3H), 1.37 (s, 12H). 19 F NMR (282 MHz, DMSO-d 6 ) δ −132.64 (s, 1F),

To a solution of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (30 g, 117 mmol) in toluene (400 mL) was added AlCl (39.2 g, 293 mmol). The mixture was stirred at 100° C. for 1 hr. After the reaction was cooled to 25° C., the mixture was poured into cold water (500 mL), and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜30% EtOAc in petroleum ether), the title compound (27.3 g, yield: 92%) was obtained as a yellow solid. MS: m/z=240.8, 242.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 10.67 (br s, 1H), 6.96 (d,)=2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 2.86 (t, J=6.0 Hz, 2H), 2.55-2.51 (m, 2H), 1.98-1.87 (m, 2H).

To a solution of 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1 (2H)-one (27.3 g, 113 mmol) in DMA (300 mL) was added NaOH (13.5 g, 339 mmol). The mixture was stirred at 20° C. for 1 hr. 2-Bromo-2-methylpropanamide (56.4 g, 339 mmol) was added, and the reaction mixture was stirred at 20° C. for 16 hr. Then NaOH (45.2 g, 1.13 mol) was added, and the resulting mixture was stirred at 50° C. for 3 hr. Then H 2 O (170 mL, 9.44 mol) was added, and the reaction mixture was stirred at 100° C. for another 2 hr. After the reaction was cooled to 25° C., the mixture was diluted with H 2 O (400 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with H 2 O (200 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜50% EtOAc in petroleum ether), the title compound (30 g, yield: 68%) was obtained as a yellow oil. MS: m/z=239.9, 241.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.73 (s, 1H), 6.36 (s, 1H), 6.22 (br s, 2H), 2.77-2.73 (m, 2H), 2.43 (t, J=6.4 Hz, 2H), 1.90-1.85 (m, 2H).

To a solution of 6-amino-8-bromo-3,4-dihydronaphthalen-1 (2H)-one (30 g, 124 mmol) in THE (500 mL) were added DMAP (1.53 g, 12.4 mmol) and BoczO (86 mL, 374 mmol). The mixture was stirred at 65° C. for 16 hr. The mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with H 2 O (200 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜5% EtOAc in petroleum ether), the title compound (16.2 g, yield: 28%) was obtained as a yellow oil. MS: m/z=461.9, 463.9 [M+Na] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 7.47 (d, J=1.6 Hz, 1H), 7.26 (d, J=1.6 Hz, 1H), 2.96 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 2.02-1.97 (m, 2H), 1.42 (s, 18H).

Step 4: tert-Butyl N-[(2E)-8-bromo-2-(hydroxymethylene)-1-oxo-tetralin-6-yl]-N-tert-butoxycarbonyl-carbamate

To a solution of tert-butyl N-(8-bromo-1-oxo-tetralin-6-yl)-N-tert-butoxycarbonyl-carbamate (5 g, 11.3 mmol) in THF (80 mL) was added NaH (908 mg, 22.7 mmol, 60% purity in oil) at 0° C. The mixture was stirred at 0° C. for 1 hr. Then HCOOEt (8 mL, 99.4 mmol) was added dropwise. The resulting mixture was stirred at 45° C. for 3 hr. The reaction mixture was quenched with saturated NH 4 Cl (30 mL) at 0° C. The resulting mixture was carefully neutralized with HCl (3 M) and the pH was adjusted to about 7. The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The title compound (5 g, crude) was obtained as a yellow solid. MS: m/z=367.9, 369.9 [M-100+H] + . 3H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.86-9.73 (m, 1H), 7.77-7.65 (m, 2H), 7.42-7.36 (m, 1H), 2.76-2.72 (m, 2H), 2.58-2.50 (m, 2H), 1.48 (s, 18H).

To a solution of tert-butyl N-[(2E)-8-bromo-2-(hydroxymethylene)-1-oxo-tetralin-6-yl]-N-tert-butoxycarbonyl-carbamate (5.5 g, 11.7 mmol) in AcOH (50 mL) was added NH 2 OH.HCl (1.63 g, 23.4 mmol). The mixture was stirred at 80° C. for 2 hr. The pH of the reaction was adjusted to about 7 with saturated NaHCO 3 . The mixture was extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The title compound (4 g, crude) was obtained as a brown solid. MS: m/z=264.8, 266.8 [M+H] +.

To a solution of 9-bromo-4,5-dihydronaphtho[2,1-d]isoxazol-7-amine (4 g, 7.54 mmol) in THF (30 mL) was added MeONa (1.63 g, 30.1 mmol). The mixture was stirred at 25° C. for 1 hr. The pH of the reaction mixture was adjusted to about 7 with HCl (IM). The mixture was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (30 mL×2) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜70% EtOAc in petroleum ether), the title compound (1.7 g, yield: 42% for three steps) was obtained as a yellow solid. MS: m/z=264.8, 266.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.79 (d, J=2.0 Hz, 1H), 6.50 (s, 2H), 6.36 (d, J=2.0 Hz, 1H), 4.29-4.23 (m, 1H), 2.97-2.87 (m, 1H), 2.86-2.78 (m, 1H), 2.37-2.29 (m, 1H), 2.26-2.14 (m, 1H).

To a solution of 6-amino-8-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (1.7 g, 6.41 mmol) in ACN (90 mL) was added PyBr3 (2.26 g, 7.05 mmol). The mixture was stirred at 70° C. for 0.5 hrs. The mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The title compound (2.2 g, crude) was obtained as a brown solid. MS: m/z=342.6, 344.6, 346.6 [M+H] +.

To a solution of 6-amino-2,8-dibromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (2.2 g, 6.40 mmol) in DMF (30 mL) was added LiBr (1.22 g, 14 mmol). The mixture was stirred at 100° C. for 1 hr. The mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜30% EtOAc in petroleum ether), the title compound (320 mg, yield: 18% for two steps) was obtained as a yellow solid. MS: m/z=262.8, 264.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) 10.66 (br s, 1H), 7.31-7.23 (m, 2H), 7.12 (d, J=8.8 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.03 (br s, 2H).

To a solution of 6-amino-8-bromo-1-hydroxy-2-naphthonitrile (300 mg, 1.14 mmol) in DMF (5 mL) was added K 2 CO 3 (315 mg, 2.28 mmol) and CD 3 I (85.2 mL, 1.37 mmol) at 0° C. The mixture was stirred at 20° C. for 1 hr. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜17% EtOAc in petroleum ether), the title compound (267 mg, yield: 78%) was obtained as a yellow solid. MS: m/z=279.8, 281.8 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 7.47-7.38 (m, 3H), 6.86 (d, J=2.0 Hz, 1H), 6.18 (br s, 2H).

To a solution of 6-amino-8-bromo-1-(methoxy-d 3 )-2-naphthonitrile (257 mg, 917 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (349 mg, 1.38 mmol) in 1,4-dioxane (4 mL) were added Cy3PPdGs (67.4 mg, 92 μmol) and KOAc (270 mg, 2.75 mmol). The mixture was degassed and purged with N 2 three times. The mixture was stirred at 100° C. for 1 hr under N 2 . The mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 100% CH 2 Cl 2 ), the title compound (Intermediate 47, 145 mg, yield: 46%) was obtained. MS: m/z=328.0 [M+H] + . 1H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.37 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 5.99 (br s, 2H), 1.35 (s, 12H).

To a solution of 4-bromo-2-fluoro-6-hydroxybenzonitrile (7 g, 32.4 mmol) in MeCN (70 mL) were added K 2 CO 3 (8.9 g, 64.8 mmol) and CD 3 I (9.2 g, 64.8 mmol) at 25° C. The mixture was stirred at 50° C. for 3 hr under N 2 . The reaction mixture was filtered concentrated under reduced pressure. The title compound (7 g, yield: 93%) was obtained as a white solid. MS: m/z=232.9, 234.9 [M+H] + . 3H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.48 (dd, J=8.8, 1.6 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −106.22.

To a solution of 4-bromo-2-fluoro-6-(methoxy-d 3 )benzonitrile (10 g, 42.9 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.6 g, 51.5 mmol) in THF (750 mL) were added Pd (PPh 3 ) 4 (5.0 g, 4.3 mmol) and CsF (20.0 g, 129 mmol). The mixture was degassed and purged with N 2 three times and stirred at 75° C. for 16 hr under N 2 . The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0˜5% of EtOAc in petroleum ether), the title compound (5.77 g, yield: 69%) was obtained as an off white solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.97 (s, 1H), 6.91 (d, J=10.0 Hz, 1H), 6.02-5,90 (m, 1H), 5.20-5.04 (m, 2H), 3.45 (d, J=6.8 Hz, 2H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −108.36.

To a solution of 4-allyl-2-fluoro-6-(methoxy-d 3 )benzonitrile (5 g, 25.7 mmol) in ACN (100 mL), H 2 O (150 mL) and EtOAc (100 mL) was added RuCl (0.5 g, 2.6 mmol) at 0° C. Then NaIO 4 (8.3 g, 38.6 mmol) was added in batches at 0° C. over 0.5 hr. The reaction mixture was stirred at 0° C. for 0.5 hr under N 2 atmosphere. The reaction mixture was poured into H 2 O (100 mL). The resulting mixture washed with EtOAc (500 mL×2). The pH of the combined aqueous phase was adjusted to 6 with 2 M HCl. The mixture was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The title compound (1.0 g, yield: 18%) was obtained as an off white solid. MS: m/z=423.1 [2M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 12.63 (s, 1H), 7.06 (s, 1H), 7.01 (d, J=10.0 Hz, 1H), 3.72 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −108.78.

To a solution of 2-(4-cyano-3-fluoro-5-(methoxy-d 3 )phenyl) acetic acid (1 g, 4.7 mmol) and KBr (2.8 g, 23.6 mmol) in H 2 O (10 mL) was added Br2 (0.6 mL, 11.8 mmol). The mixture was stirred at 50° C. for 2 hr. The reaction mixture was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure. The title compound (900 mg, yield: 63%) was obtained as an off white solid. MS: m/z=579.0, 581.0, 583.0 [2M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.24 (s, 1H), 3.76 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ−99.87,99.94.

Step 5: 3-Bromo-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-hydroxyethyl)-2-fluoro-6-(methoxy-d 3 )benzonitrile

To a solution of 2-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d 3 )phenyl) acetic acid (850 mg, 2.9 mmol) in ACN (8 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (463 mg, 3.2 mmol), DMAP (36 g, 293 μmol) and DIPEA (1.1 mL, 6.4 mmol). Then 1-BuCOCl (0.36 mL, 2.9 mmol) was added dropwise at 0° C. under N 2 . The resulting mixture was stirred at 25° C. for 1 hr under N2. The reaction mixture was quenched with 2M HCl (10 mL) at 0° C., and the precipitate was filtered and washed with water and dried under reduced pressure. The title compound (1.01 g, yield: 69%) was obtained as an off white solid. MS: m/z=414.9, 416.9 [M−H] − . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 7.23 (s, 1H), 4.56 (s, 2H), 4.03-3.95 (m, 1H), 1.65 (s, 6H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −99.76.

A solution of 3-bromo-4-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-hydroxyethyl)-2-fluoro-6-(methoxy-d 3 )benzonitrile (1.0 g, 2.4 mmol) in/-BuOH (25 mL) was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to afford the title compound (950 mg, yield: 88%) as an off white solid. MS: m/z=386.8, 388.8 [M−H] − . 1H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 7.20 (s, 1H), 4.19 (s, 2H), 3.64 (s, 2H), 1.42 (s, 9H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −99.35.

To a solution of ter-butyl 4-(2-bromo-4-cyano-3-fluoro-5-(methoxy-da)phenyl)-3-oxobutanoate (950 mg, 2.4 mmol) in CH 2 Cl 2 (3 mL) was added TFA (3.6 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (800 mg crude) as an off white solid. MS: m/z=330.9, 332.9 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 )δ 7.20 (s, 1H), 4.22 (s, 2H), 3.65 (s, 2H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −99.35.

A solution of 4-(2-bromo-4-cyano-3-fluoro-5-(methoxy-d 3 )phenyl)-3-oxobutanoic acid (800 mg, 2.4 mmol) in CF 3 SO 3 H (8 mL) was stirred at 25° C. for 16 hr. The reaction mixture was poured into ice water (10 mL). The precipitate was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure. The title compound (410 mg, yield: 47%) was obtained as a yellow solid. MS: m/z=313.0, 315.0 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 11.57-9.97 (m, 2H), 6.97 (d, J=2.0 Hz, 1H), 6.60 (d,)=2.0 Hz, 1H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −102.48.

To a solution of 4-bromo-3-fluoro-6,8-dihydroxy-1-(methoxy-da)-2-naphthonitrile (400 mg, 1.27 mmol) in MeOH (10 mL) was added Pd/C(135 mg, 10% purity). The mixture was degassed and purged with H 2 three times, and the mixture was stirred at 25° C. for 2 hr under H 2 atmosphere (15 psi). The mixture was filtered, and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give the title compound (300 mg) as an off white solid. MS: m/z=235.0 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 10.46 (s, 1H), 10.35 (s, 1H), 7.37 (d,)=11.2 Hz, 1H), 6.67 (d,)=2.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −114.93.

To a solution of 3-fluoro-6,8-dihydroxy-1-(methoxy-d 3 )-2-naphthonitrile (270 mg, 1.1 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl) sulfonyl) methanesulfonamide (837 mg, 2.3 mmol) in DMF (6 mL) were added DMAP (4 mg, 34 μmol) and TEA (256 mg, 2.5 mmol) at 0° C. The mixture was stirred at 0° C. under N 2 for 0.5 hr. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The title compound (450 mg crude) was obtained as an off white solid. MS: m/z=498.9 [M−H] − . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) 8.47 (d,)=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.09 (d, J=10.0 Hz, 1H).

Step 11: 7-Cyano-3-((diphenylmethylene)amino)-6-fluoro-8-(methoxy-d 3 ) naphthalen-1-yl trifluoromethanesulfonate

To a solution of 7-cyano-6-fluoro-8-(methoxy-d 3 ) naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (450 mg, 899 μmol) in 1,4-dioxane (40 mL) were added diphenylmethanimine (163 mg, 899 μmol), CszCO 3 (879 mg, 2.7 mmol) and XantPhosPdG3 (85 mg, 90 μmol). The mixture was stirred at 90° C. under N 2 for 2 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0˜20% EtOAc in petroleum ether), the title compound (300 mg, yield: 45%) was obtained as a yellow oil. MS: m/z=532.0 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.79-7.64 (m, 3H), 7.64-7.45 (m, 4H), 7.43-7.39 (m, 1H), 7.37-7.27 (m, 3H), 7.25-7.19 (m, 2H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −73.03, −110.67.

Step 12: 6-((Diphenylmethylene)amino)-3-fluoro-1-(methoxy-d 3 )-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthonitrile

To a solution of 7-cyano-3-((diphenylmethylene)amino)-6-fluoro-8-(methoxy-d 3 ) naphthalen-1-yl trifluoromethanesulfonate (280 mg, 527 μmol) in 1,4-dioxane (6 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (160 mg, 632 μmol), KOAc (155 mg, 1.6 mmol) and Cy3PPdG3 (34 mg, 52.7 μmol). The mixture was stirred at 100° C. under N 2 for 1 hr. The reaction mixture was concentrated under reduced pressure. After purification by silica gel flash chromatography (eluent of 0˜15% EtOAc in petroleum ether), the title compound (Intermediate 48, 135 mg, yield: 34%) was obtained as an off white solid. MS: m/z=510.2 [M+H] +.

To a solution of tert-butyl 3,4-dihydropyridine-1 (2H)-carboxylate (5.4 g, 29.5 mmol) in CH 2 Cl 2 (80 mL) was added diethylzinc (59.0 mL, 1 M in n-hexane) at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 . A solution of CH 2 I 2 (31.6 g, 39.2 mmol) in CH 2 Cl 2 (30 mL) was added dropwise to the mixture at 0° C. under N 2 , and the mixture was stirred at 20° C. for 3.5 h. The reaction mixture was quenched with sat. NH 4 Cl aq. (200 mL). The organic phase was separated and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜6% EtOAc in Petroleum ether) to give the title compound (3 g, 52% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ 3.82-3.55 (m, 1H), 2.90-2.70 (m, 1H), 2.68-2.44 (m, 1H), 1.87-1.71 (m, 211), 1.60-1.52 (m, 1H), 1.52-1.42 (m, 9H), 1.30-1.12 (m, 2H), 0.89-0.69 (m, 1H), 0.34-0.18 (m, 1H).

To a solution of tert-butyl 2-azabicyclo[4.1.0]heptane-2-carboxylate (1.4 g, 568 μmol) in CH 2 Cl 2 (20 mL) was added HCl (10 mL, 2M in EtOAc) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (900 mg, HCl salt) as a white solid, which was used in the next step without further purification.

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.70 g, 6.74 mmol) and DIPEA (3.52 mL, 20.21 mmol) in CH 2 Cl (20 mL) was added 2-azabicyclo[4.1.0]heptane (900 mg, 6.74 mmol, HCl salt) at −40° C. under N 2 . The mixture was stirred at −40° C. for 0.5 h under N2. The reaction mixture was diluted with water (30 mL) and extracted with CH 2 Cl (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.1 g, crude) as a yellow solid, which was used in the next step without further purification. MS: m/z=313.0 [M+H] +.

Step 4: 4-(2-Azabicyclo[4.1.0]heptan-2-yl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidine

To a solution of 4-(2-azabicyclo[4.1.0]heptan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (1.2 g, 3.83 mmol) and DIPEA (2.00 mL, 11.5 mmol) in 1,4-dioxane (15 mL) was added Intermediate 17 (1.11 g, 6.9 mmol). The mixture was stirred at 110° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 49, 1.57 g, 89% yield over 3 steps) as a yellow solid. MS: m/z=438.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) & 9.64-9.58 (m, 1H), 5.53-5.21 (m, 2H), 4.68 (d, J=14.0 Hz, 1H), 4.04-3.93 (m, 1H), 3.29-3.10 (m, 4H), 2.04-1.92 (m, 5H), 1.70-1.57 (m, 5H), 1.27-1.13 (m, 2H), 0.78-0.73 (m, 1H).

To a solution of NaOEt (854 mg, 12.6 mmol) in CH 2 Cl 2 (10 mL) were added tert-butyl 3,4-dihydropyridine-1 (2H)-carboxylate (1 g, 5.46 mmol) and ethyl 2,2-dibromo-2-fluoroacetate (2.88 g, 10.9 mmol). The mixture was stirred at 25° C. for 16 h under N 2 . The reaction mixture was diluted with H 2 O (50 mL) and extracted with CH 2 Cl 2 (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜6% of EtOAc in petroleum ether) to give the title compound (1.15 g, 74% yield) as a light-yellow oil. 1 H NMR (400 MHZ, Chloroform-d)δ 3.86-3.53 (m, 1H), 3.37-3.17 (m, 1H), 2.85-2.56 (m, 1H), 2.02-1.81 (m, 3H), 1.80-1.59 (m, 2H), 1.52 (d, J=2.4 Hz, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −130.36, −161.24.

Step 2: tert-Butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (cis mixture) & tert-butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (trans mixture)

To a suspension of Na (1.80 g, 78.2 mmol) in THF (15 mL) was added a solution of tert-butyl-7-bromo-7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.15 g, 3.91 mmol) in MeOH (5 mL) slowly at 0° C. under N 2 . During the addition, the reaction temperature was kept between 25° C. and 40° C. And the mixture was stirred at 25° C. for 2 h under N 2 . The reaction was quenched slowly with MeOH until the sodium metal disappeared completely. The temperature was maintained between 25° C. and 40° C. The reaction mixture was quenched with sat. NH 4 Cl aq. (50 mL) slowly at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0-4% of EtOAc in petroleum ether) to give the title compound (cis mixture) (Intermediate 50, 220 mg, 26% yield) as a colorless oil and the title compound (trans mixture) (Intermediate 51, 388 mg, 46% yield) as a colorless oil. Spectra for Example 50: 1H NMR (400 MHZ, Chloroform-d) δ 4.33-4.07 (m, 1H), 3.78-3.54 (m, 1H), 3.29-3.09 (m, 1H), 2.64-2.36 (m, 1H), 1,94-1.87 (m, 1H), 1.64-1.59 (m, 3H), 1.51-1.47 (m, 9H), 1.10-0.99 (m, 1H). 19 F NMR (376 MHZ, Chloroform-d) δ −208.77. Spectra for Intermediate 51: 1H NMR (400 MHz, Chloroform-d) δ 4.67-4.30 (m, 1H), 3.81-3.49 (m, 1H), 2.65 (s, 2H), 1.95-1.69 (m, 2H), 1.55-1.49 (m, 2H), 1.48 (s, 9H), 1.27-1.09 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −236.05, −236.30.

To a solution of Intermediate 51 (trans mixture) (388 mg, 1.80 mmol) in CH 2 Cl (2 mL) was added HCl (2 mL, 2M in EtOAc). The mixture was stirred at 20° C. for 2 h under N 2 . The reaction mixture was concentrated under reduced pressure to give the title compound (trans mixture) (200 mg, 96% yield) as a yellow oil.

Step 2: 2,7-Dichloro-8-fluoro-4-((trans)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (482 mg, 1.91 mmol) and DIPEA (1.2 mL, 898 mmol) in CH 2 Cl 2 (5 mL) was added 7-fluoro-2-azabicyclo[4.1.0]heptane (trans mixture) (200 mg, 1.74 mmol) at −40° C. under N 2 . The mixture was stirred at −40° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in petroleum ether) to give the title compound (trans mixture) (450 mg, 74% yield) as a yellow solid. MS: m/z=330.7 [M+H] +.

Step 3: 2,7-Dichloro-8-fluoro-4-((1R,6S,7R)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-y1)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1S,6R,7S)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine

2,7-Dichloro-8-fluoro-4-(7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine (400 mg, 1.21 mmol) was separated by SFC(column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2 O)]; B %: 25%, isocratic elution mode) to give the title compound (Intermediate 52, 150 mg, 37% yield, SFC Peak1: 1.524 min) as a yellow solid and the title compound (Intermediate 53, 120 mg, 30% yield, SFC Peak2: 1.631 min) as a yellow solid. Spectra for Intermediate 52: MS: m/z=330.7 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.51 (s, 1H), 4.72 (d, J=13.2 Hz, 1H), 4.68-4.49 (m, 1H), 3.61 (t, J=10.4 Hz, 1H), 2.81 (t, J=12.8 Hz, 1H), 2.19-1.83 (m, 4H), 1.31-1.24 (m, 1H), 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −131.70, −209.75. Spectra for Intermediate 53: MS: m/z=330.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) & 9.51 (s, 1H), 4.72 (d, J=13.2 Hz, 1H), 4.67-4.49 (m, 1H), 3.62 (t, J=10.4 Hz, 1H), 2.87-2.76 (m, 1H), 2.17-1.90 (m, 4H), 1.32-1.25 (m, 1H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −131.69, −209.73.

To a solution of azocan-2-one (15 g, 118 mmol) and (Boc) 2 O (28.3 g, 130 mmol) in dry THE (200 mL) was added DMAP (15.9 g, 130 mmol). The mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜30% EtOAc in petroleum ether) to give the title compound (18 g, 67% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d)δ 3.84-3.70 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.78 (m, 2H), 1.77-1.67 (m, 2H), 1.61-1.43 (m, 13H).

To a solution of tert-butyl 2-oxoazocane-1-carboxylate (18 g, 79.2 mmol) and diphenyl phosphorochloridate (31.92 g, 118.8 mmol) in THF (200 mL) was added dropwise KHMDS (95.04 mL, 1 M in THF) at −78° C. under N 2 . After addition, the mixture was stirred at −78° C. for 1 h under N 2 . The reaction mixture was diluted with sat. NH 4 Cl aq. (100 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in petroleum ether) to give the title compound (31 g, 85% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d) 8 7.37 -7.30 (m, 4H), 7.26-7.15 (m, 6H), 5.65-5.45 (m, 1H), 2.10-2.04 (m, 2H), 1.70-1.55 (m, 7H), 1.49-1.38 (m, 10H).

To a solution of tert-butyl (E)-8-((diphenoxyphosphoryl)oxy)-3,4,5,6-tetrahydroazocine-1 (2H)-carboxylate (20 g, 43.5 mmol) in DME (100 mL) were added triphenylphosphane (913 mg, 3.48 mmol) and Pd (OAc) 2 (391 mg, 1.74 mmol) at 25° C. under N 2 , and then a solution of TEA (13.2 g, 131 mmol) and formic acid (2.0 g, 43.5 mmol) in DME (60 mL) was added dropwise to the mixture at 25° C. under N 2 . The mixture was stirred at 85° C. for 40 min under N 2 . The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in petroleum ether) to give the title compound (8 g, 87% yield) as a brown oil. 1 H NMR (400 MHz, Chloroform-d) õ 6.78-6.51 (m, 1H), 4.85-4.63 (m, 1H), 3.78-3.68 (m, 2H), 2.35-2.27 (m, 2H), 1.81-1.72 (m, 2H), 1.66-1.55 (m, 4H), 1.47 (s, 9H).

To a solution of tert-butyl (Z)-3,4,5,6-tetrahydroazocine-1 (2H)-carboxylate (1 g, 4.73 mmol) in CH 2 Cl 2 (18 mL) was added diethylzinc (9.47 mL, 1 M in n-hexane). The mixture was stirred at 0° C. for 0.5 h under N 2 . A solution of CH 2 I 2 (5.07 g, 18.9 mmol) in CH 2 Cl 2 (9 mL) was added to the mixture dropwise at 0° C. under N 2 . The mixture was stirred at 20° C. for 2 h under N 2 . The reaction mixture was diluted with sat. NH 4 Cl aq. (50 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in petroleum ether) to give the title compound (160 mg, 15% yield) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) 4.09-3.95 (m, 1H), 2.80-2.67 (m, 1H), 2.22-2.13 (m, 1H), 2.03-1.93 (m, 1H), 1.83-1.70 (m, 1H), 1.69-1.63 (m, 1H), 1.61 (d, J=3.6 Hz, 1H), 1.50-1.41 (m, 12H), 1.04-0.97 (m, 1H), 0.92-0.77 (m, 2H), 0.72-0.62 (m, 1H).

To a solution of tert-butyl 2-azabicyclo[6.1.0]nonane-2-carboxylate (160 mg, 710 μmol) in CH 2 Cl 2 (2 mL) was added TFA (2 mL) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (90 mg, TFA salt) as a yellow oil, which was used in the next step without further purification.

Step 6: 4-(2-Azabicyclo[6.1.0]nonan-2-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (181 mg, 719 μmol) in CH 2 Cl 2 (2 mL) was added DIPEA (626 μL, 3.59 mmol) and 2-azabicyclo[6.1.0]nonane (90 mg, 719 μmol) at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with CH 2 Cl 2 (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (Intermediate 54, 270 mg, crude) as a yellow solid, which was used in the next step without further purification. MS: m/z=341.0 [M+H] +.

A mixture of NaOEt (3.70 g, 54.4 mmol) in CH 2 Cl 2 (70 mL) was degassed and purged with N 2 three times, then a solution of tert-butyl (Z)-3,4,5,6-tetrahydroazocine-1 (2H)-carboxylate (5 g, 23.7 mmol) in CH 2 Cl 2 (15 mL) was added dropwise into the reaction vessel at 0° C. under N 2 . Then a solution of ethyl 2,2-dibromo-2-fluoroacetate (6.56 g, 24.9 mmol) in CH 2 Cl 2 (15 mL) was added dropwise into the reaction vessel at 0° C. under N 2 , and then the mixture was stirred at 25° C. for 4 h under N 2 atmosphere. The reaction mixture was quenched with sat. NH 4 Cl aq. (200 mL) at 0° C. and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of EtOAc in Petroleum ether) to give the title compound (4.3 g, 51% yield) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) & 3.52-3.38 (m, 2H), 3.17-3.02 (m, 1H), 1.71-1.59 (m, 6H), 1.52-1.50 (m, 9H), 1.48-1.47 (m, 2H), 0.91-0.79 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −116.52, −117.00, −126.14, −126.25, −126.36, −126.38, −126.50, −156.61.

Step 2: tert-Butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (trans mixture) & fert-butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (cis mixture)

To a solution of Na (8.81 g, 383 mmol) in THF (100 mL) was added dropwise tert-butyl 9-bromo-9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (3.8 g, 11.8 mmol) in THE (20 mL) and MeOH (20 mL) at 25° C. under N 2 . Then MeOH (20 mL) was added dropwise at 35° C. under N 2 . The mixture was stirred at 40° C. for 2 h under N 2 . The reaction mixture was quenched with sat. NH 4 Cl aq. (200 mL) at 0° C. and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of EtOAc in Petroleum ether) to give the title compound (trans mixture) (Intermediate 55, 1.2 g, 42% yield) as a yellow oil and the title compound (cis mixture) (Intermediate 56, 980 mg, 34% yield) as a yellow oil. Spectra for Intermediate 55: 1H NMR (400 MHz, Chloroform-d) δ 4.78-4.51 (m, 1H), 4.01-3.89 (m, 1H), 2.78-2.68 (m, 1H), 2.61-2.48 (m, 1H), 2.10-1.98 (m, 1H), 1.80-1.58 (m, 3H), 1.56-1.52 (m, 1H), 1.50-1.48 (m, 1H), 1.47 (s, 9H), 1.43-1.38 (m, 1H), 1.30-1.19 (m, 1H), 0.93-0.78 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −206.13, −206.23, −206.26. Spectra for Intermediate 56: 3H NMR (400 MHZ, Chloroform-d)δ 5.33-5.03 (m, 1H), 4.04-3.89 (m, 1H), 3.51-3.34 (m, 1H), 3.03-2.95 (m, 1H), 2.25-2.10 (m, 1H), 1.81-1.74 (m, 3H), 1.60-1.54 (m, 3H), 1.45-1.43 (m, 9H), 1.40-1.39 (m, 1H), 0.91-0.76 (m, 1H), 19 F. NMR (376 MHz, Chloroform-d) δ −233.86.

To a solution of tert-butyl 9-fluoro-2-azabicyclo[6.1.0]nonane-2-carboxylate (trans mixture) (1.1 g, 4.52 mmol) in CH 2 Cl 2 (15 mL) was added TFA (6 mL, 81.4 mmol) at 0° C. The mixture was stirred at 20° C. for 0.1 h. The residue was concentrated under reduced pressure to give the title compound (trans mixture) (1.1 g, TFA salt) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHZ, Chloroform-d)δ 4.79-4.41 (m, 1H), 3.43-3.28 (m, 1H), 3.18-3.03 (m, 1H), 2.98-2.80 (m, 1H), 2.44-2.34 (m, 1H), 2.00-1.78 (m, 3H), 1.77-1.64 (m, 2H), 1.61-1.43 (m, 2H), 1.26-1.10 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −76.00, −209.31.

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.08 g, 4.28 mmol) in CH 2 Cl 2 (6 mL) were added DIPEA (3.72 mL, 21.4 mmol) and 9-fluoro-2-azabicyclo[6.1.0]nonane (trans mixture) (1.1 g, 4.28 mmol, TFA salt) at −40° C. under N 2 . The mixture was stirred at −40° C. for 1 h under N 2 . The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in Petroleum ether) to give the title compound (865 mg, 54% yield).

Step 3: 2,7-Dichloro-8-fluoro-4-((1R,85,9R)-9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-dichloro-8-fluoro-4-((1S,8R,9S)-9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3-d]pyrimidine

2,7-Dichloro-8-fluoro-4-(9-fluoro-2-azabicyclo[6.1.0]nonan-2-yl)pyrido[4,3-d]pyrimidine (trans mixture) (300 mg) was separated by SFC(column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -i-PrOH (0.1% NH 3 H 2 O)]; B %: 35%, isocratic elution mode) to give the title compound (Intermediate 57, 123 mg, SFC peak 1: 1.253 min) as a yellow solid and the title compound (Intermediate 58, 122 mg, SFC peak 2: 1.618 min) as a yellow solid. Spectra for Intermediate 57: MS: m/z=359.0 [M+H] + . Spectra for Intermediate 57: MS: m/z=358.9 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.19 (s, 1H), 4.49-4.31 (m, 2H), 3.96-3.77 (m, 1H), 3.32-3.28 (m, 1H), 2.00-1.48 (m, 7H), 1.43-1.33 (m, 1H), 0.84-0.69 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 )-135.87, −208.10. Spectra for Intermediate 58: MS: m/z=359.0 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.19 (s, 1H), 4.51-4.38 (m, 1H), 4.34-4.27 (m, 1H), 3.93-3.81 (m, 1H), 3.31-3.26 (m, 1H), 1.96-1.51 (m, 7H), 1.43-1.31 (m, 1H), 0.84-0.68 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) −135.87, −208.09.

To a mixture of tert-butyl 7-fluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (cis mixture) (220 mg, 1.02 mmol) in CH 2 Cl 2 (2 mL) was added HCl (2 mL, 2M in EtOAc). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (cis mixture) (117 mg, HCl salt) as a white solid, which was used in the next step without further purification.

Step 2: 2,7-Dichloro-8-fluoro-4-((cis)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine (cis mixture)

To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (282 mg, 1.12 mmol) and DIPEA (708 μL, 4.06 mmol) in CH 2 Cl 2 (5 mL) was added 7-fluoro-2-azabicyclo[4.1.0]heptane (cis mixture) (117 mg, 1.02 mmol) at −40° C. under N 2 . The mixture was stirred at −40° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜24% of EtOAc in petroleum ether) to give the title compound (cis mixture) (260 mg, 77% yield over 2 steps) as a yellow solid. MS: m/z=331.0 [M+H] +.

Step 3: 2,7-Dichloro-8-fluoro-4-((1S,6R,7R)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1R,6S,7S)-7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine

2,7-Dichloro-8-fluoro-4-(7-fluoro-2-azabicyclo[4.1.0]heptan-2-yl)pyrido[4,3-d]pyrimidine (cis mixture) (260 mg, 785 μmol) was separated by SFC(column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2 O)]; B %: 40%, isocratic elution mode) to give the title compound (Intermediate 59, 90 mg, 35% yield, SFC Peak 1; 1.819 min) as a yellow solid and the title compound (Intermediate 60, 70 mg, 27% yield, SFC Peak 2: 2.174 min) as a yellow solid. Spectra for Intermediate 59: MS: m/z=330.9 [M+H] + . 1 HNMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.74 (s, 1H), 5.19-4.92 (m, 1H), 4.73-4.57 (m, 1H), 3.81-3.64 (m, 1H), 3.14-2.94 (m, 1H), 2.17-2.02 (m, 1H), 1.84-1.63 (m, 3H), 1.50-1.35 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −134.36, −232.37. Spectra for Intermediate 60: MS: m/z=330.8 [M+H] + . 1 HNMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.74 (s, 1H), 5.17-4.94 (m, 1H), 4.74-4.55 (m, 1H), 3.81-3.65 (m, 1H), 3.13-2.94 (m, 1H), 2.17-1.99 (m, 1H), 1.84-1.66 (m, 3H), 1.51-1.36 (m, 1H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −134.36, −232.38.

To a solution of 5-bromo-1,2-difluoro-3-methoxybenzene (20 g, 89.7 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.1 g, 179 mmol) in THF (2 L) were added Pd (PPh 3 ) 4 (10.36 g, 8.97 mmol) and CsF (40.9 g, 269 mmol). The mixture was degassed, purged with N 2 three times, and stirred at 75° C. for 16 h under N 2 . The reaction mixture concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% of EtOAc in Petroleum ether) to give the title compound (35 g, 71% yield) as a colorless oil. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.65-6.53 (m, 2H), 5.97-5.82 (m, 1H), 5.17-5.03 (m, 2H), 3.91-3.88 (m, 3H), 3.32 (d, J=6.4 Hz, 2H).

To a solution of 5-allyl-1,2-difluoro-3-methoxybenzene (28 g, 152 mmol) in ACN (380 mL), H 2 O (540 mL) and EtOAc (380 mL) was added RuCl (6.31 g, 30.4 mmol) at 0° C. under N 2 atmosphere. Then NaIO 4 (130 g, 608 mmol) was added in batches at 0° C. under N 2 atmosphere over 1 h. The reaction mixture was stirred at 0° C. for 1 h under N 2 atmosphere, filtered and the filter cake was washed with EtOAc (500 mL). The filtrate was extracted with EtOAc (500 mL×3). The combined organic phases were washed with NazS2O3 (100 mL) and brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (21 g, 68% yield) as a brown solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 12.57-12.26 (m, 1H), 6.97-6.81 (m, 2H), 3.85 (s, 3H), 3.58 (s, 2H).

To a solution of 2-(3,4-difluoro-5-methoxyphenyl) acetic acid (21 g, 104 mmol) in acetic acid (80 mL) was added bromine (7.49 mL, 145.3 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (300 mL) and quenched with sat. NazS203 aq. (50 mL). The precipitate was filtered. The filter cake was washed with water (300 mL) and dried under reduced pressure to give the title compound (28.59 g, 98% yield) as a light yellow solid. 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 12.6 (br s, 1H), 7.27-7.16 (m, 1H), 3.87 (s, 3H), 3.75 (s, 2H).

Step 4: 5-(2-(2-Bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a solution of 2-(2-bromo-3,4-difluoro-5-methoxyphenyl) acetic acid (28.6 g, 101.7 mmol) in ACN (200 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (16.1 g, 111.9 mmol), DMAP (1.24 g, 10.1 mmol) and DIPEA (39.0 mL, 223.8 mmol). Then f-BuCOCl (12.5 mL, 101.7 mmol) was added dropwise at 0° C. under N 2 . The mixture was stirred at 25° C. for 3 h under N 2 . The reaction mixture was quenched with 2N HCl (400 mL), and the precipitate was filtered and washed with water and dried under reduced pressure to give the title compound (28.5 g, 69% yield) as a brown solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.23-7.15 (m, 1H), 4.52 (s, 2H), 3.87 (s, 3H), 1.69 (s, 6H).

A solution of 5-(2-(2-bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (28.5 g, 70.0 mmol) in/-BuOH (300 mL) was stirred at 90° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (26 g, crude) as a brown solid. MS: m/z=377.0 [M−H] −.

To a solution of tert-butyl 5-(2-(2-bromo-3,4-difluoro-5-methoxyphenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (26 g, 68.6 mmol) in CH 2 Cl 2 (50 mL) was added TFA (50 mL). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (22 g, crude) as a brown solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 12.9 (br s, 1H), 7.11 (d, J=7.2 Hz, 1H), 4.08 (s, 2H), 3.86 (s, 3H), 3.60 (s, 2H).

A solution of 4-(2-bromo-3,4-difluoro-5-methoxyphenyl)-3-oxobutanoic acid (22 g, 68.1 mmol) in CF 3 SO 3 H (50 mL) was stirred at 25° C. for 16 h. The reaction mixture was poured into ice water (500 mL). The precipitate was filtered. The filter cake was washed with water (200 mL) and dried under reduced pressure to give the title compound (19 g, crude) as a brown solid. 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 10.11 (s, 1H), 10.03 (s, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 3.96 (s, 3H).

To a solution of 5-bromo-6,7-difluoro-8-methoxynaphthalene-1,3-diol (19 g, 62.28 mmol) in MeOH (100 mL) was added Pd/C(2.65 g, 12.46 mmol, 10% purity). The mixture was degassed, purged with H 2 three times, and stirred at 25° C. for 2 h under Hz atmosphere (15 psi). The mixture was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜13% EtOAc in Petroleum ether) to give the title compound (10 g, 67% yield over 4 steps) as a white solid. MS: m/z=224.9 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.70 (d, J=14 Hz, 2H), 7.36 (dd, J=7.6, 12 Hz, 1H), 6.62-6.42 (m, 2H), 3.96 (s, 3H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −137.25, −137.31, −162.68, −162.74.

To a solution of 6,7-difluoro-8-methoxynaphthalene-1,3-diol (5 g, 22.1 mmol) and DIPEA (17.1 g, 132 mmol) in CH 2 Cl 2 (50 mL) was added Tf2O (24.9 g, 88.4 mmol) at 0° C. The mixture was stirred at 0° C. under N 2 for 0.5 h. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜1% EtOAc in petroleum ether) to give the title compound (9.65 g, 88% yield) as a white solid. MS: m/z=489.0 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.39 (d, J=2.4 Hz, 1H), 8.13-8.08 (m, 1H), 8.01 (s, 1H), 4.07 (d, J=2.0 Hz, 3H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −72.38, −72.87, −130.44, −130.49, −149.38, −149.43.

Step 10: 3-((Diphenylmethylene)amino)-6,7-difluoro-8-methoxynaphthalen-1-yl trifluoromethanesulfonate

To a solution of 6,7-difluoro-8-methoxynaphthalene-1,3-diyl bis(trifluoromethanesulfonate) (9.65 g, 19.6 mmol) in 1,4-dioxane (80 mL) were added diphenylmethanimine (3.57 g, 19.6 mmol), Cs 2 CO 3 (19.2 g, 59.0 mmol) and XantPhosPdG3 (1.87 g, 1.97 mmol). The mixture was stirred at 80° C. under N 2 for 1 h. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% EtOAc in petroleum ether) to give the title compound (7.67 g, 12.3 mmol, 63% yield) as a yellow oil. MS: m/z=522.4 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 )δ 7.76-7.66 (m, 4H), 7.61-7.47 (m, 4H), 7.32-7.31 (m, 2H), 7.21-7.20 (m, 2H), 7.08 (s, 1H), 3.99 (d, J=1.6 Hz, 3H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −73.17, −133.48, −154.36, −154.42.

Step 11: N-(6,7-difluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl)-1,1-diphenylmethanimine

To a solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8-methoxynaphthalen-1-yl trifluoromethanesulfonate (7.67 g, 14.7 mmol) in DMA (60 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.48 g, 17.6 mmol), AcOK (4.33 g, 44.1 mmol) and CysPPdG3 (956 mg, 1.47 mmol). The mixture was stirred at 100° C. under N 2 for 1 h. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% EtOAc in petroleum ether) to give the title compound (5.88 g, 78% yield) as a yellow solid. MS: m/z=500.0 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.71-7.66 (m, 2H), 7.58-7.53 (m, 1H), 7.51-7.41 (m, 3H), 7.31-7.30 (m, 3H), 7.21-7.14 (m, 3H), 6.91 (s, 1H), 4.03 (d, J=2.0 Hz, 3H), 1.31 (s, 12H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.65, −157.78.

To a solution of N-(6,7-difluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl)-1,1-diphenylmethanimine (2 g, 4.01 mmol) in 1,4-dioxane (200 mL) was added a solution of CuBrz (894 mg, 4.01 mmol) in H 2 O (100 mL). The mixture was stirred at 100° C. under N 2 for 4 h. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in petroleum ether) to give the title compound (760 mg, 56% yield) as a brown solid. MS: m/z=287.9 [M+H] + . 1H NMR (400 MHz, Dimethylsulfoxide-d 6 ) $7.40-7.35 (m, 1H), 7.31 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 5.72 (s, 2H), 3.89 (s, 3H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −136.22, −136.28, −160.13, −160.19.

BBr3 (S mL, 2 M in CH 2 Cl 2 ) was added to 4-bromo-6,7-difluoro-5-methoxynaphthalen-2-amine (760 mg, 2.64 mmol) at 0° C. under N 2 . The mixture was stirred at 25° C. under N 2 for 1 h. The reaction mixture was quenched with H 2 O (50 mL) at 25° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (708 mg, 88% yield) as a brown solid. MS: m/z=273.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) § 10.38 (s, 1H), 7.20 (d, J=1.6 Hz, 1H), 7.03-6.98 (m, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.05-5.13 (br d, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.93, −166.53, −166.59.

To a solution of 6-amino-8-bromo-2,3-difluoronaphthalen-1-ol (290 mg, 1.06 mmol) in ACN (30 mL) were added Cs2CO 3 (1.03 g, 3.17 mmol) and bromo (fluoro) methane (119 mg, 1.06 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜8% EtOAc in petroleum ether) to give the title compound (236 mg, 66% yield) as a white solid. MS: m/z=305.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.57-7.52 (m, 1H), 7.36 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.85 (s, 1H), 5.80 (s, 2H), 5.71 (s, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) 6-136.10, —136.16, −151.06, −151.10, −157.09, −157.15.

Step 15: 6,7-Difluoro-S-(fluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

To a solution of 4-bromo-6,7-difluoro-5-(fluoromethoxy) naphthalen-2-amine (225 mg, 735 μmol) in 1,4-dioxane (4 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (224 mg, 882 μmol), K3PO4 (468 mg, 2.21 mmol) and Cy3PPdG3 (47 mg, 73.5 μmol). The mixture was stirred at 100° C. under N 2 for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% EtOAc in petroleum ether) to give the title compound (Intermediate 61, 200 mg, 49% yield) as a brown oil. MS: m/z=353.8 [M+H] + . 1H NMR (400 MHz, Dimethylsulfoxide-d 6 ) & 7.39 (dd, J=7.6, 12.0 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 5.86 (s, 1H), 5.73 (s, 1H), 5.60 (s, 2H), 1.34 (s, 12H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −137.84, −137.90, −148.28, −162.18, −162.24.

To a solution of 6-amino-8-bromo-2,3-difluoronaphthalen-1-ol (300 mg, 1.09 mmol, refer to Intermediate 61 for detail procedures) in MeOH (3 mL) was added BoczO (360 mg, 1.64 mmol) at 25° C. The mixture was stirred at 70° C. for 1 h under N 2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜4% of EtO Ac in petroleum ether) to give the title compound (400 mg, 84% yield) as a brown solid. MS: m/z=317.8 [M+H-Bu] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) 10.75 (s, 1H), 9.67 (s, 1H), 7.97 (s, 1H), 7.80 (d,.J=1.6 Hz, 1H), 7.34 (dd, J=7.6, 11.2 Hz, 1H), 1.49 (s, 9H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −135.57, −162.03.

To a solution of tert-butyl (4-bromo-6,7-difluoro-S-hydroxynaphthalen-2-yl) carbamate (300 mg, 802 μmol) in DMF (1 mL) were added K 2 CO 3 (167 mg, 1.20 mmol) and sodium (I) 2 -chloro-2,2-difluoroacetate (135 mg, 882 μmol) at 25° C. under N 2 atmosphere. The mixture was stirred at 70° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0˜4% EtOAc in petroleum ether) to give the title compund (220 mg, 63% yield) as a yellow oil. MS: m/z=325.8 [M+H-Boc] + . JH NMR (400 MHZ, Dimethylsulfoxide-d 6 ) õ 9.86 (s, 1H), 8.20 (s, 1H), 8.04 (dd, J=8.0, 11.2 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.28 (t, J=72.8 Hz, 1H), 1.51 (s, 9H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −82.54, −134.56, −134.63, −149.89, −149.92.

Step 3: tert-Butyl (5-(difluoromethoxy)-6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) carbamate

A mixture of tert-butyl (4-bromo-5-(difluoromethoxy)-6,7-difluoronaphthalen-2-yl) carbamate (210 mg, 495 μmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (151 mg, 595 μmol), Cy3P-Pd-G3 (33 mg, 49.5 μmol) and K 3 PO 4 (316 mg, 1.49 mmol) in 1,4-dioxane (2 mL) was degassed and purged with N 2 three times. The mixture was stirred at 100° C. for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜3% EtOAc in petroleum ether) to give the title compound (140 mg, 59% yield) as a yellow solid. MS: m/z=494.0 [M+Na] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.71 (s, 1H), 8.23 (d, J=1.2 Hz, 1H), 7.90 (dd, J=8.0, 11.6 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.26 (t, J=71.2 Hz, 1H), 1.50 (s, 9H), 1.35 (s, 12H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −80.36, −80.39, −136.38, −136.44, −154.38, −154.40

Step 4: 5-(Difluoromethoxy)-6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

To a mixture of tert-butyl (5-(difluoromethoxy)-6,7-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) carbamate (120 mg, 255 μmol) in HCl (2M in EtOAc, 2 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 62, 95 mg, crude) as a yellow oil, which was used in the next step without further purification. MS: m/z=371.8 [M+H] +.

To a solution of 5-bromo-2,3-difluorophenol (20 g, 95.7 mmol) in DMF (200 mL) was added K2CO 3 (40 g, 287 mmol) at 0° C. under N 2 . Then trideuterio (iodo) methane (6.42 mL, 105 mmol) in DMF (200 mL) was added dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 h under N 2 . The mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in petroleum ether) to give the title compound (33.2 g, 77% yield) as a colorless oil. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) 8 7.37 -7.30 (m, 1H), 7.28-7.23 (m, 1H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.30,-136.97, −161.52, −161.58.

A mixture of 5-bromo-1,2-difluoro-3-(methoxy-d 3 )benzene (33.2 g, 147 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (49 g, 294 mmol), CsF (67 g, 441 mmol) and Pd (PPb3) 4 (7.49 g, 7.35 mmol) in THF (2500 mL) was degassed and purged with N 2 three times, and then the mixture was refluxed for 16 h under N 2 atmosphere. The mixture was diluted with H 2 O (500 mL) and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtO Ac in petroleum ether) to give the title compound (24.6 g, 89% yield) as a yellow oil. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.88-6.75 (m, 2H), 6.01-5.87 (m, 1H), 5.16-5.03 (m, 2H), 3.33-3.31 (m, 2H), 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −138.91, −138.97, −164.48, −164.54.

To a solution of 5-allyl-1,2-difluoro-3-(methoxy-d 3 )benzene (24.58 g, 131 mmol) in ACN (320 mL), EtOAc (320 mL) and H 2 O (520 mL) was added RuCl (5.45 g, 26.3 mmol) at 0° C. Then NaIO 4 (98 g, 458 mmol) was added slowly over 1 h while the reaction temperature was maintained between 0 and 10° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was quenched with sat. NazS2O3 aq. (200 mL) and extracted with EtOAc (200 mL×2). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (500 mL) at 25° C. for 10 min and filtered. The filter cake was washed with petroleum ether (100 mL), dried under reduced pressure to give the title compound (19.8 g, 74% yield) as a black brown solid. JH NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 12.51 (br s, 1H), 7.05-6.77 (m, 2H), 3.57 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −139.27, −139.32, −163.80, −163.86.

To a solution of 2-(3,4-difluoro-5-(methoxy-d 3 )phenyl) acetic acid (18 g, 87.7 mmol) in acetic acid (80 mL) was added Brz (6 mL, 116 mmol) at 0° C. The mixture was stirred at 20° C. for 3 h. The reaction mixture was quenched with water (160 mL) and sat. NazS2O3 aq. (15 mL) at 25° C. The precipitate was filtered, and the filter cake was washed with water (100 mL) and dried under reduced pressure to give the title compound (18 g, 66% yield, confirmed by 2D-NMR) as an off-white solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 12.57 (br s, 1H), 7.21-7.17 (m, 1H), 3.74 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −129.18, −129.24, −158.38, −158.43.

Step 5: 5-(2-(2-Bromo-3,4-difluoro-5-(methoxy-d 3 )phenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a solution of 2-(2-bromo-3,4-difluoro-5-(methoxy-d 3 )phenyl) acetic acid (18 g, 63.4 mmol) in ACN (180 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 69.7 mmol), DMAP (774 mg, 6.34 mmol) and DIPEA (24 mL, 139 mmol). Then/-BuCOCl (7.80 mL, 63.4 mmol) was added dropwise at 0° C. under N 2 . The mixture was stirred at 20° C. for 3 h under N 2 . The reaction mixture was quenched with HCl (200 mL, IN in water) at 0° C. The precipitate was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure to give the title compound (21.3 g, 80% yield) as a white solid. MS: m/z=409.9 [M−H] − . 1 H NMR (400 MHz, Chloroform-d) δ 15.50 (br s, 1H), 6.79-6.72 (m, 1H), 4.58 (s, 2H), 1.77 (s, 6H). 19 F NMR. (376 MHz, Chloroform-d) δ −125.87,˜125.93, −155.82, −155,87.

A mixture of 5-(2-(2-bromo-3,4-difluoro-5-(methoxy-d 3 )phenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (21.3 g, 43.1 mmol) in t-BuOH (500 mL) was degassed and purged with N 2 three times. The mixture was stirred at 90° C. for 2 h under N 2 atmosphere. The reaction mixture was concentrated to give the title compound (18 g, crude) as a brown solid, which was used in the next step without further purification. MS: m/z=380.0, 382.0 [M−H] −.

To a solution of tert-butyl 4-(2-bromo-3,4-difluoro-5-(methoxy-d 3 )phenyl)-3-oxobutanoate (18 g, 41.4 mmol) in CH 2 Cl 2 (50 mL) was added TFA (66.0 mL, 888 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (18 g, crude) as a black brown solid, which was used in the next step without further purification. MS: m/z=279.7 [M-COOH].

A solution of 4-(2-bromo-3,4-difluoro-5-(methoxy-d 3 )phenyl)-3-oxobutanoic acid (18 g, 55.2 mmol) in trifluoromethanesulfonic acid (150 mL) was stirred at 20° C. for 16 h. The reaction mixture was poured into ice water (200 mL) slowly. The precipitate was filtered, and the filter cake was washed with water (50 ml×3), sat. NaHCO 3 aq. (50 mL), water (50 ml) in sequence, dried under reduced pressure to give the title compound (12 g, 65% yield over 3 steps) as a black brown solid. MS: m/z=307.8 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) & 10.12 (s, 1H), 10.03 (s, 1H), 6.91 (d, J=2 Hz, 1H), 6.55 (d, J=2 Hz, 1H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −124.36, −124.42, −160.23, −160.29.

To a solution of 5-bromo-6,7-difluoro-8-(methoxy-d 3 ) naphthalene-1,3-diol (12 g, 38.9 mmol) in MeOH (120 mL) was added Pd/C(4.15 g, 3.89 mmol, 10% purity) under N 2 . The mixture was degassed, purged with Hz three times, and stirred at 25° C. for 2 h under Hz atmosphere (15 psi). The mixture was filtered, washed with MeOH (100 mL), and concentrated. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtO Ac in petroleum ether) to give the title compound (7.6 g, 77% yield) as a white solid. MS: m/z=227.9 [M−H] − . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.71 (s, 2H), 7.39-7.32 (m, 1H), 6.59 (d, J=2 Hz, 1H), 6.46 (d,.J=1.6 Hz, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −137.25, −137.30, −162.73, −162.79.

To a solution of 6,7-difluoro-8-(trideuteriomethoxy) naphthalene-1,3-diol (7.6 g, 33.16 mmol) and DIPEA (35 mL, 199 mmol) in CH 2 Cl 2 (140 mL) was added dropwise Tf2O (22 mL, 133 mmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 1 h under N 2 atmosphere. The reaction mixture was quenched with H 2 O (140 mL) and extracted with CH 2 Cl 2 (140 mL×3). The combined organic layers were washed with brine (280 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜4% of CH 2 Cl 2 in petroleum ether) to give the title compound (14.9 g, 91% yield) as a yellow solid. MS: m/z=491.7 [M−H] − . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.39 (d,.J=2.4 Hz, 1H), 8.13-8.06 (m, 1H), 8.01 (d, J=1.6 Hz, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) 6 -72.45, −72.95, −130.51, −130.56, −149.54, −149.60.

Step 11: 3-((Diphenylmethylene)amino)-6,7-difluoro-8-(methoxy-d 3 ) naphthalen-1-yl trifluoromethanesulfonate

A solution of 6,7-difluoro-8-(methoxy-d′3) naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (9.3 g, 18.9 mmol), diphenylmethanimine (3.16 mL, 18.9 mmol), Cs 2 CO 3 (18.4 g, 56.56 mmol) and XantPhosPdG3 (900 mg, 0.95 mmol) in 1,4-dioxane (180 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 80° C. under N 2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (cluent: 0˜4% of EtOAc in petroleum ether) to give the title compound (4 g, 70% yield) as a yellow oil. MS: m/z=525.1 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.77-7.63 (m, 4H), 7.63-7.47 (m, 4H), 7.35 (d, J=2.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.22-7.19 (m, 1H), 7.09 (s, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −73.20, −133.44, −133.49, −154.47, −154.52.

Step 12: N-(6,7-difluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl)-1,1-diphenylmethanimine

A solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8-(methoxy-d 3 ) naphthalen-1-yl trifluoromethanesulfonate (4 g, 7.63 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (2.32 g, 9.15 mmol), AcOK (2.25 g, 22.9 mmol), and Cy3PPdG3 (496 mg, 763 μmol) in DMA (50 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 100° C. under N 2 for 1 h. The reaction mixture was diluted with H 2 O (150 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (75 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (8 g, crude) as a black brown oil, which was used into the next step without further purification. MS: m/z=502.9 [M+H].

Step 13: 6,7-Difluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

To a solution of N-(6,7-difluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl)-1,1-diphenylmetbanimine (18 g, 16.1 mmol) in EtOH (135 mL) were added hydroxylamine hydrochloride (2.24 g, 32.3 mmol) and AcOK (4.75 g, 48.4 mmol). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in petroleum ether) to give the title compound (Intermediate 63, 4.4 g, 76% yield over 2 steps) as a yellow solid. MS: m/z=338.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.27-7.19 (m, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 5.51 (s, 2H), 1.34 (s, 12H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −138.12, −138.18, −163.21, −163.26.

To a solution of 2-(2,3,4-trifluorophenyl) acetic acid (25 g, 131.50 mmol) in ACN (250 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (20.9 g, 145 mmol), DMAP (1.61 g, 13.2 mmol) and DIPEA (50.4 mL, 289 mmol). Then/-BuCOCl (16.2 mL, 132 mmol) was added dropwise at 0° C. The mixture was stirred at 20° C. for 1 h. IN HCl (800 mL) was added dropwise to the mixture until a lot of solid appeared. Then the precipitate was filtered, washed with water (800 mL) and dried under reduced pressure to give the title compound (38 g, 91% yield) as an off-white solid, which was used in the next step without further purification. 1H NMR (400 MHz, Chloroform-d) δ 15.51 (s, 1H), 7.10-6.87 (m, 2H), 4.49 (s, 2H), 1.76 (s, 6H). 19 F NMR (376 MHz, Chloroform-d) δ −134.69, −136.10, −159.75, −159.81.

A mixture of 5-(1-hydroxy-2-(2,3,4-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (38 g, 120 mmol) in t-BuOH (350 mL) and toluene (50 mL) was stirred at 90° C. for 1 h. The reaction mixture was concentrated to dryness to give the title compound (28 g, 59% yield) as a yellow oil, which was used into the next step without further purification. 1 H NMR (400 MHz, Chloroform-d) δ 7.04-6.80 (m, 2H), 3.92-3.70 (m, 2H), 3.45 (s, 2H), 1.47 (d, J=3.2, 9H). 19 F. NMR (376 MHz, Chloroform-d) δ −135.23, −135.28, −136.85, −160.11, −160.16.

To a solution of tert-butyl 3-oxo-4-(2,3,4-trifluorophenyl) butanoate (28 g, 97.1 mmol) in CH 2 Cl 2 (150 mL) was added TFA (144 mL, 1.94 mol). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (22 g, 80% yield) as a light yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.35-7.22 (m, 1H), 7.16-7.05 (m, 1H), 4.02 (d, J=4.8, 2H), 3.62 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.99, −137.06, −137.48, −137.52, −162.37, −162.43.

A mixture of 3-oxo-4-(2,3,4-trifluorophenyl) butanoic acid (21 g, 90.5 mmol) in CF 3 SO 3 H (168 mL) was stirred at 100° C. for 0.5 h. The reaction mixture was cooled to 0° C., and slowly poured into ice-water (500 mL). The precipitate was filtered and washed with water (200 mL) to give the title compound (17.2 g, 89% yield) as a light yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 10.66 (br s, 1H), 7.73-7.56 (m, 1H), 6.71-6.57 (m, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −142.75, −146.83, −146.89, −162.67, −162.72.

A mixture of 5,6,7-trifluoronaphthalene-1,3-diol (16.2 g, 75.65 mmol), (bromoethynyl)triisopropylsilane (21.74 g, 83.22 mmol), KOAc (14.85 g, 151.30 mmol) and dichloro (p-cymene) ruthenium (II) dimer (4.63 g, 7.57 mmol) in 1,4-dioxane (160 mL) was degassed, purged with N 2 three times, and stirred at 110° C. for 2 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% of EtOAc in petroleum ether) to give the title compound (17.5 g, 56% yield) as a black brown solid. MS: m/z=393.0 [M−H] − . JH NMR (400 MHz, Dimethylsulfoxide-d 6 ) 10.56 (s, 1H), 10.11 (s, 1H), 6.72-6.55 (m, 2H), 1.16-1.06 (m, 21H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.05, −143.53, −143.60, −161.90, −161.97.

Step 6: 5,6,7-Trifluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diyl bis(trifluoromethanesulfonate)

To a solution of 5,6,7-trifluoro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diol (17.5 g, 44.36 mmol) in CH 2 Cl 2 (200 mL) were added DIPEA (38.6 mL, 221.80 mmol) and THO (21.96 mL, 133.08 mmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 1 h under N 2 . The reaction mixture was quenched with H 2 O (500 mL) and extracted with CH 2 Cl (600 mL×3). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜1% of EtOAc in petroleum ether) to give the title compound (19.5 g, 67% yield) as a yellow oil. MS: m/z=657.0 [M−H] − . 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J=2.4 Hz, 1H), 7.58-7.48 (m, 1H), 1.17-1.14 (m, 21H). 19 F NMR (376 MHz, Chloroform-d) δ −70.96, −72.30, −119.11, −119.20, −138.20, −153.71, −153.82.

Step 7: 3-((Diphenylmethylene)amino)-5,6,7-trifluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate

A solution of 3-((diphenylmethylene)amino)-5,6,7-trifluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (19.5 g, 29.6 mmol), diphenylmethanimine (5.9 g, 32.6 mmol), Cs 2 CO 3 (28.9 g, 88.8 mmol) and XantPhosPdG3 (2.81 g, 2.96 mmol) in 1,4-dioxane (200 mL) was degassed, purged with N 2 three times, and stirred at 80° C. for 1 h under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in petroleum ether) to give the title compound (12 g, 59% yield) as a yellow solid. MS: m/z=690.5 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.79-7.75 (m, 2H), 7.60-7.40 (m, 3H), 7.34-7.27 (m, 4H), 7.18-7.08 (m, 3H), 1.24-1.09 (m, 21H). 19 F. NMR (376 MHz, Chloroform-d) δ −71.24, −71.31, −124.77, −124.86, −140.84, −157.70, −157.76, −157.82.

Step 8: 1,1-Diphenyl-N-(6,7,8-trifluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-yl) methanimine

A solution of 3-((diphenylmethylene)amino)-5,6,7-trifluoro-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (310 mg, 449 μmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (285 mg, 1.12 mmol), KOAc (132 mg, 1.35 mmol) and Pd (dppf)Cl 2 (37 mg, 44.9 μmol) in tolune (3 mL) was degassed, purged with N 2 three times, and stirred at 120° C. for 1 h under N 2 . The reaction mixture was concentrated under reduced pressure to give the title compound (300 mg, crude) as a yellow oil.

Step 9: 6,7,8-Trifluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-amine

To a solution of 1,1-diphenyl-N-(6,7,8-trifluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-yl) methanimine (300 mg, 449 μmol) in EtOH (3 mL) were added NaOAc (55 mg, 674 μmol) and NH 2 OH HCl (37 mg, 539 μmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in petroleum ether) to give the title compound (Intermediate 64, 100 mg, 42% yield over 2 steps) as a yellow solid. MS: m/z=504.1 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.25 (d, J=2.0 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 5.93 (s, 2H), 1.33 (s, 12H), 1.12-1.07 (m, 21H). IF NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −135.37, −135.45, −145.08, −162.32, −163.37.

To a mixture of tert-butyl (4-bromo-6,7-difluoro-5-hydroxynaphthalen-2-yl) carbamate (1.04 g, 2.77 mmol, refer to Intermediate 62 for detail procedures) in DMF (20 mL) were added K 2 CO 3 (697 mg, 5.04 mmol) and fluoromethyl-d 2 4 -methylbenzenesulfonate (520 mg, 2.52 mmol). The mixture was stirred at 80° C. for 2 h under N 2 . The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜10% of EtOAc in petroleum ether) to give the title compound (900 mg, 79% yield) as a white solid. MS: m/z=307.9 [M+H-Boc] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.81 (s, 1H), 8.18-7.93 (m, 2H), 7.87-7.47 (m, 1H), 1.50 (s, 9H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −134.64, −152.11, −152.17, −152.54, −152.55.

Step 2: ter-Butyl (6,7-difluoro-5-(fluoromethoxy-2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) carbamate

To a mixture of ter-butyl (4-bromo-6,7-difluoro-5-(fluoromethoxy-d 2 ) naphthalen-2-yl) carbamate (290 mg, 710 μmol) in 1,4-dioxane (10 mL) were added K3PO4 (452 mg, 2.13 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (216 mg, 852 μmol) and Cy3PPdGs (46 mg, 71 μmol). The mixture was stirred at 100° C. for 16 h under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜4% of EtOAc in petroleum ether) to the title compound (160 mg, 67% yield) as a white solid. MS: m/z=478.2 [M+Na]. 3H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.64 (s, 1H), 8.17 (br s, 1H), 7.79-7.69 (m, 1H), 7.55 (s, 1H), 1.49 (s, 9H), 1.35 (s, 12H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −136.38, −136.43, −149.69, −149.72, −157.49, −157.54.

Step 3: 6,7-Difluoro-5-(fluoromethoxy-d 2 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

To a solution of tert-butyl (6,7-difluoro-5-(fluoromethoxy-d 2 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) carbamate (160 mg, 351 μmol) in HCl (10 mL, 2M in EtOAc). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 65, 124 mg, crude) as a white solid, which was used into the next step without further purification. MS: m/z=356.2 [M+H].

To a mixture of 8-bromo-2-fluoronaphthalen-1-ol (500 mg, 2.07 mmol, refer to Intermediate 46 for detail procedures) in DMF (10 mL) were added K 2 CO 3 (573 mg, 4.15 mmol) and fluoromethyl-d 2 4 -methylbenzenesulfonate (385 mg, 1.87 mmol). The mixture was stirred at 80° C. for 2 h under N 2 . The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜1% of EtOAc in petroleum ether) to give the title compound (560 mg, 98% yield) as a white solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.06 (d, J=8.4 Hz, 1H), 8.01-7.92 (m, 2H), 7.67 (t, J=9.2 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −126.85, −126.89, −152.93, −152.95.

A mixture of 8-bromo-2-fluoro-1-(fluoromethoxy-d 2 ) naphthalene (500 mg, 1.82 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (508 mg, 2.00 mmol), KOAc (535 mg, 5.45 mmol) and CysPPdG3 (118 mg, 182 μmol) in 1,4-dioxane (5 mL) was degassed, purged with N 2 three times, and stirred at 100° C. for 1 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in Petroleum ether) to give the title compound (Intermediate 66, 350 mg, 60% yield) as a white solid. 1 HNMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 8.03-7.97 (m, 1H), 7.89-7.81 (m, 1H), 7.61-7.49 (m, 3H), 1.36 (s, 12H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −132.07, −132.13, −150.04.

To a mixture of 8-bromo-2-fluoronaphthalen-1-ol (1 g, 4.15 mmol) and Cs2CO 3 (3.38 g, 10.4 mmol) in ACN (10 mL) was added bromo (fluoro) methane (1.40 g, 12.4 mmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 1h N 2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (1.1 g, 97% yield) as a black solid. 1 HNMR (400 MHz, Dimethylsulfoxide-d 6 ) õ 8.05 (d, J=8.0 Hz, 1H), 8.00-7.92 (m, 2H), 7.66 (t, J=9.6 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 5.90-5.72 (d, J=53.6 Hz, 2H), 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −126.82, −126.86, −151.63, −151.68.

A mixture of 8-bromo-2-fluoro-1-(fluoromethoxy) naphthalene (1 g, 3.66 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1.02 g, 4.03 mmol), K 3 PO 4 (2.33 g, 11.0 mmol) and Cy 3 PPdG 3 (269 mg, 366 μmol) in 1,4-dioxane (10 mL) was degassed, purged with N 2 three times, and stirred at 100° C. for 1 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in petroleum ether) to give the title compound (Intermediate 67, 388 mg, 30% yield) as a yellow solid. 1 HNMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.04-7.96 (m, 1H), 7.89-7.82 (m, 1H), 7.62-7.50 (m, 3H), 5.92-5.72 (d, J=53.6 Hz, 2H), 1.36 (s, 12H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −132.00, −132.03, −148.73, −148.77.

To a solution of 7-chloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidine (200 mg, 426 μmol, refer to Example 16 for detail procedures) in MeCN (100 mL) was added TMSBr (326 mg, 2.1 mmol) at 25° C. The mixture was stirred at 80° C. for 12 hr. The mixture was added to saturated NaHCO 3 (200 mL) and extracted with CH 2 Cl 2 (100 mL×2). The combined organic layers was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜6% MeOH in CH: Cl 2 ), the title compound (Intermediate 68, 200 mg, yield: 90%) was obtained as a yellow solid. MS: m/z=514.0, 516.0 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.14 (s, 1H), 5.39-5.15 (m, 1H), 4.68-4.49 (m, 1H), 4.37 (d, J=13.2 Hz, 1H), 4.06-3.95 (m, 1H), 3.12-2.98 (m, 3H), 2.87-2.78 (m, 1H), 2.26-2.19 (m, 1H), 2.14-2.09 (m, 1H), 2.06-1.93 (m, 3H), 1.90-1.70 (m, 6H), 1.68-1.62 (m, 1H), 1.52-1.42 (m, 1H), 1.10-0.97 (m, 1H). 19 F NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ −130.33, −132.27, −172.15.

To a solution of 6-fluoroisoquinoline (5 g, 33.9 mmol) in H 2 SO 4 (50 mL) was added NCS (9.0 g, 67.9 mmol) at 0° C. The mixture was stirred at 25° C. for 16 hr. Then the mixture was stirred at 80° C. for another 24 hr. The reaction mixture was poured into ice and neutralized with saturated NaHCO 3 (pH about 8) and extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine (500 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜15% EtOAc in petroleum ether), the title compound (4.3 g, yield: 47%) was obtained as a light yellow solid. MS: m/z=181.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 9.27 (s, 1H), 8.67 (d, J=5.6 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H), 7.96 (dd, J=9.2, 5.2 Hz, 1H), 7.48 (t, J=8.8 Hz, 1H). 19 F NMR (400 MHZ, Chloroform-d) δ −106.43.

To a solution of 5-chloro-6-fluoroisoquinoline (4.3 g, 23.7 mmol) in ACN (40 mL) were added 12 (9.0 g, 35.5 mmol) and TBHP (18.2 mL, 189 mmol, 70% purity in H 2 O). The mixture was stirred at 80° C. for 16 hr under N 2 atmosphere. The reaction mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜9% EtOAc in petroleum ether) and triturated with petroleum ether: EtOAc=10: 1 at 25° C. for 10 min, the title compound (1.38 g, yield: 17%) was obtained as an off-white solid. MS: m/z=307.7 [M+H] + . JH NMR (400 MHZ, Chloroform-d) δ 9.18 (s, 1H), 9.12 (s, 1H), 7.93 (dd, J=8.8, 5.6 Hz, 1H), 7.53 (t, J=8.8 Hz, 1H). 19 F. NMR (400 MHZ, Chloroform-d) δ −98.67.

To a solution of 5-chloro-6-fluoro-4-iodoisoquinoline (1.38 g, 4.49 mmol) in toluene (20 mL) were added SnzMes (5.3 mL, 25.8 mmol) and Pd (PPh 3 ) 4 (519 mg, 449 μmol). The mixture was stirred at 100° C. for 20 hr under N 2 atmosphere. The reaction mixture was quenched with KF (10 mL) at 25° C., diluted with H 2 O (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether) and reversed-phase HPLC(40% ACN in H 2 O), the title compound (Intermediate 69, 400 mg, yield: 25%) was obtained as an off-white solid. MS: m/z=345.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 9.19 (s, 1H), 8.72 (s, 1H), 7.97-7.91 (m, 1H), 7.52-7.45 (m, 1H), 0.53-0.45 (m, 9H). 19 F. NMR (400 MHZ, Chloroform-d) δ −104.13.

To a solution of 3,4-difluoro-5-methoxy-benzaldehyde (12.9 g, 74.9 mmol) in H 2 O (135 mL) were added KBr (44.6 g, 375 mmol) and Brz (225 mmol, 11.6 mL). The mixture was stirred at 25° C. for 48 hr. The mixture was filtered, and the wet cake was washed with H 2 O (100 mL×3). Then the wet cake was concentrated to give the title compound (17.9 g, yield: 95%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 10.27 (s, 1H), 7.39 (dd, J=8.0, 2.0 Hz, 1H), 3.97 (s, 3H). 19 F. NMR (400 MHz, Chloroform-d) δ −127.555, −127.608, −144.810, −144.862.

To a solution of 2-bromo-3,4-difluoro-5-methoxybenzaldehyde (2.0 g, 7.97 mmol) and 2,2-dimethoxyethanamine (1.0 g, 9.56 mmol) in CH 2 Cl 2 (50 mL) was added NaBH (OAc) 3 (5.0 g, 23.9 mmol) at 0° C. The mixture was stirred at 25° C. for 16 hr under N 2 atmosphere. The reaction mixture was quenched with saturated NaHCOs (100 mL) at 0° C. and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜8% MeOH in CH 2 Cl 2 ), the title compound (2.6 g, yield: 95%) was obtained as a white solid. MS: m/z=339.9, 341.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 6.93 (dd, J=8.0, 2.0 Hz, 1H), 4.49 (t, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 2H), 3.38 (s, 6H), 2.75 (d,)=5.6 Hz, 2H). 19 F NMR (400 MHz, Chloroform-d) δ −127.495, −127.548, −157.321, −157.381.

To a solution of N-(2-bromo-3,4-difluoro-5-methoxybenzyl)-2,2-dimethoxyethan-1-amine (2.2 g, 6.47 mmol) in CH 2 Cl 2 (25 mL) were added Py (1.6 mL, 19.4 mmol) and TsCl (1.5 g, 7.76 mmol). The mixture was stirred at 25° C. for 16 hr. The reaction mixture was diluted with H 2 O (50 mL) and extracted with CH 2 Cl 2 (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜2% MeOH in CH 2 Cl 2 ), the title compound (2.6 g, yield: 95%) was obtained as a white solid. MS: m/z=516.0, 517.9 [M+Na] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.02 (dd, J=8.0, 2.0 Hz, 1H), 4.47 (s, 2H), 4.37 (t, J=5.6 Hz, 1H), 3.86 (s, 3H), 3.28 (d, J=5.6 Hz, 2H), 3.24 (s, 6H), 2.44 (s, 3H). 19 F NMR (400 MHZ, Chloroform-d) δ −127.803, −127.856, −156.781, −156.841.

To N-(2-bromo-3,4-difluoro-5-methoxybenzyl)-2,2-dimethoxyethanamine (20 g, 40.5 mmol) was added ClSO3H (10 mL) at 0° C. The mixture was stirred at 90° C. for 10 min. The reaction mixture was poured into ice and neutralized with NaHCO 3 , and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜30% EtOAc in petroleum ether), the title compound (6 g, yield: 52%) was obtained as a white solid. MS: m/z=273.9, 275.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.51 (s, 1H), 8.62 (d, J=5.6 Hz, 1H), 7.93 (d, J=5.6 Hz, 1H), 4.23 (d, J=3.6 Hz, 3H). 19 F. NMR (400 MHz, Chloroform-d) δ −122.497, −122.549, −148.007, −148.060.

To a solution of 8-bromo-6,7-difluoro-5-methoxyisoquinoline (1.5 g, 5.47 mmol) and I 2 (1.7 g, 6.57 mmol) in ACN (15 mL) was added TBHP (6.00 mL, 43.8 mmol, 70% purity in H 2 O). The mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether), the title compound (1.6 g, yield: 71%) was obtained as a white solid. MS: m/z=399.7, 401.7 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.48 (s, 1H), 9.07 (s, 1H), 4.11 (d, J=3.6 Hz, 3H). 19 F NMR (400 MHZ, Chloroform-d) δ −119.713, −119.773, −142.513, −142.573.

A mixture of 8-bromo-6,7-difluoro-4-iodo-5-methoxyisoquinoline (1.0 g, 2.50 mmol), Sn2Me6 (2.2 mL, 10.5 mmol) and Pd (PPh 3 ) 4 (289 mg, 250 μmol) in 1,4-dioxane (10 mL) was degassed, purged with N 2 three times, and stirred at 90° C. for 30 hr under Na atmosphere. The reaction mixture was quenched with saturated KF (20 mL) at 25° C., diluted with H 2 O (50 mL), and extracted with CH 2 Cl 2 (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜8% EtOAc in petroleum ether), the title compound (200 mg, yield: 16%) was obtained as a white solid and 6,7-difluoro-5-methoxy-4-(trimethylstannyl) isoquinolinewas (25 mg, yield: 2%) was obtained as a white solid. MS: m/z=437.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.56 (s, 1H), 8.58 (s, 1H), 4.35-4.31 (m, 3H), 0.50-0.37 (m, 9H).

To a solution of 8-bromo-6,7-difluoro-5-methoxy-4-(trimethylstannyl) isoquinoline (120 mg, 275 μmol) in THF (1.5 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at −40° C. for 5 min under N 2 atmosphere. Then i-PrMgCl (2 M, 412 μL) was added dropwise at −40° C. The resulting mixture was stirred at −40° C. for 30 min. The reaction mixture was quenched with 1 M HCl (5 mL) at 0° C. and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜30% EtOAc in petroleum ether), the title compound (Intermediate 70, 68 mg, yield: 58%) was obtained as a white solid. MS: m/z=359.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) § 9.12 (s, 1H), 8.50 (s, 1H), 7.41 (dd, J=9.2, 7.2 Hz, 1H), 4.31 (d, J=5.6 Hz, 3H), 0.47-0.33 (m, 9H).

To a solution of Intermediate 18 (4,300 g, crude) in EtOH (15 L) at room temperature were added NaOAc (1,085.87 g, 13,236.878 mmol) and NH 2 OH.HCl (919.83 g, 13,236.878 mmol) at room temperature. The resulting mixture was stirred for 8 h at room temperature. Additional NaOAc (1,085.87 g, 13,236.878 mmol) and NH 2 OH.HCl (919.83 g, 13,236.878 mmol) were added at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was diluted with MTBE (15 L). The resulting mixture was washed with of brine (30 L). The aqueous layer was extracted with MTBE (1x2 L). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (5: 1) to afford the title compound (Intermediate 71, 560 g, 52.8%) as a yellow solid. MS: m/z=527.3 [M+H] + . 1H-NMR: (400 MHz, DMSO-d 6 ) δ 7.64 (dd, J=11.8, 8.3 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 5.66 (s, 2H), 1.33 (s, 12H), 1.10 (d, J=4.4 Hz, 21H). 19 F-NMR: (400 MHz, DMSO-d 6 ) 6 -136.79 (d, J=23.5 Hz), —139.06 (d, J=23.5 Hz).

To a solution of Intermediate 2 (16 g, 68.59 mmol) in DCM (160 mL) under nitrogen atmosphere was added ZnEt 2 (171.48 mL, 171.48 mmol, 1 M in n-hexane) at room temperature. After stirring at room temperature for 0.5 hours, a solution of CH 2 I 2 (73.48 g, 274.36 mmol) in DCM (20 mL) was added to the above mixture dropwise with an ice bath. The ice bath was removed, and the reaction was stirred at room temperature for 12 hours. The resulting mixture was poured into cold saturated aq. NH 4 Cl (300 mL) and extracted with DCM (3×300 mL). The combined organic layers were washed with brine (300 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE to afford the title compound (12.3 g, 72% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d)δ 7.38-7.29 (m, 5H), 5.21-5.11 (m, 2H), 4.43-4.39 (m, 1H), 4.13-3.72 (m, 2H), 3.52-3.46 (m, 1H), 3.33-3.26 (m, 1H), 3.10-3.04 (m, 1H), 3.52-3.46 (m, 1H), 1.48-1.38 (m, 1H), 1.20-0.88 (m, 2H).

To an ice-cooled solution of benzyl 5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (5 g, 20.21 mmol) in MeOH (250 mL) was added Pd/C(1.67 g, 10% wt) under nitrogen atmosphere. The reaction mixture was stirred in an ice bath for 40 min under hydrogen atmosphere. The resulting mixture filtered and concentrated under reduced pressure to afford the title compound (2.0 g, crude used through) as a light-yellow oil.

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.46 g, 17.674 mmol) and 5-oxa-2-azabicyclo[5.1.0]octane (2.0 g, crude) in DCM (40 mL) under nitrogen atmosphere was added DIEA (6.85 g, 53.022 mmol) dropwise at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% aq. citric acid (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (4 g, crude used through) as a light yellow solid. MS: m/z=329.10, 331.10 [M+H] +.

Step 4: 2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-S-oxa-2-azabicyclo[5.1.0]octane

To a solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (4 g, crude) in DMSO (40 mL) under nitrogen atmosphere were added KF (2.47 g, 42.52 mmol) and Intermediate 17 (3.13 g, 19.44 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl/MeOH (10: 1) to afford the title compound (750 mg, 9.3% yield for three steps) as a light yellow solid. MS: m/z=454.20 [M+H] +.

Step 5: (1R,7S)-2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5/I)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7R)-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane

2-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (900 mg, 1.98 mmol) was separated by Prep-SFC with the following conditions: Column: OptiChiral-C 9 -5 3×25 cm, 5 μm; Mobile Phase A: CO 2 , Mobile Phase B: IPA (0.1% DEA); Flow rate: 100 mL/min; Gradient: isocratic 30% B; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 7.9 min; RT2: 11.3 min; Sample Solvent: MEOH; Injection Volume: 1.2 mL. The first eluting peak (RT1: 7.9 min) was concentrated and lyophilized to give the title compound (Intermediate 72, 320 mg, 35% yield) as a light yellow solid. MS: m/z=454.15 [M+H] + . The second eluting peak (RT2: 11.3 min) was concentrated and lyophilized to give the title compound (Intermediate 73, 310 mg, 34% yield) as a light yellow solid. MS: m/z=454.20 [M+H].

To a solution of 1,5-dibromo-2,3,4-trifluoro-benzene (80 g, 276 mmol) in THE (2.7 L) was added dropwise i-PrMgCl (152 mL, 2 M in THF) at −20° C. under N 2 , and the reaction mixture was warmed to 0° C. and stirred for 0.5 h under N 2 . Trimethyl borate (34.4 g, 331.2 mmol) in THF (200 mL) was added dropwise at 0° C. under N 2 , then the mixture was warmed to 20° C. and stirred for 1 h under N 2 . The solution was cooled to −20° C., and peracetic acid (177 g, 372.6 mmol, 16% purity) in THF (400 mL) was added dropwise. The solution was stirred for 0.5 h at 20° C. under N 2 . The reaction mixture was quenched with sat. NH 4 Cl (1 L) aq. and sat. Na 2 SO 3 aq. (1 L) in sequence at 20° C. The mixture was then diluted with H 2 O (2 L) and extracted with EtOAc (2 L×3). The combined organic layers were washed with brine (1.6 L), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of EtOAc in petroleum ether) to give the title compound (42 g, 56% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d)δ 7.07-6.96 (m, 1H), 5.75 (br s, 1H). 19 F. NMR (376 MHz, Chloroform-d) δ −136.76, −136.82, −155.27, −158.39.

To a solution of 5-bromo-2,3,4-trifluorophenol (10 g, 44.1 mmol) in DMF (80 mL) was added K 2 CO 3 (18.3 g, 132 mmol). Then trideuterio (iodo) methane (2.95 mL, 48.5 mmol) in DMF (20 mL) was added dropwise to the mixture at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 h under N 2 . The mixture was diluted with H 2 O (500 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of EtOAc in petroleum ether) to give the title compound (9.8 g, 91% yield) as a colorless oil. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 )δ 7.48-7.38 (m, 1H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −138.15, −138.21, −155.58, −155.61, −156.48-156.53, −156.55, −156.60.

A mixture of 1-bromo-2,3,4-trifluoro-5-(methoxy-d 3 )benzene (30 g, 123 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41.3 g, 246 mmol), Cs 2 CO 3 (80.1 g, 246 mmol) and Pd (PPh 3 ) 4 (14.2 g, 12.3 mmol) in 1,4-dioxane (300 mL) and H 2 O (60 mL) was degassed, purged with N 2 three times, and stirred at 90° C. for 3 h under N 2 . The mixture was diluted with H 2 O (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜1% of EtOAc in petroleum ether) to give the title compound (24 g, 95% yield) as a colorless oil. 1 H NMR (400 MHZ, Chloroform-d) δ 6.58-6.46 (m, 1H), 5.97-5.82 (m, 1H), 5.19-5.05 (m, 2H), 3.37 (d, J=6.8 Hz, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −149.08, −149.13, −158.06, −158.97, −159.02.

To a solution of 1-allyl-2,3,4-trifluoro-5-(methoxy-d 3 )benzene (6.0 g, 29.2 mmol) in ACN (100 mL) and H 2 O (100 mL) was added RuCl (606 mg, 2.92 mmol) at 0° C. Then NaIO 4 (32 g, 146 mmol) was added slowly over 1 h, and the reaction temperature was maintained at 0˜10° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (200 mL). The filtrate was quenched with sat. NazSzO3 aq. (200 mL) and extracted with EtOAc (200 mL×2). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of MeOH in CH 2 Cl 2 ) to give the title compound (6.2 g, 86% yield) as a yellow oil. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 12.63 (br s, 1H), 7.10-7.00 (m, 1H), 3.69-3.65 (m, 2H). IF NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −143.32, −157.96, −158.01, −160.64, −160.70, −160.76.

Step 5: 5-(1-Hydroxy-2-(2,3,4-trifluoro-5-(methoxy-d 3 )phenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a solution of 2-(2,3,4-trifluoro-5-(methoxy-d 3 )phenyl) acetic acid (6.2 g, 27.8 mmol) in ACN (30 mL) were added 2,2-dimethyl-1,3-dioxane-4,6-dione (4.4 g, 30.6 mmol), DMAP (340 mg, 2.78 mmol) and DIPEA (11 mL, 61.2 mmol). Then/-BuCOCl (3.42 mL, 27.8 mmol) was added dropwise at 0° C. under N 2 . The mixture was stirred at 20° C. for 3 h under N 2 . The reaction mixture was quenched with HCl aq. (200 mL, IN in water) at 0° C. The precipitate was filtered, and the filter cake was washed with water (100 mL), dried under reduced pressure to give the title compound (9.2 g, 88% yield) as a yellow solid. MS: m/z=347.9 [M−H] − . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 7.03-6.97 (m, 1H), 4.40 (s, 2H), 1.67 (s, 6H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −147.80, −147.86, −157.82, −160.64, −160.70.

A mixture of 5-(1-hydroxy-2-(2,3,4-trifluoro-5-(methoxy-d 3 )phenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.2 g, 26.3 mmol) in t-BuOH (100 mL) was degassed, purged with N 2 three times, and stirred at 90° C. for 2 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the title compound (8.2 g, crude) as a yellow oil, which was used in the next step without further purification. MS: m/z=320.1 [M−H] − . 1H NMR (400 MHz, Chloroform-d) δ 6.59-6.44 (m, 1H), 3.85 (s, 2H), 3.45 (s, 2H), 1.48 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −147.16, −147.22, −155.63, −155.69, −158.16, −158.21.

To a solution of tert-butyl 3-oxo-4-(2,3,4-trifluoro-5-(methoxy-d 3 )phenyl) butanoate (8.0 g, 24.9 mmol) in CH 2 Cl 2 (30 mL) was added TFA (30 mL, 404 mmol). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (6.4 g, crude) as a black brown oil, which was used in the next step without further purification. MS: m/z=220.1 [M-COOH]. 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 6.99-6.89 (m, 1H), 4.00 (s, 2H), 3.62 (s, 2H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −147.90,-147.96, −157.72, −160.64, −160.70.

A solution of 3-oxo-4-(2,3,4-trifluoro-5-(methoxy-d 3 )phenyl) butanoic acid (6.4 g, 24.2 mmol) in trifluoromethanesulfonic acid (10 mL) was stirred at 25° C. for 16 h. The reaction mixture was poured into ice water (200 mL) slowly, and the precipitate was filtered. The filter cake was washed with water (50 ml×3), sat. NaHCO 3 aq. (50 mL), and water (50 ml) in sequence, dried under reduced pressure to give the title compound (5.4 g, 64% yield over 3 steps) as a black brown solid. MS: m/z=246.0 [M−H] − . 3H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 10.43-9.70 (m, 2H), 6.65 (d, J=2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −152.32, −152.37, −160.81, −160.86, −161.65.

To a solution of 5,6,7-trifluoro-8-(methoxy-d 3 ) naphthalene-1,3-diol (5.4 g, 21.9 mmol) and DIPEA (23 mL, 131 mmol) in CH 2 Cl 2 (30 mL) was added Tf2O (15 mL, 87.4 mmol) dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 h under N 2 . The reaction mixture was quenched with H 2 O (200 mL) and extracted with CH 2 Cl 2 (300 mL×3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜1% of CH 2 Cl 2 in petroleum ether) to give the title compound (8.2 g, 67% yield) as a yellow solid. MS: m/z=509.9 [M−H] − . 1 H NMR (400 MHZ, Chloroform-d) 8 8.00 (d, J=1.6 Hz, 1H), 7.31 (s, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −72.31, −72.77, −146.25, −146.31, −146.93,˜146.99-152.12, −152.17.

Step 10: 3-((Diphenylmethylene)amino)-5,6,7-trifluoro-8-(methoxy-d′3) naphthalen-1-yl trifluoromethanesulfonate

A solution of 5,6,7-trifluoro-8-(methoxy-d 3 ) naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (8.0 g, 15.7 mmol), diphenylmethanimine (2.7 mL, 15.7 mmol), Cs 2 CO 3 (15.3 g, 47.0 mmol) and XantPhosPdG 3 (742 mg, 0.78 mmol) in 1,4-dioxane (150 mL) was degassed, purged with N 2 three times, and stirred at 80° C. under N 2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in petroleum ether) to give the title compound (5.2 g, 44% yield) as a brown oil. MS: m/z=543.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.86-7.76 (m, 5H), 7.59 (s, 1H), 7.51-7.44 (m, 5H), 7.14-7.12 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −72.66, −73.20, −149.64,˜151.60, −151.66, −156.22, −156.27.

Step 11: 1,1-Diphenyl-N-(6,7,8-trifluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) methanimine

A solution of 3-((diphenylmethylene)amino)-5,6,7-trifluoro-8-(methoxy-d 3 ) naphthalen-1-yl trifluoromethanesulfonate (5 g, 9.22 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (2.81 g, 11.1 mmol), AcOK (2.71 g, 27.7 mmol) and CysPPdG3 (600 mg, 922 μmol) in DMA (50 mL) was degassed and purged with N 2 three 3 times, and the mixture was stirred at 100° C. under N 2 for 2 h. The reaction mixture was diluted with H 2 O (400 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (5 g, crude) as a black brown oil, which was used in the next step without further purification. MS: m/z=521.0 [M+H] +.

Step 12: 6,7,8-Trifluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

To a solution of 1,1-diphenyl-N-(6,7,8-trifluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl) methanimine (5.0 g, 9.61 mmol) in EtOH (10 mL) were added hydroxylamine hydrochloride (1.34 g, 19.2 mmol) and AcOK (2.83 g, 28.8 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated and purified by silica gel flash chromatography (eluent: 0˜8% of EtOAc in petroleum ether) to give the title compound (Intermediate 74, 3.0 g, 76% yield over 2 steps, confirmed by 2D-NMR) as a brown solid. MS: m/z=356.7 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 6.98 (d, J=1.6 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 5.80 (s, 2H), 1.34 (s, 12H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −155.94, −156.00, −162.09, −162.15, −162.28, −162.33.

To an ice-cooled solution of 1-bromo-2-chloro-4-fluoro-5-methoxybenzene (13.4 g, 55.96 mmol) in THE (135 mL) under nitrogen atmosphere was added isopropylmagnesium chloride (56 mL, 111.91 mmol, 2 M in THF) dropwise for 1 hour, then followed by the addition of DMF (20.45 g, 279.79 mmol) dropwise in portions with an ice bath. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. aq. NH 4 Cl (100 mL) in an ice bath and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (6: 1) to afford the title compound (10.9 g, 83% yield) as a light yellow solid. 1 H NMR (300 MHz, Chloroform-d) & 10.37 (s, 1H), 7.53-7.50 (m, 1H), 7.22-7.18 (m, 1H), 3.94 (s, 3H). 19 F NMR (282 MHz, Chloroform-d) δ −121.55 (s, 1F).

To a solution of 2-chloro-4-fluoro-5-methoxybenzaldehyde (5 g, 26.51 mmol) in toluene (50 mL) were added 4-methylbenzenesulfonic acid (0.46 g, 2.65 mmol) and 2,2-dimethoxyethanamine (3.07 g, 29.16 mmol) at room temperature. The reaction mixture was heated at 130° C. for 3 hours. The resulting mixture was cooled to room temperature, neutralized to pH 8 with sat. a. NaHCO 3 , and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (7.3 g, 99% yield) as an orange oil. MS: m/z=276.05 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 8.63-8.62 (m, 1H), 7.67-7.64 (m, 1H), 7.18-7.10 (m, 1H), 4.72-4.68 (m, 1H), 3.94 (s, 3H), 3.83-3.80 (m, 2H), 3.43 (s, 6H).

To an ice-cooled solution of 1-(2-chloro-4-fluoro-5-methoxyphenyl)-N-(2,2-dimethoxyethyl) methanimine (1 g, 3.62 mmol) in EtOH (10 mL) was added NaBH4 (0.17 g, 4.53 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with acetic acid in an ice bath and concentrated under reduced pressure. The residue was diluted with DCM (10 mL), neutralized to pH 8 with sat. aq. NaHCO 3 and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1 g, crude used through) as a brown oil. MS: m/z=278.10 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 7.18-7.05 (m, 2H), 4.52-4.48 (m, 1H), 3.88 (s, 3H), 3.84 (s, 2H), 3.38 (s, 6H), 2.76 (d,)=5.4 Hz, 2H).

To an ice-cooled solution of N-(2-chloro-4-fluoro-5-methoxybenzyl)-2,2-dimethoxyethan-1-amine (1.0 g, crude) in DCM (12 mL) were added pyridine (1.0 g, 12.60 mmol) and 4-methylbenzenesulfonyl chloride (858 mg, 4.50 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with DCM (50 mL), washed with HCl (1.5 M in H 2 O, 15 mL), sat. aq. NaHCO 3 (15 mL), and brine (15 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the title compound (1.5 g, 96% yield for two steps) as a brown oil. 1 H NMR (400 MHZ, Chloroform-d)δ 7.76-7.68 (m, 2H), 7.36-7.28 (m, 2H), 7.15-7.13 (m, 1H), 7.06-7.03 (m, 1H), 4.47 (s, 2H), 4.41-4.32 (m, 1H), 3.83 (s, 3H), 3.28-3.24 (m, 8H), 2.43 (s, 3H).

To an ice-cooled solution of N-(2-chloro-4-fluoro-5-methoxybenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (3 g, 6.94 mmol) in DCM (30 mL) under nitrogen atmosphere was added aluminium chloride (4.63 g, 34.73 mmol). The ice bath was removed, and the reaction mixture was heated at 50° C. for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/MeOH (10: 1) to afford 1.7 g crude product. The crude product (1.7 g) was triturated with sat. aq. NaHICO3 (30 mL) and filtered. The filter-cake was washed with water (3×5 mL) and dried under reduced pressure to afford the title compound (1.1 g, 80% yield) as a grey solid. MS: m/z=198.00 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.41 (s, 1H), 8.60-8.58 (m, 1H), 8.08 (s, 1H), 7.86-7.82 (m, 1H).

To a mixture of triphenylphosphine (15.92 mg, 6.07 mmol) in THF (10 mL) under nitrogen atmosphere was added diisopropyl azodicarboxylate (1.43 g, 7.08 mmol) at room temperature. After stirring for 5 min, 8-chloro-6-fluoroisoquinolin-5-ol (1.0 g, 5.06 mmol) and CD 3 OD (219.0 mg, 6.07 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (3: 1) to afford the title compound (680 mg, 62% yield) as a light yellow solid. MS: m/z=215.05 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) & 9.55 (s, 1H), 8.63-8.60 (m, 1H), 7.99-7.97 (m, 1H), 7.47-7.43 (m, 1H).

To a mixture of 8-chloro-6-fluoro-5-(methoxy-d 3 ) isoquinoline (700 mg, 3.26 mmol) in MeCN (7 mL) was added N-bromosuccinimide (870.7 mg, 4.89 mmol) at room temperature. The reaction mixture was heated at 60° C. for 5 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (Intermediate 75, 130 mg, 13% yield) as an off-white solid. MS: m/z=292.90, 294.90 [M+H] + . 1 H NMR (300 MHZ, Chloroform-d)δ 9.57 (s, 1H), 8.78 (s, 1H), 7.67-7.63 (m, 1H), 19 F NMR (282 MHZ, Chloroform-d) δ −118.48 (s, IF).

To a solution of Intermediate 34 (500 mg, 1.1 mmol) in MeCN (500 mL) was added TMSBr (811 mg, 5.3 mmol) at 25° C. The mixture was stirred at 80° C. for 3 hr. The mixture was added to saturated NaHCOs (500 mL) and extracted with CH 2 Cl 2 (200 mL×2). The combined organic layers was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜6% MeOH in CH 2 Cl 2 ), the title compound (Intermediate 76, 510 mg, yield: 90%) was obtained as a yellow solid. MS: m/z=516.0, 518.0 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.19 (s, 1H), 5.40-5.18 (m, 1H), 4.88-4.67 (m, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.36-4.25 (m, 2H), 4.01-3.91 (m, 1H), 3.68-3.54 (m, 2H), 3.17-3.00 (m, 4H), 2.90-2.79 (m, 1H), 2.38-2.28 (m, 1H), 2.19-2.04 (m, 2H), 2.02-1.95 (m, 1H), 1.93-1.76 (m, 3H). 19 F NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ −130.07, −172.22.

To a solution of 8-bromo-6-fluoro-4-iodoisoquinolin-5-ol (900 mg, 2.45 mmol, HBr salt) in DMF (20 mL) were added K 2 CO 3 (1 g, 7.34 mmol) and CH 2 FBr (276 mg, 2.45 mmol). The mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with H 2 O (40 mL) and extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜7% EtOAc in petroleum ether), the title compound (660 mg, yield: 67%) was obtained as an off-white solid. MS: m/z=399.6, 401.7 [M+H] + . 1 HNMR (400 MHZ, Chloroform-d) δ 9.51 (s, 1H), 9.14 (s, 1H), 7.81 (d, J=9.6 Hz, 1H), 5.79 (d, J=52.8 Hz, 2H). 19 F. NMR (400 MHz, Chloroform-d) δ −119.592, −119.630, −152.488.

A mixture of 8-bromo-6-fluoro-5-(fluoromethoxy)-4-jodoisoquinoline (660 mg, 1.65 mmol), Sn 2 Me 6 (3.46 mL, 16.0 mmol) and Pd (PPh 3 ) 4 (190 mg, 165 μmol) in 1,4-dioxane (10 mL) was degassed and purged with N 2 three times, then the mixture was stirred at 90° C. for 20 hr under N 2 atmosphere. Another SnzMe6 (1.31 mL, 6.32 mmol) and Pd (PPh 3 ) 4 (190 mg, 165 μmol) were added, and the mixture was degassed and purged with N 2 three times. The mixture was stirred at 90° C. for another 20 hr under N 2 atmosphere. The reaction mixture was quenched with saturated KF (10 mL) at 25° C., diluted with H 2 O (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜3% EtOAc in petroleum ether), the title compound (200 mg, yield: 25%) was obtained as an off-white solid. MS: m/z=437.7, 439.8 [M+H] + . 1 HNMR (400 MHZ, Chloroform-d) δ 9.51 (s, 1H), 8.73-8.64 (m, 1H), 7.70 (d, J=12.0 Hz, 1H), 5.98 (d, J=52.8 Hz, 2H), 0.40 (s, 9H). 19 F NMR (400 MHz, Chloroform-d) δ −127.057, −150.704, −150.749.

A solution of 8-bromo-6-fluoro-5-(fluoromethoxy)-4-(trimethylstannyl) isoquinoline (200 mg, 457 μmol) in THE (4 mL) was degassed and purged with N 2 three times, and the mixture was stirred at −40° C. for 5 min under N 2 atmosphere. Then i-PrMgCl (1.4 mL, 2 M) was added dropwise at −40° C. The resulting mixture was stirred at −40° C. for 2 hr under N 2 atmosphere. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution (5 mL) at 0° C. and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜5% EtOAc in petroleum ether), the title compound (Intermediate 77, 100 mg, yield: 57%) was obtained as an off-white solid. MS: m/z=357.8 [M+H] + . 1 HNMR (400 MHZ, Chloroform-d) δ 9.15 (s, 1H), 8.60 (s, 1H), 7.74 (dd, J=9.2, 5.2 Hz, 1H), 7.43 (dd, J=12.4, 9.2 Hz, 1H), 6.00 (d, J=52.0 Hz, 2H), 0.40 (s, 9H). 19 F NMR (400 MHz, Chloroform-d) 6-127.405, −150.461.

To a solution of 4-fluoro-3-methoxybenzaldehyde (4.3 g, 27.9 mmol) in H 2 O (45 mL) were added KBr (16.6 g, 139 mmol) and Brz (69.9 mmol, 3.6 mL). The mixture was stirred at 25° C. for 16 hr. The mixture was filtered, and the wet cake washed with H 2 O (50 mL×3). Then the wet cake was dried to give the title compound (6.4 g, yield: 98%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 10.24 (s, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.38 (d, J=10.0 Hz, 1H), 3.94 (s, 3H). 19 F NMR (400 MHz, Chloroform-d) δ −121.761.

To a solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (36 g, 154 mmol) and 2,2-dimethoxyethanamine (19.5 g, 185 mmol) in CH 2 Cl 2 (500 mL) was added NaBH (OAc) 3 (98.2 g, 463 mmol) at 0° C. The mixture was stirred at 25° C. for 16 hr under N 2 atmosphere. The reaction mixture was quenched with saturated NaHCO 3 (500 mL) at 0° C. and extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜100% EtOAc in petroleum ether), the title compound (18.4 g, yield: 69%) was obtained as a yellow oil. MS: m/z=321.9, 323.9 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J=4.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 2H), 3.64 (br s, 1H), 3.36 (s, 6H), 2.75 (d, J=5.2 Hz, 2H). 19 F. NMR (400 MHz, Chloroform-d) δ −134.569.

To a solution of N-(2-bromo-4-fluoro-5-methoxybenzyl)-2,2-dimethoxyethan-1-amine (16 g, 49.7 mmol) in CH 2 Cl (500 mL) were added Py (12 mL, 149 mmol) and TsCl (11.4 g, 59.6 mmol) at 0° C. The mixture was stirred at 25° C. for 16 hr. The reaction mixture was diluted with H 2 O (500 mL) and extracted with CH 2 Cl 2 (500 mL×2). The combined organic layers were washed with brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜100% EtOAc in petroleum ether), the title compound (22.6 g, yield: 93%) was obtained as a white solid. MS: m/z=497.8, 499.8 [M+Na] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.73 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.21 (d,.J=10.4 Hz, 1H), 7.16 (d,.J=8.8 Hz, 1H), 4.45 (s, 2H), 4.37 (t, J=5.2 Hz, 1H), 3.83 (s, 3H), 3.28 (d, J=5.6 Hz, 2H), 3.23 (s, 6H), 2.44 (s, 3H). 19 F. NMR (400 MHz, Chloroform-d) δ −134.509.

N-(2-bromo-4-fluoro-5-methoxybenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (19 g, 39.9 mmol) was added in ClSO3H (20 mL) at 0° C., then the mixture was stirred at 90° C. for 5 min. The reaction mixture was poured onto ice, neutralized with NaHICOs, and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether), the title compound (7.1 g, yield: 69%) was obtained as a white solid. MS: m/z=256.0, 258.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H), 7.66 (d, J=11.2 Hz, 1H), 4.16 (d, J=2.8 Hz, 3H). 19 F NMR (400 MHZ, Chloroform-d) δ −125.589.

To a solution of 8-bromo-6-fluoro-5-methoxyisoquinoline (2.6 g, 10.15 mmol) and I 2 (3.09 g, 12.18 mmol) in ACN (30 mL) was added TBHP (11 mL, 81.2 mmol, 70% purity in H 2 O). The mixture was stirred at 90° C. for 16 hr under N 2 atmosphere. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether), the title compound (3.2 g, yield: 80%) was obtained as a yellow solid. MS: m/z=381.9, 383.8 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.49 (s, 1H), 9.07 (s, 1H), 7.78 (d, J=10.4 Hz, 1H), 4.05 (d, J=0.8 Hz, 3H). 19 F. NMR (400 MHz, Chloroform-d) δ −120.516.

A mixture of 8-bromo-6-fluoro-4-iodo-5-methoxyisoquinoline (1.7 g, 4.45 mmol), SnzMe6 (5.49 mL, 26.5 mmol) and Pd (PPh 3 ) 4 (514 mg, 445 μmol) in 1,4-dioxane (30 mL) was degassed and purged with N 2 three times, then the mixture was stirred at 90° C. for 16 hr under N 2 atmosphere. The reaction mixture was quenched with sat. KF solution (20 mL) at 25° C., and diluted with H 2 O) (50 mL), and extracted with CH 2 Cl 2 (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether), the title compound (500 mg, yield: 18%) was obtained as a white solid. MS: m/z=418.0, 420.0, 422.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.48 (s, 1H), 8.63 (s, 1H), 7.65 (d,.J=12.4 Hz, 1H), 4.21 (d,.J=5.2 Hz, 3H), 0.38 (s, 9H). 19 F NMR (400 MHZ, Chloroform-d) δ −121.611.

A solution of 8-bromo-6-fluoro-5-methoxy-4-(trimethylstannyl) isoquinoline (450 mg, 1.07 mmol) in THE (5 mL) was degassed and purged with N 2 three times, then the mixture was stirred at −40° C. for 10 min under N 2 atmosphere. Then i-PrMgCl (2 M, 3.22 mL) was added dropwise at −40° C. The resulting mixture was stirred at −40° C. for 30 min. The reaction mixture was quenched with 1 M HCl (5 mL) at 0° C. and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜30% EtOAc in petroleum ether), the title compound (Intermediate 78, 130 mg, yield: 35%) was obtained as a white solid. MS: m/z=342.1 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.12 (s, 1H), 8.55 (s, 1H), 7.58 (dd, J=8.8, 4.8 Hz, 1H), 7.36 (dd, J=13.2, 9.2 Hz, 1H), 4.21 (d, J=5.2 Hz, 3H), 0.37 (s, 9H). 19 F NMR (400 MHZ, Chloroform-d) δ −127.751.

To a solution of 8-bromo-6-fluoro-4-iodo-5-methoxyisoquinoline (5 g, 13.1 mmol) in HBr (50 mL, 40% in H 2 O) was degassed and purged with N 2 three times. The mixture was stirred at 120° C. for 16 hr under N 2 atmosphere. The reaction mixture was filtered, and the wet cake was concentrated under reduced pressure. The title compound (3.98 g, HBr salt, yield: 82%) was obtained as a yellow solid. MS: m/z=367.9, 369.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) § 11.2 (br s, 1H), 9.33 (s, 1H), 8.98 (s, 1H), 8.16 (d, J=10.4 Hz, 1H). 19 F NMR (400 MHz, Dimethylsulfoxide-d 6 ) ¿-127.200.

To a solution of 8-bromo-6-fluoro-4-iodo-isoquinolin-5-ol (2 g, 4.46 mmol, HBr salt) in DMF (50 mL) was added K 2 CO 3 (1.9 g, 13.3 mmol). After addition, the mixture was stirred at 25° C. for 1 hr, and then fluoromethyl-d 2 4 -methylbenzenesulfonate (918 mg, 4.46 mmol) was added at 25° C. The resulting mixture was stirred at 70° C. for 15 hr. The reaction mixture was diluted with H 2 O) (200 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜10% EtOAc in petroleum ether), the title compound (1.3 g, yield: 72%) was obtained as a white solid. MS: m/z=401.7, 403.7 [M+H] + . HNMR (400 MHZ, Chloroform-d)δ 9.51 (s, 1H), 9.14 (s, 1H), 7.80 (d, J=9.6 Hz, 1H). 19 F. NMR (400 MHZ, Chloroform-d) δ −119.713, −153.749, −153.771.

A mixture of 8-bromo-6-fluoro-5-(fluoromethoxy-d 2 )-4-iodoisoquinoline (1.3 g, 3.23 mmol), Sn 2 Me 6 (4.0 mL, 19.4 mmol) and Pd (PPb 3 ) 4 (373 mg, 323 μmol) in 1,4-dioxane (15 mL) was degassed and purged with N 2 three times, and the mixture was stirred at 90° C. for 20 hr under N 2 atmosphere. Sn 2 Me 6 (4.05 mL, 19.5 mmol) and Pd(PPh 3 ) 4 (373 mg, 323 μmol) were added. The mixture was degassed and purged with N 2 three times. The mixture was stirred at 90° C. for another 20 hr under N 2 atmosphere. The reaction mixture was quenched with sat. KF solution (10 mL) at 25° C., diluted with H 2 O (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. After purification by silica gel flash chromatography (Eluent of 0˜6% EtOAc in petroleum ether), the title compound (Intermediate 79, 200 mg, yield: 16%) was obtained as an off-white solid. MS: m/z=361.9 [M+H] + . 1 HNMR (400 MHZ, Chloroform-d)δ 9.19 (s, 1H), 8.60-8.50 (m, 1H), 8.06-8.01 (m, 1H), 7.58-7.51 (m, 1H), 0.50 (s, 9H). 19 F NMR (400 MHz, Chloroform-d) δ −128.178, −149.276, −149.298.

To a solution of 6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (100 g, 567.5 mmol) and O-methylhydroxylamine hydrochloride (56.9 g, 681 mmol) in EtOH (1.5 L) was added pyridine (68.7 mL, 851 mmol) dropwise at 20° C. The mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (800 mL) and extracted with EtOAc (800 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (110 g, 98% purity) as a brown oil, which was used in the step without further purification. MS: m/z=206.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J=8.8 Hz, 1H), 6.75 (dd, J=2.8, 8.8 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 3.96 (s, 3H), 3.81 (s, 3H), 2.71 (t, J=6.4 Hz, 4H), 1.90-1.75 (m, 2H).

To a solution of 6-methoxy-3,4-dihydronaphthalen-1 (2H)-one O-methyl oxime (48 g, 234 mmol) in AcOH (2 L) were added NBS (41.62 g, 234 mmol) and Pd (OAc) 2 (5.25 g, 23.4 mmol). The mixture was stirred at 60° C. for 1 h under N 2 . The reaction mixture was concentrated under reduced pressure, diluted with H 2 O (1 L), and extracted with EtOAc (1 L×3). The combined organic layers were washed with brine (1 L), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (130 g, 88% purity) as a black-brown solid, which used in the next step without further purification. MS: m/z=283.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 )δ 7.09 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.64 (d,.J=2.4 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 2.67-2.55 (m, 6H).

To a solution of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one O-methyl oxime (29 g, 102.06 mmol) in 1,4-dioxane (300 mL) was added HCl (6 M in water, 290 mL). The mixture was stirred at 90° C. for 2 h. The reaction mixture was quenched with sat. Na 2 COsaq. (300 mL) at 0° C. and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜7% of EtOAc in Petroleum ether) to give the title compound (17.6 g, 61% yield for 3 step) as a yellow solid. MS: m/z=254.9, 256.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 7.14 (d, J=2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 3.84 (s, 3H), 2.94 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.4 Hz, 2H), 2.01-1.92 (m, 2H).

To a solution of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (48 g, 188 mmol) in MeOH (480 mL) was added H 2 SO 4 (3.36 mL, 63.03 mmol) and SelectFluor (80 g, 225.8 mmol). The mixture was stirred at 50° C. for 5 h. The reaction mixture was concentrated under reduced pressure, diluted with H 2 O (400 mL) and extracted with EtOAc (400 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (48 g, 86% yield) as a brown solid, which was used in the next step without further purification. MS: m/z=272.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.15 (d, J=2.4, 1H), 7.79 (d, J=2.4, 1H), 5.13-4.97 (m, 1H), 3.86 (s, 3H), 3.14-3.09 (m, 2H), 2.54-2.46 (m, 1H), 2.36-2.30 (m, 1H). 19 F. NMR (376 MHz, Chloroform-d) δ −188.61.

To a solution of 8-bromo-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (47 g, 173.6 mmol) in ACN (470 mL) was added PyBr3 (60.54 g, 189.3 mmol). The mixture was stirred at 70° C. for 2 h under N 2 . The reaction mixture was quenched with H 2 O (500 mL) at 25° C. and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was triturated with mixture solvents (Petroleum ether/Ethyl acetate=10/1, 200 mL) at 25° C. for 30 min to give the title compound (55 g, 90% yield) as a brown solid. MS: m/z=352.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) & 7.22 (s, 1H), 6.72 (d, J=1.6 Hz, 1H), 3.89 (s, 3H), 3.38-3.30 (m, 1H), 3.13-3.07 (m, 1H), 2.85-2.79 (m, 1H), 2.67-2.57 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −111.58.

To a solution of 2,8-dibromo-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (54 g, 153.4 mmol) in DMF (540 mL) was added LiBr (29.3 g, 337.5 mmol). The mixture was stirred at 100° C. for 1 h. The reaction mixture was quenched with H 2 O (500 mL) at 25° C. and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (400 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was triturated with mixture solvents (Petroleum ether/Ethyl acetate=10/1, 200 mL) at 25° C. for 30 min to give the title compound (40.17 g, 96% yield) as a brown solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J=2.4, 1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.11-7.10 (m, 1H), 7.06-7.05 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −141.77.

To a solution of 8-bromo-2-fluoro-6-methoxynaphthalen-1-ol (6 g, 22.13 mmol) in CH 2 Cl 2 (6.5 mL) was added BBr3 (6.40 mL, 66.40 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was quenched with H 2 O (100 mL) dropwise at 25° C. The pH of the mixture was adjusted to 7 with sat. NaHCO 3 aq. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was triturated with CH 2 Cl 2 (10 mL) at 25° C. for 0.5 h to give the title compound (4.86 g, 86% yield) as a white solid. 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.94-9.90 (m, 2H), 7.37-7.32 (m, 2H), 7.23-7.19 (m, 1H), 7.09-7.08 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −141.22.

To a solution of 8-bromo-2-fluoronaphthalene-1,6-diol (2 g, 7.78 mmol) in DMF (12 mL) was added K 2 CO 3 (3.23 g, 23.3 mmol). Then iodomethane-d 3 (1.21 g, 8.56 mmol) was added dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. for 2 h under N 2 . The reaction mixture was quenched with H 2 O (80 mL) at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜6% of EtOAc in Petroleum ether) to give the title compound (1.65 g, 77% yield) as a yellow oil. MS: m/z=271.8, 273.8 [M−H] − . 3H NMR (400 MHZ, Chloroform-d)δ 7.44 (d,)=2.4 Hz, 1H), 7.37-7.30 (m, 1H), 7.25-7.20 (m, 1H), 7.08-7.03 (m, 1H), 5.45-5.18 (m, 1H). 1F NMR (376 MHz, Chloroform-d) δ −133.58.

To a solution of 4-bromo-6-fluoro-5-(methoxy-d 3 ) naphthalen-2-ol (1.65 g, 6.02 mmol) in CH 2 Cl 2 (60 mL) was added DIPEA (3.15 mL, 18.1 mmol). Then Tf2O (1.19 mL, 7.22 mmol) was added dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 . The reaction mixture was quenched with H 2 O (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜15% of EtOAc in Petroleum ether) to give the title compound (2.3 g, 94% yield) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ 7.77-7.66 (m, 2H), 7.64-7.58 (m, 1H), 7.50-7.42 (m, 1H), 19 F. NMR (376 MHz, Chloroform-d) 6-72.65, −127.40.

A mixture of 4-bromo-6-fluoro-5-(methoxy-d 3 ) naphthalen-2-yl trifluoromethanesulfonate (2.2 g, 5.42 mmol), diphenylmethanimine (982 mg, 5.42 mmol), XantPhosPdG3 (514 mg, 542 μmol) and Cs 2 CO 3 (5.29 g, 16.3 mmol) in 1,4-dioxane (30 mL) was degassed, purged with N 2 three times, and stirred at 80° C. for 8 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜2% of EtOAc in Petroleum ether) to give the title compound (900 mg, 36% yield) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) & 7.79-7.74 (m, 2H), 7.53-7.48 (m, 1H), 7.45-7.40 (m, 2H), 7.33-7.27 (m, 5H), 7.24-7.18 (m, 1H), 7.17-7.12 (m, 2H), 7.02 (d,.J=1.6 Hz, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −132.05.

Step 11: N-(6-Fluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-yl)-1,1-diphenylmethanimine & 6-fluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-2-amine

A mixture of N-(4-bromo-6-fluoro-5-(methoxy-d 3 ) naphthalen-2-yl)-1,1-diphenylmethanimine (850 mg, 1.94 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (592 mg, 2.33 mmol), CysPPdG3 (159 mg, 194 μmol) and KOAc (572 mg, 5.83 mmol) in 1,4-dioxane (18 mL) was degassed, purged with N 2 three times, and stirred at 100° C. for 1 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜100% of EtOAc in Petroleum ether) to give the title compound (Intermediate 80, 400 mg, 41% yield) as a yellow solid and the title compound (Intermediate 81, 400 mg, 51% yield) as a yellow solid. Spectrum for Intermediate 80: MS: m/z=485.3 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.77 (d, J=7.6, 2H), 7.50-7.37 (m, 3H), 7.25-7.17 (m, 4H), 7.17-7.07 (m, 4H), 6.95 (s, 1H), 1.38 (s, 12H). 19 F NMR (376 MHz, Chloroform-d) δ −134.96. Spectrum for Intermediate 81: MS: m/z=321.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) ò 7.24-7.20 (m, 1H), 7.17-7.11 (m, 1H), 6.99 (s, 1H), 6.95-6.92 (m, 1H), 1.24 (s, 12H). 19 F NMR (376 MHz, Chloroform-d) δ −137.97.

To a solution of methyl (triphenyl)phosphonium bromide (37.21 g, 104.16 mmol) in THF (200 mL) was added dropwise t-BuOK (94.69 mL, 1 M in THF) at 0° C. under N 2 . The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to 25° C. A solution of ethyl(S)-2,5-dioxotetrahydro-1/-pyrrolizine-7a (5H)-carboxylate (10 g, 47.4 mmol) in THF (200 mL) was added dropwise to the above mixture at 25° C. The mixture was stirred for another 1 h at the same temperature. The reaction mixture was quenched with sat. NHACl aq. (300 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 20˜50% EtOAc in petroleum ether) to give the title compound (6.9 g, 18% yield) as a yellow oil. MS: m/z=210.1 [M+H] + . 3H NMR (400 MHZ, Chloroform-d)δ 5.16-4.95 (m, 2H), 4.29 (d, J=15.6 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.72 (d, J=15.6 Hz, 1H), 3.05 (d, J=16.0 Hz, 1H), 2.85-2.71 (m, 1H), 2.66-2.56 (m, 1H), 2.53-2.39 (m, 2H), 2.12 (td, J=10.4, 12.8 Hz, 1H), 1.27 (,)=7.2 Hz, 3H).

Step 2: Ethyl (1R,7a'S)-2-bromo-2-fluoro-5′-oxodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizine]-7a′(5′H)-carboxylate & ethyl (15,7a'S)-2-bromo-2-fluoro-5′-oxodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizine]-7a′(5′H)-carboxylate

A mixture of ethyl(S)-2-methylene-5-oxotetrahydro-1/-pyrrolizine-7a (5H)-carboxylate (6.9 g, 33.0 mmol), dibromo (fluoro) methane (18.7 g, 97.5 mmol, 11.0 mL) and benzyl (triethyl) ammonium chloride (740 mg, 3.25 mmol) in CH 2 Cl 2 (100 mL) and NaOH (20 mL, 50% in water) was degassed, purged with N 2 three times, and stirred at 40° C. for 16 h under N 2 atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 20%˜60% EtOAc in petroleum ether) to give the title compound (Intermediate 82, 2.0 g, 19% yield, the first peak) as a yellow oil and the title compound (Intermediate 83, 1.2 g, 12% yield, the second peak) as a yellow oil. Spectra for Intermediate 82: MS: m/z=319.9, 321.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 4.25 (qd, J=1.2, 7.2 Hz, 2H), 4.14-4.01 (m, 1H), 3.19-2.96 (m, 1H), 2.89-2.74 (m, 1H), 2.63-2.45 (m, 2H), 2.36-2.12 (m, 3H), 1.72-1.58 (m, 1H), 1.45-1.33 (m, 1H), 1.30 (t, J=7.2 Hz, 3H). 19 F. NMR (376 MHz, Chloroform-d) δ −134.78, −135.52. Spectra for Intermediate 83: MS: m/z=320.0, 322.0 [M+H] + . 3H NMR (400 MHz, Chloroform-d) δ 4.36-4.20 (m, 2H), 3.79-3.63 (m, 1H), 3.48 (t, J=11.8 Hz, 1H), 2.86-2.67 (m, 2H), 2.62-2.44 (m, 2H), 2.21-1.97 (m, 2H), 1.66 (dd, J=8.4, 17.2 Hz, 1H), 1.46-1.37 (m, 1H), 1.34 (td, J=3.2, 7.2 Hz, 3H). 19 F NMR (376 MHz, Chloroform-d) δ −136.09, −136.57.

To a solution of Intermediate 83 (1.20 g, 3.75 mmol) in EtOH (24 mL) were added NH 4 Cl (4.01 g, 75.0 mmol) and Zn (2.21 g, 33.73 mmol) in batches. The mixture was stirred at 80° C. for 6 h under N 2 . The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC(column: CD 02 -Waters Xbidge BEH C 18 150×25 x 10 μm, mobile phase: [water (NH 3 H 2 O)-ACN]; gradient: 16%˜36% B over 13 min) to give the title compound (Intermediate 84, 19 FNMR: −211.68 ppm, 250 mg, 28% yield, LCMS peak 1, retention time: 1.122 min) as a yellow oil and the title compound (Intermediate 85, 19FNMR: −210.32 ppm, 340 mg, 38% yield, LCMS peak 2, retention time: 1.178 min) as a yellow oil. Spectra for Intermediate 84: MS: m/z=242.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 4.49-4.18 (m, 3H), 3.69 (d, J=11.6 Hz, 1H), 3.32 (d, J=11.6 Hz, 1H), 2.92-2.76 (m, 1H), 2.60-2.42 (m, 2H), 2.20-1.97 (m, 2H), 1.85 (dd, J=7.2, 12.8 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H), 1.07-0.88 (m, 2H), 19 F. NMR (376 MHz, Chloroform-d) δ −211.68. Spectra for Intermediate 85: MS: m/z=242.1 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 4.50-4.28 (m, 1H), 4.28-4.16 (m, 2H), 3.55 (dd, J=5.6, 11.2 Hz, 1H), 2.98 (d,J=11.2 Hz, 1H), 2.85-2.72 (m, 1H), 2.69-2.57 (m, 1H), 2.54-2.42 (m, 2H), 2.24-2.11 (m, 1H), 2.02 (d, J=12.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H), 1.11-0.91 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −210.32.

To a solution of Intermediate 84 (150 mg, 622 μmol) in THF (5 mL) was added dropwise LiAlH4 (1.24 mL, 2.5 M in THF) at 0° C. under N 2 . The mixture was stirred at 65° C. for 2 h under N 2 . The reaction mixture was quenched with Na 2 SO 4 ·10H 2 O (300 mg) slowly. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜15% MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 86, 95 mg, 82% yield, structure tentatively assigned) as a yellow oil. MS: m/z=185.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 4.64-4.32 (m, 1H), 3.46-3.30 (m, 2H), 3.25 (d, J=10.8 Hz, 1H), 3.13-3.04 (m, 1H), 2.88-2.77 (m, 2H), 2.02-1.77 (m, 4H), 1.75-1.67 (m, 2H), 1.01-0.78 (m, 2H). 19 F NMR (376 MHZ, Chloroform-d) δ −213.17.

Intermediate 87 (structure tentatively assigned) was prepared in a manner similar to Intermediate 86. MS: m/z=185.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) 4.56-4.33 (m, 1H), 3.47-3.33 (m, 2H), 3.11-3.03 (m, 1H), 2.90-2.62 (m, 4H), 2.01-1.83 (m, 5H), 1.80-1.72 (m, 1H), 0.99-0.80 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −210.87.

To a solution of Intermediate 82 (2.05 g, 6.40 mmol) in EtOH (40 mL) were added Zn (2.09 g, 32.0 mmol) and NH 4 Cl (3.08 g, 57.63 mmol) slowly under N 2 . The mixture was stirred at 70° C. for 8 h under N 2 . The reaction mixture was filtered, diluted with H 2 O (50 mL), and extracted with CH 2 Cl 2 (100 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜40% of ethyl acetate in petroleum ether) to give crude product. Then the crude product was purified by prep-HPLC (column: CD06-Waters Xbidge C18 150×40×10 μm; mobile phase: [water (NH 3 H 2 O)-ACN]; gradient: 15%˜45% B over 10 min) to give the title compound (Intermediate 88, 19F NMR: −211.75 ppm, 600 mg, 31% yield) and the title compound (Intermediate 89, 1° F. NMR: −211.09 ppm, 595 mg, 37% yield). Spectra for Intermediate 88: MS: m/z=242.0 [M+H] + . 1H NMR (400 MHZ, Chloroform-d)δ 4.63-4.37 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.98 (d, J=12.0 Hz, 1H), 3.10 (d, J=12.0 Hz, 1H), 2.87-2.69 (m, 1H), 2.59-2.39 (m, 2H), 2.18-1.93 (m, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.05-0.85 (m, 2H). 19 F. NMR (376 MHz, Chloroform-d)δ −211.75. Spectra for Intermediate 89: MS: m/z=242.1 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 4.67-4.40 (m, 1H), 4.25 (q,)=7.2 Hz, 2H), 3.65 (dd, J=2.0, 11.6 Hz, 1H), 2.91 (dd, J=6.0, 11.6 Hz, 1H), 2.83-2.72 (m, 1H), 2.66-2.57 (m, 1H), 2.50-2.41 (m, 1H), 2.36 (d, J=13.2 Hz, 1H), 2.19-2.07 (m, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.09-0.98 (m, 1H), 0.93-0.84 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) 6-211.09.

To a solution of Intermediate 88 (300 mg, 1.24 mmol) in THF (6 mL) was added dropwise LiAIH4 (2.49 mL, 2.5 M in THF) at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 . Then the mixture was stirred at 70° C. for 2.5 h under N 2 . The reaction mixture was quenched with Na 2 SO 4 . 10H 2 O) (3 g) slowly, filtered and the filter cake was washed with EtOAc (80 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (cluent: 0˜15% of MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 90, 178 mg, 77% yield, structure tentatively assigned) as an off-white solid. 1 H NMR (400 MHz, Chloroform-d) & 4.61-4.33 (m, 1H), 3.43-3.26 (m, 2H), 3.21-3.11 (m, 2H), 2.85 (d, J=12.0 Hz, 1H), 2.78-2.66 (m, 1H), 1.92-1.71 (m, 5H), 1.48 (d, J=13.2 Hz, 1H), 0.94-0.76 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −207.27.

To a solution of Intermediate 89 (300 mg, 1.24 mmol) in THF (6 mL) was added dropwise LiAlH 4 (2.5 M in THE, 2.49 mL) at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 , and then at 70° C. for 2.5 h under N 2 . The reaction mixture was quenched with Na 2 SO 4 ·10·H 2 O (3 g) slowly and washed with EtOAc (80 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 91, 200 mg, 87% yield, structure tentatively assigned) as a colorless gum. MS: m/z=185.8 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 4.66-4.36 (m, 1H), 3.46-3.41 (m, 1H), 3.40-3.33 (m, 1H), 3.21-3.14 (m, 1H), 3.00 (dd, J=7.2, 12.0 Hz, 1H), 2.82-2.74 (m, 1H), 2.47 (d, J=11.6 Hz, 1H), 2.04-1.98 (m, 1H), 1.94-1.84 (m, 3H), 1.83-1.68 (m, 2H), 0.94-0.83 (m, 1H), 0.79-0.71 (m, 1H). 19 F. NMR (376 MHZ, Chloroform-d) δ −209.92.

To an ice-cooled solution of 5-bromo-2-fluoro-3-methylaniline (2 g, 9.80 mmol) in DMF (16.7 mL) was added NaH (0.71 g, 29.40 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring in an ice bath for 30 min, PMBCl (3.07 g, 19.60 mmol) was added to the above mixture in an ice bath. The ice bath was removed, and the reaction mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was quenched with sat. aq. NH 4 Cl (50 mL) in an ice bath and extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (3.7 g, 84% yield) as a light yellow oil. MS: m/z=443.90, 445.90 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.18-7.16 (m, 4H), 6.88-6.81 (m, 6H), 4.19 (s, 4H), 3.79 (s, 6H), 3.79 (s, 6H), 2.24 (d, J=2.8 Hz, 3H). 19 F NMR (376 MHz, Chloroform-d) δ −128.45 (s, 1F).

To an ice-cooled solution of 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methylaniline (2.7 g, 6.07 mmol) in acetic acid (22 mL) was added NIS (1.50 g, 6.68 mmol) under nitrogen atmosphere. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1.5 hours. The resulting mixture was quenched with sat. aq. NazS2O3 (15 mL) in an ice bath, diluted with EtOAc (150 mL), and washed with water (4×30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (2.7 g, 77% yield) as a light yellow oil. MS: m/z=570.10, 572.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.17-7.00 (m, 5H), 6.85-6.81 (m, 4H), 4.23 (s, 4H), 3.79 (s, 6H), 2.47 (d, J=3.6 Hz, 3H), 19 F NMR (376 MHz, Chloroform-d) δ −119.22-˜119.30 (d, 1F).

To a stirred solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline (900 mg, 1.57 mmol) and Cul (3.00 g, 15.78 mmol) in DMF (9 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.91 g, 15.14 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 75° C. for 4 hours. The resulting mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-10% EA in PE to afford the title compound (700 mg, 86% yield) as a colorless oil. MS: m/z=512.10, 514.10 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.18-6.83 (m, 9H), 4.33 (s, 4H), 3.80 (s, 6H), 2.42-2.35 (m, 3H). 19 F NMR (376 MHZ, Chloroform-d) δ −53.01-−54.40 (m, 3F), −138.23 (s, IF).

Step 4: 2-Fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl) aniline

To a stirred solution of 5-bromo-2-fluoro-N,N-bis [(4-methoxyphenyl)methyl]-3-methyl-4-(trifluoromethyl) aniline (700 mg, 1.36 mmol) and bis (pinacolato)diboron (693.90 mg, 2.732 mmol) in 1,4-dioxane (7.0 mL) were added Pd (dppf)Cl 2 -DCM (222.60 mg, 0.27 mmol) and KOAc (402.27 mg, 4.09 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 110° C. for 2 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (10: 1) to afford the title compound (Intermediate 92, 300 mg, 39% yield) as a colorless oil. MS: m/z=560.40 [M+H] +.

To an ice-cooled mixture of(S)-(2-methylenetetrahydro-1H-pyrrolizin-7a (5H)-yl) methanol (3 g, 19.57 mmol) and imidazole (3327.31 mg, 48.94 mmol) in DMF (30 mL) under nitrogen atmosphere was added TBDPSCl (6457.80 mg, 23.49 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with EA (500 mL), washed with water (3×100 mL) and brine (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 3% MeOH in DCM to afford the title compound (6.5 g, 84% yield) as a yellow oil. MS: m/z=392.20 [M+H] +.

Step 2: (7a'S)-7a′-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-difluorotetrahydro-1′,3′H-spiro[cyclopropane-1,2′-pyrrolizine]

To a solution of(S)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylenehexahydro-1H-pyrrolizine (4 g, 10.21 mmol) and Nal (765.49 mg, 5.10 mmol) in THF (50 mL) under nitrogen atmosphere was added TMSCF3 (5083.23 mg, 35.74 mmol) at room temperature. The reaction mixture was heated at 65° C. for 2.5 hours. The resulting mixture was cooled to room temperature, diluted with DCM (500 mL), washed with sat. aq. NazS2O3 (3×100 mL), dried over with Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 5% MeOH in DCM to afford the title compound (1.0 g, 22% yield) as a brown oil. MS: m/z=442.15 [M+H] +.

Step 3: ((7a'S)-2,2-Difluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizin]-7a′(5′H)-yl) methanol

To a solution of (7a'S)-7a′-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorotetrahydro-l′H,3′H-spiro[cyclopropane-1,2′-pyrrolizine](1.0 g, 2.26 mmol) in MeOH (10 mL) under nitrogen atmosphere was added NH 4 F (3354.51 mg, 90.56 mmol) at room temperature. The reaction mixture was heated at 65° C. for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 15% MeOH in DCM to afford the title compound (Intermediate 93, 450 mg, crude) as a yellow oil. MS: m/z=204.10 [M+H] +.

To a solution of ethyl (R)-6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a (5′H)-carboxylate (1.8 g, 7.65 mmol) and RuCl (60 mg, 268 μmol) in CH 2 Cl (20 mL), ACN (20 mL) and H 2 O (20 mL) was added NaIO 4 (9.82 g, 45.9 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was filtered and extracted with EtOAc (500 mL). The combined organic layers were washed with 50% Na 2 S 2 O 3 aq. (200 mL) and washed with brine (100 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 25˜50% of EtOAc in petroleum ether) to give the title compound (1.66 g, 82% yield) as a white solid. MS: m/z=238.0 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 4.39-4.14 (m, 3H), 3.45 (d, J=18.8 Hz, 1H), 3.13 (d, J=16.8 Hz, 1H), 2.91 (d, J=17.6 Hz, 1H), 2.38 (d, J=17.6 Hz, 1H), 2.19 (d, J=16.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H), 0.94-0.68 (m, 4H).

Step 2: Ethyl (7a′R)-6′-hydroxy-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate-6′-d

To a solution of ethyl (R)-3′,6′-dioxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate (1.66 g, 7.00 mmol) in EtOH (20 mL) was added NaBD4 (80 mg, 2.10 mmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 15 min under N 2 . The reaction mixture was quenched with 1N HCl (0.5 mL) at 0° C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜70% of EtOAc in petroleum ether) to give the title compound (1.6 g, 90% yield) as a colorless oil. MS: m/z=240.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) ò 5.12 (m, 1H), 4.96 (s, 1H), 4.22˜4.04 (m, 2H), 3.69-2.77 (m, 3H), 2.29-2.02 (m, 2H), 1.67-1.51 (m, 1H), 1.26-1.13 (m, 3H), 0.92-0.56 (m, 4H).

Step 3: Ethyl (6′R,7a′R)-6′-fluoro-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate-6′-d & ethyl (6'S,7a′R)-6′-fluoro-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate-6′-d

To a mixture of ethyl (7a′R)-6′-hydroxy-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate-6′-d (2.0 g, 8.32 mmol) in CH 2 Cl 2 (30 mL) was added DAST (2.2 mL, 16.7 mmol) at −70° C. under N 2 . The mixture was stirred at 25° C. for 5 h under N 2 . The reaction mixture was quenched with MeOH (10 mL) at 25° C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜35% of EtOAc in petroleum ether) to give the title compound (Intermediate 94, 400 mg, 19% yield) and (eluent: 35˜42% of EtOAc in petroleum ether) to give the title compound (Intermediate 95, 700 mg, 33% yield) as a white solid. Spectra for Intermediate 94: MS: m/z=243.1 [M+H] + . 1 HNMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 4.22-4.10 (m, 2H), 4.05-3.90 (m, 1H), 3.18-3.02 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 2.47-2.34 (m, 1H), 2.09-1.95 (m, 2H), 1.25-1.19 (m, 3H), 1.00-0.92 (m, 1H), 0.74-0.57 (m, 3H). 19 F NMR. (376 MHz, Dimethylsulfoxide-d 6 ) δ −176.26, −176.29. Spectra for Intermediate 95: MS: m/z=243.0 [M+H] + . 1 HNMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 4.21-4.09 (m, 2H), 4.00-3.83 (m, 1H), 3.21-3.06 (m, 1H), 2.95-2.86 (m, 1H), 2.44-2.33 (m, 1H), 2.15 (d, J=16.8 Hz, 1H), 2.00-1.78 (m, 1H), 1.19 (t, J=7.2 Hz, 3H), 0.88-0.80 (m, 1H), 0.73-0.60 (m, 3H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) 8 -169.86.

To a solution of Intermediate 94 (200 mg, 826 μmmol) in THF (10 mL) was added LiAlD 4 (95 mg, 2.06 mmol) at 0° C. under N 2 . The mixture was stirred at 65° C. for 2 h. Then D 2 O (0.5 mL) was added to the reaction at 0° C. And then 15 wt % NaOH (0.5 mL) was added dropwise followed by addition of water (1.5 mL). The mixture was stirred at 20° C. for 0.5 h, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (CH 2 Cl/McOH (0.5% NH 3 )=10/1 to 5/1) to give the title compound (210 mg, 64% yield) as a brown solid. 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 )δ: 3. 24-3.12 (m, 2H), 2.09-1.94 (m, 1H), 1.87-1.68 (m, 3H), 0.75-0.66 (m, 1H), 0.64-0.54 (m, 1H), 0.50-0.40 (m, 2H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −173.27.

Intermediate 97 was prepared in a manner similar to Intermediate 96. JH NMR (400 MHZ, Chloroform-d)δ 4.54-4.05 (m, 1H), 3.23-3.12 (m, 1H), 2.97-2.82 (m, 1H), 2.07-1.95 (m, 1H), 1.84-1.49 (m, 3H), 0.94-0.85 (m, 1H), 0.50-0.31 (m, 3H). 19 F NMR (376 MHZ, Chloroform-d) δ −. 173.62, −173.63.

To a solution of 2-(6-bromo-2,3-difluorophenyl) acetonitrile (49 g, 211 mmol) in DMF (500 mL) was added/-BuOK (26 g, 232 mmol) at −10° C. and stirred for 30 min, then O-ethyl carbonisothiocyanatidate (27 mL, 229 mmol) was added at −10° C. The mixture was stirred at 100° C. for 2 h. The resulting mixture was added to water (500 mL), filtered and the filter cake was dried to give the title compound (67 g, crude) as a yellow solid, which was used in the next step without further purification.

To a solution of ethyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl) carbamate (31 g, 90.3 mmol) in MeOH (115 mL) was added NaOH (19.9 g, 497 mmol) in Water (95 mL), then stirred at 65° C. for 18 h. The resulting mixture was added to water (300 mL), filtered to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0˜80% of EtOAc in petroleum ether) to give the title compound (29 g, 54% yield for two steps) as a yellow solid. 1H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.22 (s, 2H), 7.55-7.44 (m, 1H), 7.02-6.92 (m, 1H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −118.10.

Step 3: 2-Amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-carbonitrile

To a solution of 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile (8 g, 29.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (14.9 g, 59 mmol), Pd (PPh 3 ) 4 (4.09 g, 3.54 mmol) and KOAc (11.6 g, 118 mmol) in 1,4-dioxane (200 mL) was stirred at 95° C. for 6 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (eluent: 0˜60% of EtOAc in petroleum ether) to give the title compound (3.8 g, 28% yield) as a yellow solid. 1H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 8.10 (s, 2H), 7.50-7.46 (m, 1H), 7.00-6.95 (m, 1H), 1.33 (s, 12H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −113.79.

To a solution of (1-ethoxycyclopropoxy)trimethylsilane (10 g, 28.68 mmol) in 2,5,8,11,14-pentaoxapentadecane (20 mL) under nitrogen atmosphere was added acetic acid (0.86 g, 14.34 mmol) at room temperature. The mixture was heated at 100° C. Ethyl 2-(triphenyl-lambda5-phosphanylidene)acetate (8.99 g, 25.81 mmol) in DCM (30 mL) was added dropwise at 100° C. for 2 hours. The reaction mixture was heated at 100° C. for 1 hour. The resulting mixture was purified by distillation under reduced pressure (0.1 atm) and the fraction was collected at 100° C. to afford the title compound (1.3 g, 18% yield) as a colorless oil. MS: m/z=127.05 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 6.23-6.22 (m, 1H), 4.25-4.18 (m, 2H), 1.49-1.41 (m, 2H), 1.32-1.19 (m, 5H).

To a stirred solution of ethyl 2-cyclopropylideneacetate (1.3 g, 10.30 mmol) in THF (30 mL) under nitrogen atmosphere were added K 2 CO 3 (1.63 g, 11.85 mmol) and methyl 2-nitroacetate (1.41 g, 11.85 mmol) at room temperature. The reaction mixture was heated at 65° C. for 16 hours. The resulting mixture was cooled to room temperature. The precipitated solids were collected by filtration and washed with EtOAc (3×30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4: 1) to afford the title compound (1.2 g, 47% yield) as a colorless oil. MS: m/z=246.00 [M+H] + . JH NMR (300 MHz, Chloroform-d) δ 5.00 (s, 1H), 4.15-4.08 (m, 2H), 3.81 (s, 3H), 2.70-2.51 (m, 2H), 1.28-1.23 (m, 3H), 1.06-0.79 (m, 4H).

To a stirred solution of methyl 2-(1-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetate (1.2 g, 4.89 mmol) in acetic acid (0.6 mL) and methanol (12 mL) was added zinc (3.20 g, 48.93 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EtOAc (1: 3) to afford the title compound (0.45 g, 54% yield) as a white solid. MS: m/z=170.00 [M+H] + . H NMR (300 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 3.74 (s, 1H), 3.67 (s, 3H), 2.44-2.39 (m, 1H), 2.02-1.96 (m, 1H), 0.84-0.55 (m, 4H).

Step 4: Methyl 6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′ #)-carboxylate

To a stirred solution of methyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylate (450 mg, 2.66 mmol) and 3-chloro-2-(chloromethyl) prop-1-ene (1.33 g, 10.64 mmol) in THF (6 mL) under nitrogen atmosphere was added LiHMDS (1 M in THF, 5.58 mL, 5.58 mmol) dropwise at −40° C. for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The resulting mixture was quenched with sat. aq. NHACl (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /EA (1: 1) to afford the title compound (170 mg, 28% yield) as a colorless oil. MS: m/z=222.00 [M+H] + . 1 H NMR (300 MHZ, Acetonitrile-d 3 ) δ 5.07-5.00 (m, 2H), 4.26-4.20 (m, 1H), 3.70 (s, 3H), 3.59-3.54 (m, 1H), 2.94-2.77 (m, 2H), 2.49-2.48 (m, 1H), 2.18-2.12 (m, 1H), 0.90-0.87 (m, 1H), 0.71-0.64 (m, 3H).

To an ice-cooled solution of methyl 6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate (170 mg, 0.76 mmol) in THF (2 mL) under nitrogen atmosphere was added LiAlH4 (0.77 mL, 1.536 mmol, 2 M in THF) dropwise. The ice bath was removed, and the reaction mixture was heated at 65° C. for 2 hours. The resulting mixture was cooled and quenched with water (0.05 mL), NaOH (0.05 mL, 15% in H 2 O), and water (0.15 mL) in an ice bath. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10% NH 4 OH) (1: 4) to afford the title compound (Intermediate 99, 90 mg, 65% yield) as a colorless oil. MS: m/z=180.05 [M+H] + . JH NMR (300 MHz, Methanol-d 4 ) δ 4.96-4.93 (m, 2H), 3.77-3.64 (m, 1H), 3.43-3.35 (m, 3H), 3.19-3.09 (m, 1H), 2.84-2.72 (m, 1H), 2.50-2.41 (m, 1H), 2.31-2.23 (m, 1H), 2.04-1.91 (m, 1H), 1.87-1.74 (m, 1H), 0.92-0.81 (m, 1H), 0.61-0.48 (m, 3H).

Step 1: (1S,7S,8S)-2-(7-Chloro-8-fluoro-2-((6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-7a′(5′/)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To an ice-cooled solution of Intermediate 99 (195.15 mg, 1.08 mmol) in THF (3 mL) under nitrogen atmosphere was added NaH (43.54 mg, 1.088 mmol, 60% dispersion in mineral oil). After stirring at ice bath for 30 min, Intermediate 112 (300 mg, 0.90 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with sat. aq. NH 4 Cl (50 mL) in an ice bath and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(CH 2 Cl 2 /MeOH 15: 1) to afford the title compound (230 mg, 51% yield) as a light yellow solid. MS: m/z=490.15 [M+H] +.

Step 2: (15,7S,8S)-2-(7-chloro-8-fluoro-2-(((S)-6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-7a′(5′H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(((R)-6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-7a′(5′/)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

The mixture of (1S,7S,8S)-2-(7-chloro-8-fluoro-2-((6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-7a′(5′/)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (230 mg, 0.46 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A: MTBE (0.5% 2 M NH 3 -MeOH)-HPLC; Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: isocratic 10% B; Detector: UV 220 & 254 nm; RT1: 10.423 min; RT2: 13.104 min.

The first eluting peak (RTI: 10.423 min) was concentrated and lyophilized to give the title compound (Intermediate 100, 80 mg, 34% yield) as an off-white lyophilized powder. MS: m/z=490.25 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.22 (s, 1H), 4.94 (s, 2H), 4.67-4.63 (m, 1H), 4.42-4.22 (m, 4H), 3.94-3.79 (m, 4H), 3.66-3.59 (m, 1H), 3.42-3.30 (m, 3H), 2.87-2.55 (m, 2H), 2.41-2.08 (m, 3H), 1.73 (s, 1H), 0.88-0.46 (m, 4H). 19 F. NMR (376 MHZ, Chloroform-d) δ −133.82-−134.52 (m, 1F), −208.48 (s, IF). The second eluting peak (RT2: 13.104 min) was concentrated and lyophilized to give the title compound (Intermediate 101, 85 mg, 36% yield) as a light-yellow lyophilized powder. MS: m/z=490.25 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 4.92 (s, 2H), 4.66-4.61 (m, 1H), 4.43-4.22 (m, 4H), 3.94-3.79 (m, 4H), 3.65-3.58 (m, 1H), 3.40-3.15 (m, 3H), 2.77-2.55 (m, 2H), 2.36-2.10 (m, 3H), 1.73-1.67 (m, 1H), 0.94-0.47 (m, 4H). 19 F NMR (376 MHz, Chloroform-d) δ −133.81-−134.52 (m, 1F), −208.47 (s, 1F).

To a solution of Intermediate 99 (150 mg, 0.84 mmol) in DCM (2.0 mL) were added diethylzinc (4.2 mL, 1 M in hexane, 4.19 mmol) and diiodomethane (1.01 g, 3.77 mmol) at −40° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The pH of the resulting mixture was adjusted to 7 with sat. aq. NH 4 Cl, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH/NHs.H 2 O (4: 1: 0.1) to afford the title compound (130 mg, 80% yield) as a yellow oil. MS: m/z=194.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 3.97-3.65 (m, 5H), 3.21-3.03 (m, 1H), 2.89-2.85 (m, 1H), 2.34-2.23 (m, 1H), 2.07-2.00 (m, 2H), 1.62-1.59 (m, 1H), 0.90-0.50 (m, 8H).

Step 2: (1S,7S,8S)-2-(7-Chloro-2-((dihydro-5′H-dispiro[cyclopropane-1,1′-pyrrolizine-6′,1″-cyclopropan]-7a′(TH)-yl) methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To an ice-cooled solution of (dihydro-5′W-dispiro[cyclopropane-1, l′-pyrrolizine-6′,1″-cyclopropan]-7a′(7′H)-yl) methanol (200 mg, 1.04 mmol) in THF (5.0 mL) was added NaH (40 mg, 1.04 mmol, 60% dispersion in mineral oil) under nitrogen atmosphere. After stirring in an ice bath for 30 minutes, a solution of Intermediate 112 (308 mg, 0.93 mmol) in THF (5.0 mL) was added to the above mixture dropwise in an ice bath. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with sat. aq. NH 4 Cl (20 mL) in an ice bath and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (300 mg, 57% yield) as a yellow oil. MS: m/z=504.15 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 9.32 (s, 1H), 4.71-4.50 (m, 4H), 4.43-4.38 (m, 1H), 4.21-4.12 (m, 1H), 3.97-3.93 (m, 1H), 3.84-3.63 (m, 3H), 3.47-3.34 (m, 3H), 2.40-1.97 (m, 6H), 0.91-0.74 (m, 8H).

Step 3: (1S,7S,8S)-2-(7-Chloro-2-(((S)-dihydro-5′H-dispiro[cyclopropane-1,1′-pyrrolizine-6′,1″-cyclopropan]-7a (7′H)-yl) methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (15,7S,8S)-2-(7-chloro-2-(((R)-dihydro-S′H-dispiro[cyclopropane-1,l′-pyrrolizine-6′,1″-cyclopropan]-7a′(7′/)-yl) methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

(1S,7S,8S)-2-(7-Chloro-2-((dihydro-5′H-dispiro[cyclopropane-1, l′-pyrrolizine-6′,1″-cyclopropan]-7a′(7H)-yl) methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (300 mg, 0.60 mmol) was separated by Prep-SFC with the following condition: Column: CHIRALPAK IG 2×25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH 3 .MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 40%; Detector: UV 220 & 254 nm; RT1: 11.89 min; RT2: 15.00 min. The first eluting peak (RT1: 11.89 min) was combined and concentrated to give the title compound (Intermediate 102, 100 mg, 33% yield) as a yellow oil. MS: m/z=504.20 [M+H] + . The second eluting peak (RT2: 15.00 min) was combined and concentrated to give the title compound (Intermediate 103, 100 mg, 33% yield) as a yellow oil. MS: m/z=504.15 [M+H] +.

To a solution of 1,4-dioxaspiro[4.5]decan-8-one (190 g, 1.22 mol) and hydroxylamine hydrochloride (338 g, 4.86 mol) in H 2 O (2000 mL) was added Na 2 CO 3 (387 g, 3.65 mol) in batches and stirred at 25° C. for 1 h. The reaction mixture was extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na 2 SO 4 , filtered and the concentrated under reduced pressure to give the title compound (200 g, crude) as a white solid, which was used in the next step without further purification. 1 HI NMR (400 MHz, Chloroform-d) δ 3.98 (d, J=1.6 Hz, 4H), 2.72-2.63 (m, 2H), 2.46-2.34 (m, 2H), 1.84-1.74 (m, 4H).

To a solution of 1,4-dioxaspiro[4.5]decan-8-one oxime (180 g, 1.05 mol) in acetone (1.8 L) was added NaOH (525 mL, 4 M in H 2 O) and then 4-methylbenzenesulfonyl chloride (200 g, 1.05 mol) in acetone (1.8 L) was added dropwise to the mixture at 25° C. under N 2 . The resulting mixture was stirred at 25° C. for 2 h. Then the reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (200 mL), and the pH of the mixture was adjusted with HCl (4 M in H 2 O) to around 7. The reaction mixture was stirred at 25° C. for 16 h. After rearrangement, the reaction mixture was extracted with CH 2 Cl 2 (5× 200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was dissolved with toluene (100 mL), and then, n-hexane (200 mL) was added to give a precipitate. The precipitate was filtered, washed with n-hexane (100 mL), and dried under reduced pressure to give the title compound (43 g, 20% yield over 2 steps) as a yellow oil. MS: m/z=171.9 [M+H] +.

To a solution of 1,4-dioxa-8-azaspiro[4.6]undecan-9-one (43 g, 251 mmol) in THF (1100 mL) was added n-BuLi (100 mL, 2.5 M in hexanes) dropwise at −78° C. under N 2 . The mixture was stirred−78° C. for 1 h, and then CbzCl (35 ml, 251 mmol) in THF (110 mL) was added dropwise at −78° C. under N 2 . The resulting mixture was stirred at 20° C. for 2 h under N 2 . The reaction mixture was quenched with sat. NH 4 Cl aq. (500 mL) at 0° C. and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜50% EtOAc in petroleum ether) to give the title compound (66 g, 87% yield) as a brown oil. 1 H NMR (400 MHZ, Chloroform-d)δ 7.45-7.28 (m, 5H), 5.28 (s, 2H), 3.96 (s, 4H), 3.94-3.88 (m, 2H), 2.79-2.72 (m, 2H), 1.94-1.85 (m, 4H).

To a solution of benzyl 9-oxo-1,4-dioxa-8-azaspiro[4.6]undecane-8-carboxylate (66 g, 216 mmol) in toluene (1.2 L) was added Lithium triethylborohydride (238 mL, 1 M in THF) dropwise at −70° C. under N 2 and stirred at −70° C. for 1 h. DMAP (264 mg, 2.16 mmol) was added in one portion. DIPEA (215 mL, 1.23 mol) and TFAA (45 mL, 324 mmol) were added dropwise by syringe in sequence while maintaining the temperature below-55° C. under N 2 . The cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. and stirred for 2 h under N 2 . The reaction mixture was quenched with water (600 mL) slowly at 0° C. while keeping the temperature below 15° C. The combined organic layers were washed with brine (300 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% EtOAc in petroleum ether) to give benzyl 1,4-dioxa-8-azaspiro[4.6]undec-9-ene-8-carboxylate (33.6 g, 58% yield) as a colorless oil. MS: m/z=289.9 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.39-7.34 (m, 5H), 8 6.72-6.49 (m, 1H), 5.18 (s, 2H), 5.02-4.87 (m, 1H), 3.92 (s, 4H), 3.80-3.73 (m, 2H), 2.46 (d, J=6.4 Hz, 2H), 2.08-2.01 (m, 2H).

A solution of benzyl 1,4-dioxa-8-azaspiro[4.6]undec-9-ene-8-carboxylate (30 g, 104 mmol), Bu4NI (128 mg, 10.4 mmol) in CH 2 Cl 2 (36 mL) and 50% (w %) NaOH aqueous (36 mL) was degassed and purged with N 2 three times. Dibromofluoromethane (60 g, 311 mmol) was added using a syringe, and the mixture was stirred at 35° C. for 7 h under N 2 . The reaction mixture was quenched with sat. NH 4 Cl aq. (600 mL) and extracted with EtOAc (400 mL×2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (37.2 g, crude) as a yellow solid, which was used into the next step without further purification. MS: m/z=421.8, 423.8 [M+Na] + . 1 H NMR (400 MHZ, Chloroform-d) δ 7.45-7.21 (m, 5H), 6 5.25-5.03 (m, 2H), 3.94-3.82 (s, 4H), 3.64-2.98 (m, 3H), 2.34-2.09 (m, 1H), 1.89-1.69 (m, 4H). 19 F. NMR (376 MHz, Chloroform-d) δ −128.56, −157.95.

Step 6: Benzyl 8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2′-[1,3]dioxolane]-6-carboxylate (trans mixture) and benzyl 8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2′-[1,3]dioxolane]-6-carboxylate (cis mixture)

To a solution of benzyl 8-bromo-8-fluoro-6-azaspiro[bicyclo[5.1.0]octane-3,2′-[1,3]dioxolane]-6-carboxylate (28 g, 70 mmol) in EtOH (280 mL) was added Zn (18.1 g, 275 mmol) and NH 4 Cl (34 g, 630 mmol) at 20° C. The mixture was stirred at 70° C. for 3 h under N 2 . The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜30% EtOAc in petroleum ether) to give the title compound (trans mixture) (Intermediate 104, 15.5 g, 62% yield over 2 steps, the first peak) as a yellow oil and the title compound (cis mixture) (Intermediate 105, 3.5 g, 14% yield over 2 steps, the second peak) as a yellow oil. Spectra for Intermediate 104: MS: m/z=321.9 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.43-7.28 (m, 5H), 5.27-5.09 (m, 2H), 4.59-4.29 (m, 1H), 3.99-3.90 (m, 4H), 3.17-3.07 (m, 4H), 2.97 (dd, J=9.2, 18 Hz, 1H), 2.41-2.30 (m, 1H), 1.91-1.54 (m, 4H), 1.42-1.30 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −204.23. Spectra for Intermediate 105: MS: m/z=321.9 [M+H] + . 3H NMR (400 MHZ, Chloroform-d)δ 7.41-7.28 (m, 5H), 5.13 (s, 2H), 4.66-4.39 (m, 1H), 4.00-3.94 (m, 4H), 3.36-3.23 (m, 1H), 2.55 (s, 1H), 2.03-1.89 (m, 4H), 1.27-1.23 (m, 1H). 19 F. NMR (376 MHz, Chloroform-d) 6-232.90.

To a solution of Intermediate 104 (14 g, 43.6 mmol) in acetone (112 mL) was added dropwise con. HCl (56 mL, 12 M in H 2 O) at 20° C. and stirred at 50° C. for 1 h. The reaction mixture was quenched with sat. NaHCOsaq. (200 mL) at 0° C. and extracted with EtOAc (300 mL×2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/Ethyl acetate=I/O to 1/1) to give the title compound (11.4 g, 78% yield) as a yellow oil. MS: m/z=299.8 [M+Na] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.44-7.28 (m, 5H), 5.30-5.18 (m, 2H), 4.66-4.27 (m, 1H), 4.07-3.92 (m, 1H), 3.28-3.05 (m, 2H), 2.99 (dd, J=6.0, 13.6 Hz, 1H), 2.66-2.60 (m, 1H), 2.58-2.47 (m, 1H), 2.31-2.21 (m, 1H), 1.76-1.64 (m, 1H). 19 F. NMR (376 MHz, Chloroform-d) δ −203.83.

To a solution of benzyl 8-fluoro-5-oxo-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) (11.4 g, 41.1 mmol) in MeOH (80 mL) was added NaBH4 (2.97 g, 78.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with sat. NH 4 Cl aq. (230 mL) at 0° C. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3× 500 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (10.6 g, crude) as a white solid, which was used in the next step without further purification. MS: m/z=301.9 [M+Na] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.41-7.30 (m, 5H), 5.25-5.10 (m, 2H), 4.62-4.26 (m, 1H), 4.20-4.11 (m, 1H), 4.07-3.92 (m, 1H), 3.66-3.29 (m, 2H), 3.05-2.82 (m, 1H), 2.56-2.42 (m, 1H), 1.90-1.60 (m, 1H), 1.73-1.61 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) ô-203.94, −204.37, −204.45.

A mixture of benzyl 8-fluoro-5-hydroxy-2-azabicyclo [S.1.0]octane-2-carboxylate (trans mixture) (10.5 g, 37.6), imidazole (5.12 g, 75.2 mmol), PPh 3 (14.8 g, 56.4 mmol) and I2 (14.3 g, 56.4 mmol) in toluene (160 mL) was degassed, purged with N 2 three times, and stirred at 105° C. for 1 h under N 2 . The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (13 g, crude) as a brown oil, which was used in the next step without further purification.

Step 4: Benzyl 8-fluoro-2-azabicyclo[5.1.0]oct-5-ene-2-carboxylate (trans mixture) & benzyl 8-fluoro-2-azabicyclo[5.1.0]oct-4-ene-2-carboxylate (trans mixture)

A mixture of benzyl 8-fluoro-5-iodo-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) (13 g, 33.4 mmol) and DBU (40 mL, 265 mmol) in toluene (160 mL) was stirred at 105° C. for 2 h under N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (cluent: 0˜10% EtOAc in petroleum ether) to give the title compound (Intermediate 106, 2.5 g, 25% yield over 3 steps, the first peak) and benzyl 8-fluoro-2-azabicyclo[5.1.0]oct-5-ene-2-carboxylate (trans mixture) (Intermediate 107, 5.7 g, 56% yield over 3 steps, the second peak). Spectra for Intermediate 106: 1H NMR (400 MHZ, Chloroform-d) δ 7.46-7.28 (m, 5H), 5.81-5.69 (m, 1H), 5.45-5.33 (m, 1H), 5.26-5.10 (m, 2H), 4.57-4.26 (m, 1H), 4.02-3.83 (m, 1H), 3.40-3.24 (m, 2H), 2.44-2.15 (m, 2H), 2.09-1.96 (m, 1H). 1F NMR (376 MHz, Chloroform-d) δ −204.30, −204.63. Spectra for Intermediate 107: 1H NMR (400 MHz, Chloroform-d) δ 7.44-7.28 (m, 5H), 5.80-5.35 (m, 2H), 5.28-5.10 (m, 2H), 4.76-4.52 (m, 1H), 4.05-3.77 (m, 1H), 3.57-3.49 (m, 1H), 3.04-2.47 (m, 1H), 2.36-2.06 (m, 2H), 1.95-1.77 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −206.68.

To a solution of Intermediate 106 (1.50 g, 5.74 mmol) in CH 2 Cl (16 mL) was added HBr (4 mL, 33% in AcOH) at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.15 g, HBr salt) as a colorless oil, which was used in the next step without further purification. MS: m/z=127.9 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 10.57-10.04 (m, 1H), 9.53-9.04 (m, 1H), 5.91-5.83 (m, 1H), 5.69-5.59 (m, 1H), 5.41-5.15 (m, 1H), 3.54-3.26 (m, 3H), 2.80-2.62 (m, 2H), 2.40-2.20 (m, 1H), 19 F NMR (376 MHz, Chloroform-d) δ −205.15.

Step 2: 2,7-Dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-y1)pyrido[4,3-d]pyrimidine (trans mixture)

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.40 g, 5.35 mmol), DIPEA (4.81 mL, 27.6 mmol) in CH 2 Cl 2 (5 mL) was added a solution of 8-fluoro-2-azabicyclo[5.1.0]oct-5-ene (trans) (1.15 g, 5.35 mmol, HBr salt) in CH 2 Cl 2 (3 mL) at −40° C. under N 2 atmosphere. The reaction mixture was stirred at −40° C. for 0.5 h under N 2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was dissolved with EtOAc (10 mL) to give a precipitate. The solid was filtered, and the filter cake was washed with EtOAc (5 mL), dried under reduced pressure to give the title compound (1.80 g, 90% yield over 2 steps) as a yellow solid.

Step 3: 2,7-Dichloro-8-fluoro-4-((1R,7S,8R)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)pyrido[4,3-d]pyrimidine & 2,7-Dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)pyrido[4,3-d]pyrimidine

2,7-Dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)pyrido[4,3-d]pyrimidine (trans mixture) was separated by SFC(column: DAICEL CHIRALPAK IC(250 mm×3 0 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 ·H 2 O)]; B %: 30%, isocratic elution mode) to give the title compound (Intermediate 108, 500 mg, 26% yield, SFC peak 1 retention time: 1.839 min) as a yellow solid and the title compound (Intermediate 109, 1.00 g, 47% yield, SFC peak 2 retention time: 2.193 min) as a yellow solid. Spectra for Intermediate 108: MS: m/z=342.9 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.29 (s, 1H), 5.80-5.38 (m, 2H), 4.75-4.35 (m, 3H), 3.85-3.70 (m, 1H), 2.90-2.74 (m, 1H), 2.63-2.52 (m, 1H), 2.41-2.30 (m, 1H). 19 F NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −135.46, −205.06. Spectra for Intermediate 109: MS: m/z=342.8 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.29 (s, 1H), 5.79-5.37 (m, 2H), 4.67-4.40 (m, 3H), 3.85-3.70 (m, 1H), 2.78-2.74 (m, 1H), 2.57-2.52 (m, 1H), 2.40-2.31 (m, 1H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −135.46, −205.06.

To a solution of Intermediate 109 (1.00 g, 2.91 mmol), DIPEA (1.52 mL, 8.74 mmol) and Intermediate 17 (845 mg, 5.25 mmol) in 1,4-dioxane (4 mL) was stirred at 105° C. under N 2 for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜3% of MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 110, 1.00 g, 68% yield) as a yellow solid. MS: m/z=468.2 [M+H] + . 1 H NMR (400 MHz, Dimethylsulfoxide-d 6 ) δ 9.16 (s, 1H), 5.76-5.70 (m, 1H), 5.76-5.70 (m, 1H), 5.47-5.38 (m, 1H), 4.70-4.60 (m, 1H), 4.55-4.39 (m, 3H), 3.85-3.65 (m, 1H), 3.09-2.99 (m, 3H), 2.86-2.76 (m, 2H), 2.39-2.30 (m, 1H), 2.10-1.98 (m, 3H), 1.84-1.73 (m, 3H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −137.06, −172.13, −204.65.

Step 1: 2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

To a stirred solution of 2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (4.8 g, 13.82 mmol, refer to Intermediate 33 &34 for detail procedures) in DMSO (96 mL) was added KF (1.45 g, 24.88 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (300 mL), and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM/EA (5: 1) to afford the title compound (2 g, 43% yield) as a light-yellow solid. MS: m/z=331.05 [M+H] +.

Step 2: (1R,7R,8R)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (2.7 g, 8.16 mmol, two batches) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Cellulose-SB 5×25 cm, 5 μm; Mobile Phase A: CO 2 , Mobile Phase B: MeOH (0.1% 2 M NH 3 -MeOH); Flow rate: 140 mL/min; Gradient: isocratic 40% B; RT1: 8 min; RT2: 9.5 min. The first eluting peak (RT1: 8 min) was concentrated and lyophilized to give the title compound (Intermediate 111, 1 g, 37% yield) as a light yellow solid. MS: m/z=331.10 [M+H] + . The second eluting peak (RT2: 9.5 min) was concentrated and lyophilized to give the title compound (Intermediate 112, 970 mg, 35% yield) as a light yellow solid. MS: m/z=331.10 [M+H] +.

To an ice-cooled solution of 7-chloro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diol (4.6 g, 12.26 mmol) in DCM (46 mL) under nitrogen atmosphere was added DIEA (9.53 g, 73.72 mmol) and (trifluoromethane) sulfonyl trifluoromethanesulfonate (13.88 g, 49.19 mmol). The reaction mixture was stirred in an ice bath for 2 hours. The resulting mixture was diluted with H 2 O (150 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE to afford the title compound (7 g, 89% yield) as a brown oil. MS: m/z=637.15 [M−H] −

Step 2: 7-Chloro-3-((diphenylmethylene)amino)-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate

To a solution of 7-chloro-8-((triisopropylsilyl) ethynyl) naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (2.44 g, 13.47 mmol) in toluene (70 mL) under nitrogen atmosphere were added XantPhos (380.27 mg, 0.65 mmol), Pd2 (dba) 3 (100.30 mg, 0.11 mmol) and Cs2CO 3 (7.14 g, 21.90 mmol) under nitrogen atmosphere. The reaction mixture was heated at 100° C. for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was triturated with MeOH (3×30 mL) to afford the title compound (3.5 g, 48% yield) as a yellow solid. MS: m/z=670.15 [M+H] +.

Step 3: N-(6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl) ethynyl) naphthalen-2-yl)-1,1-diphenylmethanimine

To a solution of 7-chloro-3-((diphenylmethylene)amino)-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (3.5 g, 5.22 mmol) and bis (pinacolato)diboron (3.33 g, 13.10 mmol) in 1,4-dioxane (35 mL) under nitrogen atmosphere were added Pd (dppf)C 1 >>CH 2 Cl 2 (111.14 mg, 1.04 mmol) and KOAc (2.07 g, 21.04 mmol) at room temperature. The reaction mixture was heated at 100° C. for 3 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 3% EA in PE to afford the title compound (Intermediate 113, 1.21 g, 36% yield) as a yellow solid. MS: m/z=648.45 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 7.79-7.75 (m, 2H), 7.56-7.36 (m, 6H), 7.25-7.14 (m, 6H), 1.29-1.27 (m, 12H), 1.17-1.12 (m, 21H).

To an ice-cooled solution of Intermediate 2 (20 g, 85.73 mmol) and TBAI (6.33 g, 17.14 mmol) in DCM (100 mL) and NaOH (200 mL, 50% aq.) under nitrogen atmosphere was added chloroform (30.70 g, 257.21 mmol) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (3: 1) to afford the title compound (22 g, 73% yield) as a light yellow solid. MS: m/z=316.00, 318.00 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.50-7.31 (m, 5H), 5.29-5.16 (m, 2H), 4.56-4.50 (m, 1H), 4.14-3.93 (m, 2H), 3.64-3.50 (m, 2H), 3.34-3.28 (m, 2H), 2.28-2.16 (m, 1H).

Step 2: Benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) & benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)

To a stirred mixture of benzyl 8,8-dichloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (10 g, 31.62 mmol) in EtOH (100 mL) under nitrogen atmosphere were added ammonium chloride (15.23 g, 284.65 mmol) and Zn (18.61 g, 284.65 mmol) at room temperature. The reaction mixture was heated at 70° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% EA in PE to afford two mixtures. The first eluting mixtures were collected and concentrated under reduced pressure to give benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (trans mixture) (Intermediate 114, 4.8 g, 53% yield) as an off-white semi-solid. MS: m/z=282.05 [M+H] + . JH NMR (300 MHZ, Chloroform-d) δ 7.46-7.29 (m, 5H), 5.29-5.14 (m, 2H), 4.40-4.34 (m, 1H), 4.05-3.78 (m, 2H), 3.51-3.06 (m, 5H), 1.87-1.78 (m, 1H). The second eluting mixtures were collected and concentrated under reduced pressure to give the title compound (Intermediate 115, 2.2 g, 24% yield) as a yellow oil. 1 H NMR (300 MHz, Chloroform-d) δ 7.41-7.30 (m, 5H), 5.23-5.08 (m, 2H), 4.43-4.36 (m, 1H), 4.14-3.97 (m, 2H), 3.77-3.57 (m, 2H) 3.40-3.32 (m, 2H), 2.97-2.92 (m, H), 1.74-1.63 (m, 1H).

A mixture of Intermediate 114 (1.8 g, 6.39 mmol) in HBr (33 wt % in AcOH, 18 mL) under nitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3×50 mL) to afford the title compound (1.2 g, crude used through) as a yellow solid.

Step 2: 8-Chloro-2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1027.43 mg, 4.07 mmol) in DCM (10 mL) under nitrogen atmosphere were added DIEA (1578.05 mg, 12.21 mmol) and 8-Chloro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture) (930 mg, crude) at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 30% EA in PE to give the title compound (1.4 g, 94% yield) as a light yellow solid. MS: m/z=362.90, 364.90 [M+H] +.

Step 3: 8-Chloro-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

To a stirred solution of 8-chloro-2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (1.4 g, 3.85 mmol) in DMSO (10 mL) were added KF (782.93 mg, 13.48 mmol) and Intermediate 17 (0.99 g, 6.16 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (50 mL), extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×80 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 9% MeOH in DCM to afford the title compound (1.1 g, 54% yield) as a yellow solid. MS: m/z=488.15 [M+H] +.

Step 4: (15,7S,8S)-8-Chloro-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane & (IR,7R,8R)-8-chloro-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5/1)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane 8-Chloro-2-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-y1) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (490 mg, 0.96 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA 2×25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH 3 -MeOH); Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: isocratic 25% B; Detector: UV 220 & 254 nm; RTI: 14.80 min; RT2: 19.68 min. The first eluting peak (RT1: 14.80 min) was concentrated and lyophilized to give the title compound (Intermediate 116, 170 mg, 34% yield) as a yellow solid. MS: m/z=488.15 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 5.38-5.20 (m, 1H), 4.62-4.57 (m, 1H), 4.44-4.40 (m, 1H), 3.98-3.80 (m, 2H), 3.77-3.61 (m, 2H), 3.50-3.13 (m, 4H), 3.10-2.95 (m, 2H), 2.20-1.80 (m, 7H). The second eluting peak (RT2: 19.68 min) was concentrated and lyophilized to give the title compound (Intermediate 117, 170 mg, 31% yield) as a light-yellow solid. MS: m/z=488.15 [M+H] + . 1H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 5.38-5.21 (m, 1H), 4.62-4.57 (m, 1H), 4.45-4.39 (m, 1H), 3.98-3.90 (m, 2H), 3.78-3.61 (m, 2H), 3.50-3.22 (m, 4H), 3.03-2.94 (m, 2H), 2.30-1.80 (m, 7H).

A mixture of Intermediate 112 (12 g, 36.28 mmol), Intermediate 20 (36.58 g, 72.58 mmol, HCl), AdanBuP-Pd-G3 (cataCXiumAPdG3) (5.28 g, 7.26 mmol), and KsPO4 (23.1 g, 108.86 mmol) in THF (240 mL) and H 2 O (48 mL) was degassed, purged with N 2 three times, and the mixture was stirred at 80° C. for 5 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of MeOH in CH 2 Cl 2 ) to give the crude product. The crude was purified by prep-HPLC(column: XPT C18 250×70×7 μm; mobile phase: [water (ammonia hydroxide v/v)-ACN], gradient: 65%˜95% B over 23 min) to give the title compound (Intermediate 118, 13.239 g, 60% purity) as a yellow solid. MS: m/z=636.3 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 9.56 (s, 1H), 7.84-7.76 (m, 1H), 7.41-7.32 (m, 1H), 7.15-6.97 (m, 2H), 5.69 (s, 2H), 5.14-4.87 (m, 1H), 4.50-4.27 (m, 3H), 4.07-3.96 (m, 1H), 3.75-3.59 (m, 2H), 3.26-3.07 (m, 1H), 2.48-2.29 (m, 1H), 0.85-0.79 (m, 18H), 0.53-0.36 (m, 3H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) δ −41.05, −41.78, −110.77, −111.09, −138.96, −207.86.

Step 1: 7a′-((((ert-Butyldiphenylsilyl)oxy)methyl)-6′-methylenehexahydrospiro[cyclopropane-1,1′-pyrrolizine]

To a mixture of Intermediate 99 (570 mg, 3.18 mmol) in N,N-dimethylformamide (5.5 mL) were added 1H-imidazole (439 mg, 6.46 mmol) and tert-butyl (chloro)diphenylsilane (961 mg, 3.50 mmol) at 25° C. under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 25° C. under nitrogen atmosphere. The reaction was monitored by TLC and LCMS. The mixture was quenched with sat. aq. NH 4 Cl (0.2 mL). The mixture was filtered, and the filtrate was directly purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH 3 ·H 2 O), 2% to 100% gradient in 20 min; detector, UV 254 nm & 210 nm. The product-containing fractions were collected and concentrated to afford the title compound (1.2 g, 90%) as an off-white oil. MS: m/z=418.20 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 7.68-7.57 (m, 4H), 7.46-7.29 (m, 6H), 4.85 (s, 2H), 3.70-3.04 (m, 5H), 2.73-2.55 (m, 2H), 2.30 (d, J=15.8 Hz, 1H), 1.96-1.67 (m, 2H), 1.12 (s, 1H), 1.05 (s, 9H), 0.66-0.59 (m, 1H), 0.53-0.39 (m, 2H).

Step 2: (R)-7a′-(((tert-Butyldiphenylsilyl)oxy)methyl)-6′-methylenehexahydrospiro [cyclopropane-1,1′-pyrrolizine]& (S)-7a-(( (iert-butyldiphenylsilyl)oxy)methyl)-6′-methylenehexahydrospiro[cyclopropane-1,1′-pyrrolizine]7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6′-methylenehexahydrospiro[cyclopropane-1,1′-pyrrolizine](2.8 g, 6.7 mmol) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: CO 2 , Mobile Phase B: MeOH (0.1% 7M NH 3 . MeOH); Flow rate: 100 mL/min; Gradient: isocratic 18% B; Wave Length: 220 nm; RT1 (min): 8.1; RT2 (min): 11.3; Injection Volume: 0.5 mL; Number Of Runs: 40. The first eluting peak was combined and concentrated to give the title compound (Intermediate 119, 1.34 g, 47%) as an off-white oil. MS: m/z=418.25 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) õ 7.76-7.54 (m, 4H), 7.45-7.30 (m, 6H), 4.85 (s, 2H), 3.73-3.01 (m, 5H), 2.77-2.56 (m, 2H), 2.30 (d, J=15.8 Hz, 1H), 1.82 (d, J=48.4 Hz, 2H), 1.12 (s, 1H), 1.05 (s, 9H), 0.67-0.58 (m, 1H), 0.56-0.35 (m, 2H). The second eluting peak was combined and concentrated to give the title compound (Intermediate 120, 1.26 g, 45%). MS: m/z=418.20 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.70-7.59 (m, 4H), 7.47-7.32 (m, 6H), 4.86 (s, 2H), 3.75-3.01 (m, 5H), 2.76-2.55 (m, 2H), 2.30 (d, J=15.9 Hz, 1H), 1.82 (d, J=57.4 Hz, 2H), 1.12 (s, 1H), 1.05 (s, 9H), 0.68-0.58 (m, 1H), 0.56-0.38 (m, 2H).

Step 1: (7a′R)-7a′-(((tert-Butyldiphenylsilyl)oxy)methyl)-2″,2″-difluorotetrahydro-5′//-dispiro[cyclopropane-1,1′-pyrrolizine-6′,1″-cyclopropane]

To a stirred solution of Intermediate 119 (850 mg, 2.03 mmol) in toluene (3 mL) were added tetrabutylammonium bromide (19.7 mg, 0.06 mmol) and (bromodifluoromethyl)trimethylsilane (620 mg, 3.05 mmol) under argon atmosphere at 25° C. The resulting mixture was heated at 110° C. for 2 hours under argon atmosphere. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with the following conditions: column, C 18 column, 40 g, 20-35 μm, 100 A; mobile phase A: water; mobile phase B: MeOH, 2% to 98% gradient in 25 min; detector, UV 254 & 210 nm. The fractions containing desired product were combined and concentrated under reduced pressure to afford the title compound (320 mg, 34%) as a colorless oil. MS: m/z=468.25 [M+H] + . 1 H NMR (400 MHZ, Acetonitrile-3) δ 7.78-7.62 (m, 4H), 7.55-7.32 (m, 6H), 3.55-3.31 (m, 2H), 3.15-2.96 (m, 2H), 2.90-2.58 (m, 2H), 1.90-1.71 (m, 3H), 1.68-1.59 (m, 1H), 1.07-0.98 (m, 9H), 0.96-0.78 (m, 3H), 0.68-0.57 (m, 1H), 0.54-0.41 (m, 2H). 19 F. NMR (376 MHz, CD: CN) δ −134.83-−136.56 (m, 1F), —136.59-−139.32 (m, IF).

Step 2: ((7a′R)-2″,2″-Difluorodihydro-5′H-dispiro[cyclopropane-1,1′-pyrrolizine-6′,1″-cyclopropan]-7a′(7H)-yl) methanol

To a stirred solution of (Ta′R)-7a′-(((tert-butyldiphenylsilyl)oxy)methyl)-2″,2″-difluorotetrahydro-5′H-dispiro[cyclopropane-1,1′-pyrrolizine-6′,1″-cyclopropane](246 mg, 0.53 mmol) in methanol (4 mL) was added amine hydrofluoride (780 mg, 21.0 mmol) under argon atmosphere at room temperature. The resulting mixture was stirred at room temperature for 12 hours under the argon atmosphere. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with MeOH/NH 3 -H 2 O/CH 2 Cl 2 (1: 0.1: 9) to afford the title compound (Intermediate 121, 105 mg, 87%) as a colorless oil. MS: m/z=230.05 [M+H] + . 1 H NMR (400 MHZ, Acetonitrile-d 3 ) δ 4.16-3.32 (m, 1H), 3.31-3.08 (m, 4H), 3.02-2.71 (m, 2H), 1.92-1.68 (m, 4H), 1.46-1.25 (m, 2H), 0.77-0.44 (m, 4H). 19 F NMR (376 MHZ, CD 3 CN) δ −135.20-−136.54 (m, IF), —137.26-−139.45 (m, IF).

A mixture of ethyl (R)-6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1, l′-pyrrolizine]-7a′(5′H)-carboxylate (4 g, 17.0 mmol), dibromo (fluoro) methane (9.78 g, 51.0 mmol, 5.78 mL) and benzyl (triethyl) ammonium;chloride (387 mg, 1.70 mmol) in CH 2 Cl 2 (80 mL) and NaOH (16 mL, 50% in water) was degassed and purged with N 2 three times, and the mixture was stirred at 40° C. for 16 h under N 2 atmosphere. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 30%˜60% of EtOAc in petroleum ether) to give the title compound (Intermediate 122, 1.20 g, 19% yield, the first peak) as a yellow oil and the title compound (Intermediate 123, 1.07 g, 17% yield, the second peak) as a yellow oil. Spectra for Intermediate 122: 1H NMR (400 MHZ, Chloroform-d)δ 4.33-4.04 (m, 3H), 3.13-2.87 (m, 2H), 2.32-1.95 (m, 3H), 1.71-1.50 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 0.96-0.86 (m, 1H), 0.83-0.74 (m, 1H), 0.73-0.65 (m, 2H). 19 F. NMR (376 MHz, Chloroform-d) ô-135.15, −136.17. Spectra for Intermediate 123: 1H NMR (400 MHz, Chloroform-d) δ 4.38-4.19 (m, 2H), 3.84-3.70 (m, 1H), 3.44-3.33 (m, 1H), 3.11-2.97 (m, 1H), 2.43-2.18 (m, 2H), 2.06-1.59 (m, 3H), 1.35-1.28 (m, 3H), 1.03-0.81 (m, 2H), 0.73-0.61 (m, 2H). 19 F. NMR (376 MHz, Chloroform-d) δ −135.59, −136.44.

To a solution of Intermediate 122 (1.20 g, 3.47 mmol) in EtOH (28 mL) was added NH 4 Cl (1.67 g, 31.2 mmol) and Zn (1.18 g, 18.0 mmol) in batches. The mixture was stirred at 70° C. for 3 h under N 2 . The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 30%˜50% of EtOAc in petroleum ether) to give the title compound (Intermediate 124, 19 FNMR: −213.19 ppm, 388 mg, 42% yield, the first peak) as a yellow oil and the title compound (Intermediate 125, 19FNMR: −212.77 ppm, 156 mg, 17% yield, the second peak) as a yellow oil. Spectra for Intermediate 124: 1H NMR (400 MHz, Chloroform-d) δ 4.67-4.42 (m, 1H), 4.34-4.18 (m, 2H), 4.06 (d, J=11.6 Hz, 1H), 3.14-3.01 (m, 2H), 2.28-2.18 (m, 1H), 1.99-1.91 (m, 1H), 1.80-1.82 (m, 1H), 1.30 (t, J=7.2 Hz, 3H), 1.00-0.74 (m, 4H), 0.70-0.62 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −213.19. Spectra for Intermediate 125: 1 H NMR (400 MHz, Chloroform-d) δ 4.68-4.44 (m, 1H), 4.34-4.19 (m, 2H), 3.84-3.74 (m, 1H), 3.12-3.04 (m, 1H), 2.81-2.72 (m, 1H), 2.26-2.01 (m, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.08-0.96 (m, 1H), 0.96-0.89 (m, 1H), 0.85-0.76 (m, 2H), 0.72-0.61 (m, 2H), 19 F NMR (376 MHz, Chloroform-d) δ −212.77.

To a solution of Intermediate 124 (288 mg, 1.08 mmol) in THF (3 mL) was added LiAlH4 (2.15 mL, 2.5 M in THF) dropwise at 0° C. under N 2 atmosphere. The mixture was stirred at 0° C. for 0.5 h under N 2 , warmed to 65° C., and stirred at 65° C. for 1.5 h. The reaction mixture was quenched with Na 2 SO 4 $10H 2 O (1.74 g) slowly. The reaction mixture dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (Intermediate 126, 184 mg, crude) as a yellow solid. 1 H NMR (400 MHZ, Dimethylsulfoxide-ď6) δ 4.78-4.56 (m, 1H), 4.32-4.15 (m, 1H), 3.24-3.13 (m, 2H), 3.05 (d, J=11.2 Hz, 1H), 3.00-2.93 (m, 1H), 2.71 (d, J=11.6 Hz, 1H), 2.64-2.57 (m, 1H), 1.85-1.77 (m, 1H), 1.64-1.54 (m, 2H), 1.37-1.27 (m, 1H), 0.85-0.69 (m, 3H), 0.51-0.44 (m, 1H), 0.43-0.36 (m, 2H). 19 F. NMR (376 MHz, Dimethylsulfoxide-d 6 ) 6 -206.69.

To a stirred solution of (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H-pyrrolizin-3-one (4.0 g, 9.71 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2394.74 mg, 11.66 mmol) in DCM (40 mL) was added (trifluoromethane) sulfonyl trifluoromethanesulfonate (3290.21 mg, 11.66 mmol) dropwise at −78° C. under nitrogen atmosphere. After stirring at −78° C. for 45 min, MeMgBr (3 M in THF, 3.24 mL, 9.71 mmol) was added to the above mixture. The dry ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. NaBH4 (1102.94 mg, 29.15 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for another an hour. The resulting mixture was diluted with 20% sodium hydroxide aqueous solution (80 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (5: 1) to give two peaks. The first eluting peak was collected and concentrated under reduced pressure to give the title compound (Intermediate 127, 1.0 g, 25% yield) as a light-yellow oil. MS: m/z=412.35 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 7.73-7.63 (m, 4H), 7.44-7.35 (m, 6H), 5.30-5.17 (m, 1H), 3.55-2.82 (m, 4H), 2.18-1.98 (m, 3H), 1.92-1.32 (m, 4H), 1.10-1.02 (m, 12H). 19 F NMR (376 MHZ, CDCl) δ −173.43 (s, 1F). The second eluting peak was collected and concentrated under reduced pressure to give the title compound (Intermediate 128, 380 mg, 9% yield) as a light-yellow oil. MS: m/z=426.35 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.67-7.60 (m, 4H), 7.37-7.28 (m, 6H), 5.25-5.00 (m, 1H), 3.40-3.10 (m, 3H), 3.03-2.85 (m, 1H), 2.37-2.25 (m, 1H), 1.80-1.59 (m, 5H), 1.09-0.92 (m, 15H). 19 F NMR (376 MHz, CDCl) δ −171.79 (s, IF).

To a mixture of Intermediate 127 (1.04 g, 2.52 mmol) in methanol (10 mL) was added ammonium fluoride (3742.97 mg, 101.08 mmol) under nitrogen atmosphere. The reaction mixture was heated at 60° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 15% MeOH in DCM to afford the title compound (Intermediate 129, 250 mg, 57% yield) as a yellow oil. 1 H NMR (400 MHZ, DMSO-d 6 ) δ 5.32-5.17 (m, 1H), 4.50 (bs, 1H), 3.17-2.91 (m, 4H), 2.87-2.77 (m, 1H), 2.03-1.77 (m, 4H), 1.67-1.59 (m, 1H), 1.38-1.23 (m, 1H), 1.01-1.00 (d, J=6.0 Hz, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ−170.21 (s, IF).

To a slurry of LiAlD 4 (143 mg, 3.11 mmol) in THF (5 mL) was added Intermediate 88 (150 mg, 624 μmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 . The mixture was then stirred at 70° C. for 1.5 h under N 2 . The reaction mixture was quenched with D 2 O (0.14 mL) slowly. 15% w/NaOH aq. (0.14 mL) was added dropwise, followed by addition of H 2 O (0.42 mL). The mixture was filtered, and the filter cake was washed with EtOAc (40 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜15% of MeOH in CH 2 Cl) to give the title compound (Intermediate 130, 92 mg, 78% yield) as a yellow oil. 1 H NMR (400 MHZ, Chloroform-d) δ 4.62-4.32 (m, 1H), 3.16 (d,)=12.0 Hz, 1H), 2.84 (d, J=12.0 Hz, 1H), 1.94-1.64 (m, 6H), 1.48 (d, J=13.4 Hz, 1H), 0.90-0.77 (m, 2H). 19 F NMR (376 MHz, Chloroform-d) δ −207.35.

Intermediate 131 was prepared in a manner similar to Intermediate 130. MS: m/z=189.9 [M+H] + . HJ+. 1 H NMR (400 MHZ, Chloroform-d) δ 4.66-4.38 (m, 1H), 3.29-3.15 (m, 1H), 2.53 (d, J=12.0 Hz, 1H), 2.23-2.14 (m, 1H), 2.03-1.73 (m, 5H), 1.02-0.77 (m, 2H). 19 F NMR. (376 MHz, Chloroform-d) δ −210.05.

To a suspension of NaH (596 mg, 14.9 mmol) in THF (10 mL) was added MeOH (241 μL, 5.96 mmol) dropwise at 0° C. under N 2 . The mixture was stirred at 0° C. under N 2 for 0.5 h. The mixture was added to a solution of 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4 (3H)-one (2 g, 7.45 mmol) in THF (10 mL) dropwise at 0° C. The resulting mixture was stirred at the same temperature for another 1 h under N 2 . The reaction mixture was quenched with sat. NH 4 CL. aq. (20 mL) at 0° C., and then the pH of the mixture was adjusted to around 3 with HCl aq. (10 mL, 6 M in H 2 O). The mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (2 g, crude) as a yellow solid. MS: m/z=263.8 [M+H] +.

To a solution of 2,7-dichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-4 (3H)-one (2 g, 7.57 mmol) in CH 2 Cl 2 (20 mL) was added DIPEA (7.83 g, 60.6 mmol) and POCl 3 (4.65 g, 30.3 mmol) at 0° C. under N 2 . The mixture was stirred at 0° C. for 1 h under N 2 . The reaction mixture was concentrated under reduced pressure to give the title compound (2.14 g, crude) as a black-brown oil. MS: m/z=281.9 [M+H] +.

Step 3: (1S,7S,8S)-2-(2,7-Dichloro-8-fluoro-S-methoxypyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of 2,4,7-trichloro-8-fluoro-5-methoxypyrido[4,3-d]pyrimidine (2.14 g, 7.58 mmol) in CH 2 Cl 2 (20 mL) was added DIPEA (2.94 g, 22.7 mmol) and Intermediate 153 (1.61 g, 7.58 mmol, HBr) at −40° C. under N 2 and stirred at the same temperature for 1 h under N 2 . The reaction mixture was quenched with H 2 O (50 mL) and extracted with CH 2 Cl 2 (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (Intermediate 132, 2.8 g, crude) as a black-brown oil. MS: m/z=376.9 [M+H] +.

To an ice-cooled mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (7.00 g, 21.19 mmol) in DCM (70 mL) were added DIEA (8.22 g, 63.57 mmol) and Intermediate 153 (4.47 g, 21.19 mmol, refer to Intermediate 33 & 34 for detail procedures) under nitrogen atmosphere. The reaction mixture was cooled to −40° C. and stirred for 2 hours. The mixture was warmed up to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 45% EA in PE to afford the title compound (6.9 g, 76%) as a yellow oil. MS: m/z=424.15, 426.15, 428.15 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 8.35 (s, 1H), 4.63-4.53 (m, 1H), 4.48-4.37 (m, 1H), 4.37-4.16 (m, 1H), 4.02-3.85 (m, 3H), 3.70-3.59 (m, 1H), 3.45-3.07 (m, 1H), 2.40-2.21 (m, 1H).

Step 2: 2-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 ) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To an ice-cooled mixture of 2-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (6.9 g, 16.23 mmol) in DMSO (70 mL) were added Intermediate 17 (4.19 g, 25.97 mmol) and potassium fluoride (3.30 g, 56.82 mmol) under nitrogen atmosphere. The reaction mixture was heated at 100° C. for 16 hours. The mixture was cooled down to room temperature. The resulting mixture was extracted with EA (3×200 mL), washed with H 2 O (1×200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford the title compound (3.4 g, 38%) as a white solid. MS: m/z=549.05, 551.05 [M+H] +.

Step 3: (1R,7R,8R)-2-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 ) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-y1) methoxy-d 2 ) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

2-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 ) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (3.4 g, 6.2 mmol) was separated by Prep-SFC with the following conditions: Column: CHIRALPAK IH, 7*25 cm, 10 μm; Mobile Phase A: IPA (0.1% 7M NH 3 -MeOH), Mobile Phase B: CO 2 ; Flow rate: 240 mL/min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Wave Length: 220 nm; RT1 (min): 11.05; RT2 (min): 12.92; Injection Volume: 10 mL. The first eluting peak (RT1: 11.05 min) was concentrated and lyophilized to give the title compound (Intermediate 133, 800 mg, 23% yield) as a white solid. MS: m/z=549.10, 551.10 [M+H] + , 1 H NMR. (400 MHZ, DMSO-d 6 ) δ 8.40 (s, 1H), 5.37-5.18 (m, 1H), 4.82-4.59 (m, 1H), 4.43-4.21 (m, 3H), 3.95 (d, J=12.2 Hz, 1H), 3.72-3.62 (m, 1H), 3.58-3.46 (m, 1H), 3.16-2.99 (m, 4H), 2.88-2.79 (m, 1H), 2.36˜2.20 (m, 1H), 2.14-2.09 (m, 1H), 2.06-1.95 (m, 2H), 1.89-1.71 (m, 3H). 19 F NMR (376 MHZ, DMSO-d 6 ) δ −112.72 (IF),˜172.18 (IF), —207.84 (1F). The second eluting peak (RT2: 12.92 min) was concentrated and lyophilized to give the title compound (Intermediate 134, 1.1 g, 32% yield) as a light yellow solid. MS: m/z=549.10, 551.00 [M+H] + . 1 H NMR (400 MHZ, DMSO-d 6 ) δ 8.40 (s, 1H), 5.39-5.19 (m, 1H), 4.81-4.61 (m, 1H), 4.44-4.21 (m, 3H), 3.95 (d, J=12.2 Hz, 1H), 3.73-3.63 (m, 1H), 3.58-3.48 (m, 1H), 3.19-2.99 (m, 4H), 2.91-2.80 (m, 1H), 2.37-2.22 (m, 1H), 2.19-1.95 (m, 3H), 1.90-1.69 (m, 3H). 19 F. NMR (376 MHZ, DMSO-d 6 ) δ −112.70 (1F), —172.18 (IF), —207.87 (IF).

To a solution of 2-fluoromethanesulfonylpyridine (4.40 g, 25.09 mmol) in THF (200 mL) was added KHMDS (1 M in THF, 29.83 mL, 29.83 mmol) dropwise at −78° C. under argon atmosphere. After stirring at −78° C. for 0.5 hour, a solution of ethyl (7aS)-2,5-dioxo-tetrahydropyrrolizine-7a-carboxylate (5 g, 23.67 mmol) in THF (20 mL) was added dropwise to the above mixture at −78° C. The resulting mixture was warmed to room temperature and stirred for 16 hours. The resulting mixture was quenched with sat. aq. NH 4 Cl (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford the title compound (2 g, 18% yield) as a light-yellow oil. MS: m/z=228.00 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) § 6.70-6.45 (m, 1H), 4.40-4.32 (m, 1H), 4.23-4.21 (m, 2H), 3.91-3.70 (m, 1H), 3.33-3.01 (m, 1H), 2.86-2.56 (m, 2H), 2.52-2.40 (m, 2H), 2.18-2.10 (m, 1H), 1.31-1.27 (m, 3H).

Step 2: Ethyl (S,E)-2-(fluoromethylene)-5-oxotetrahydro-1/-pyrrolizine-7a (5H)-carboxylate & ethyl (S,Z)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolizine-7a (5H)-carboxylate

Ethyl(S)-2-(fluoromethylene)-5-oxotetrahydro-1/-pyrrolizine-7a (5H)-carboxylate (550 mg) was separated by Achiral-Prep-SFC with the following conditions: Column: GreenSep Nitro, 30× 150 mm 5 μm; Mobile Phase A: CO 2 ; Mobile Phase B: IPA (20 mM NH 3 ); Flow rate: 60 mL/min; Gradient: isocratic 12% B; Column Temperature (° C.): 35; Back Pressure (bar): 100; Detector: UV 220 nm; RT1: 3.22 min; RT2: 4.50 min. The first eluting peak (RT1: 3.22 min) was combined and concentrated under reduced pressure to give the title compound (Intermediate 135, 164 mg, 29% yield) as a colorless oil. MS: m/z=228.00 [M+H] + . 1 H NMR (300 MHZ, Chloroform-d) § 6.74-6.45 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.19 (m, 2H), 3.74-3.69 (m, 1H), 3.33-3.28 (m, 1H), 2.82-2.62 (m, 2H), 2.51-2.40 (m, 2H), 2.19-2.08 (m, 1H), 1.29 (t, J=7.2 Hz, 3H). 19 F. NMR (282 MHz, Chloroform-d) δ -128.69 (s, IF). The second eluting peak (RT1: 4.50 min) was combined and concentrated under reduced pressure to give the title compound (Intermediate 136, 140 mg, 25% yield) as a colorless oil. MS: m/z=228.00 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 6.69-6.41 (m, 1H), 4.41-4.36 (m, 1H), 4.26-4.18 (m, 2H), 3.91-3.86 (m, 1H), 3.05-3.00 (m, 1H), 2.84-2.75 (m, 1H), 2.63-2.34 (m, 3H), 2.20-2.01 (m, 1H), 1.28 (t,)=7.2 Hz, 3H). 19 F. NMR (282 MHz, Chloroform-d) d-127.96 (s, IF).

To an ice-cooled solution of Intermediate 136 (164 mg, 0.72 mmol) in THF (13 mL) was added DIBAL-H (1 M in hexane, 7.33 mL, 7.33 mmol) under argon atmosphere. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. aq. NaOH (0.29 mL) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% methanol (10% NH 3 H 2 O) in dichloromethane to afford the title compound (Intermediate 137, 91.6 mg, 74% yield) as a light-yellow oil. MS: m/z=172.00 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 6.65-6.35 (m, 1H), 3.80-3.75 (m, 1H), 3.49-3.43 (m, 1H), 3.37-3.29 (m, 2H), 3.20-3.13 (m, 2H), 2.71-2.65 (m, 1H), 2.47-2.41 (m, 1H), 2.30-2.22 (m, 1H), 1.94-1.67 (m, 4H). 19 F NMR (282 MHz, Chloroform-d) 6-129.94 (s, 1F).

To an ice-cooled solution of Intermediate 137 (116.49 mg, 0.68 mmol) in THF (3 mL) under nitrogen atmosphere was added 1-BuOK (61.08 mg, 0.54 mmol). After stirring in an ice bath for 30 min, Intermediate 112 (150 mg, 0.45 mmol) was added to the above mixture in portions. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. aq. NH 4 Cl (20 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(CH 2 Cl 2 /MeOH 10: 1) to afford the title compound (Intermediate 138, 210 mg, 96% yield) as a light yellow solid. MS: m/z=482.05 [M+H] +.

To a mixture of (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H-pyrrolizin-3-one (2 g, 4.85 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (0.08 g, 0.09 mmol) in DCM (30 mL) under N 2 was added 1,1,3,3-tetramethyldisiloxane (1.31 g, 9.71 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hours. Methylmagnesium bromide (1.0 M in THE, 9.72 mL, 9.72 mmol) was added dropwise at −70° C. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with aq. NH 4 Cl (100 mL) in an ice bath and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (7: 1) to give two isomers. The first eluting isomer was concentrated to give the title compound (Intermediate 139, 200 mg, 10% yield) as a light-yellow oil. MS: m/z=412.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d)δ 7.73-7.67 (m, 4H), 7.44-7.35 (m, 6H), 5.30-5.17 (m, 1H), 3.45-2.75 (m, 5H), 2.27-1.67 (m, 6H), 1.10-1.00 (m, 12H). 19 F NMR (376 MHz, Chloroform-d) d-171.79 (s, IF). The second eluting isomer was concentrated to give the other title compound (Intermediate 140, 1500 mg, 74% yield) as a light-yellow oil. MS: m/z=412.15 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.72-7.67 (m, 4H), 7.44-7.34 (m, 6H), 5.30-5.17 (m, 1H), 3.43 (s, 2H), 3.13-3.06 (m, 3H), 2.44-2.34 (m, 1H), 1.94-1.59 (m, 5H), 1.18 (d, J=6.4 Hz, 3H), 1.06 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −172.76-179.88 (m, 1F).

To a solution of Intermediate 140 (1.5 g, 3.64 mmol) in methanol (20 mL) was added NH 4 F (5.40 g, 145.76 mmol) at room temperature. The reaction mixture was heated at 60° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with CH 2 Cl 2 /MeOH (8: 1)) to afford the title compound (Intermediate 141, 400 mg, 63% yield) as a light-yellow oil. MS: m/z=174.05 [M+H] + . 1 H NMR (400 MHZ, DMSO-d 6 ) & 5.18-5.01 (m, 1H), 4.52 (s, 1H), 3.13-2.91 (m, 5H), 1.70-1.50 (m, 5H), 1.09 (d, J=6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) 6 -171.42-178.74 (m, IF).

Step 1: (1S,7S,8S)-2-(2,7-Dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 2,4,7-trichloro-8-methylpyrido[4,3-d]pyrimidine (200 mg, 0.81 mmol) and Intermediate 153 (170.68 mg, 0.81 mmol, refer to Intermediate 33 & 34 for detail procedures) in DCM (5 mL) was added DIEA (312.08 mg, 2.42 mmol) dropwise at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(PE/EA 3: 1) to afford the title compound (200 mg, 72% yield) as a light yellow solid. MS: m/z=343.05, 345.05 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) & 9.40 (s, 1H), 4.67-4.62 (m, 1H), 4.43-4.22 (m, 2H), 3.96-3.82 (m, 3H), 3.69-3.62 (m, 1H), 3.28 (s, 1H), 2.67 (s, 3H), 2.35-2.30 (m, 1H).

Step 2: (1S,7S,8S)-2-(7-Chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a (5H)-yl) methoxy-d 2 )-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of (1S,7S,8S)-2-(2,7-dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (200 mg, 0.58 mmol) in DMSO (2.0 mL) under N 2 were added KF (118.50 mg, 2.04 mmol) and Intermediate 17 (150.33 mg, 0.93 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(CH 2 Cl 2 /MeOH 15: 1) to afford the title compound (Intermediate 142, 220 mg, 80% yield) as a light yellow solid. MS: m/z=468.15 [M+H] +.

To an ice-cooled solution of Intermediate 17 (30 g, 186.08 mmol) and Imidazole (25.34 g, 372.17 mmol) in DMF (300 mL) under N 2 was added tert-butyl (chloro)diphenylsilane (61.38 g, 223.30 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with CH 2 Cl 2 (1000 mL), washed with water (3×300 mL) and brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% EA in PE to afford the title compound (60 g, 80% yield) as a light-yellow oil. MS: m/z=400.15 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.73-7.65 (m, 4H), 7.44-7.35 (m, 6H), 5.26-5.11 (m, 1H), 3.15-3.08 (m, 2H), 2.95-2.88 (m, 3H), 2.15-1.63 (m, 5H), 1.07 (s, 9H).

Step 2: (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl-d 2 )-6-fluorohexahydro-3/-pyrrolizin-3-one & (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )-2-fluorohexahydro-3H-pyrrolizin-3-one

To an ice-cooled solution of (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )-2-fluorohexahydro-1/-pyrrolizine (60 g, 150.14 mmol) and trichlororuthenium hydrate (16.92 g, 75.07 mmol) in CC14 (300 mL) and H 2 O (300 mL) was added NaIO 4 (160.57 g, 750.71 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was filtered, and then extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-20% EA in PE to afford 60 g mixture of two isomers as a light-yellow solid. The mixture was purified by Prep-Achiral-SFC with the following conditions: Column: XA-GreenSep Naphthyl, 3×25 cm, 5 μm; Mobile Phase A: CO 2 ; Mobile Phase B: IPA (0.1% 7 M NH 3 a MeOH); Flow rate: 200 mL/min; Gradient: isocratic 20% B; Detector: UV 220 nm; RT1=4.30 min; RT2: 6.07 min. The first eluting peak (RT1: 4.30 min) was concentrated and lyophilized to give the title compound (Intermediate 143, 40 g, 66% yield) as a yellow solid. MS: m/z=414.30 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.64-7.61 (m, 4H), 7.47-7.38 (m, 6H), 5.34-5.20 (m, 1H), 4.23-4.07 (m, 1H), 3.19-2.99 (m, 1H), 2.81-2.65 (m, 1H), 2.43-2.12 (m, 3H), 2.05-1.97 (m, 2H), 1.04 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −173.04 (s, 1F). The second eluting peak (RT2: 6.07 min) was concentrated and lyophilized to give the title compound (Intermediate 144, 12 g, 20% yield) as a yellow solid. MS: m/z=414.30 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.65-7.58 (m, 4H), 7.47-7.37 (m, 6H), 5.74-5.51 (m, 1H), 3.84-3.72 (m, 1H), 2.94-2.86 (m, 2H), 2.10-1.71 (m, 4H), 1.66-1.55 (m, 1H), 1.05 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) 6-184.21 (s, 1F).

To a mixture of Intermediate 144 (3.6 g, 8.70 mmol) and chloroiridium; methanidylidyneoxidanium; bis(triphenylphosphane) (0.14 g, 0.17 mmol) in DCM (36 mL) under N 2 was added 1,1,3,3-tetramethyldisiloxane (2.34 g, 17.40 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hours. Methylmagnesium bromide (1.0 M in THF, 17.41 mL, 17.40 mmol) was added to the above mixture at −70° C. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with sat. NH 4 Cl aq. (100 mL) in an ice bath and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with PE/EA (7: 1) to give two isomers. The first eluting isomer was concentrated to give the title compound (Intermediate 145, 0.6 g, 16% yield) as a light-yellow oil. MS: m/z=414.20 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 7.71-7.57 (m, 4H), 7.43-7.35 (m, 6H), 4.78-4.63 (m, 1H), 3.16-2.70 (m, 3H), 2.39-2.31 (m, 1H), 2.03-1.78 (m, 3H), 1.75-1.62 (m, 2H), 1.08-1.06 (m, 12H). 19 F NMR (376 MHz, Chloroform-d) δ −182.46 (s, 1F). The second eluting isomer was concentrated to give the title compound (Intermediate 146, 1.8 g, 49% yield) as a light-yellow oil. MS: m/z=414.25 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) & 7.68-7.64 (m, 4H), 7.43-7.34 (m, 6H), 5.00-4.85 (m, 1H), 3.19-2.79 (m, 3H), 2.23-1.95 (m, 3H), 1.82-1.63 (m, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.06 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) δ −187.10 (s, 1F).

To a solution of Intermediate 146 (400 mg, 0.97 mmol) in methanol (4.0 mL) was added NH 4 F (1.43 g, 38.61 mmol) at room temperature. The reaction mixture was heated at 65° C. for 4 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(DCM: MeOH=10: 1) to afford the title compound (Intermediate 147, 110 mg, 64% yield) as a yellow oil. MS: m/z=176.05 [M+H] + . 1 HI NMR (400 MHz, DMSO-d 6 ) δ 5.11-4.96 (m, 1H), 3.26-2.24 (m, 1H), 3.17-2.87 (m, 2H), 2.18-1.54 (m, 6H), 1.25-1.19 (m, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ −186.00 (s, 1F).

Step 1: (1R,2R,7a'S)-2-fluoro-7a′-(hydroxymethyl-d 2 )tetrahydro-3′H,5′H-spiro[cyclopropane-1,2′-pyrrolizin]-5′-one

To a solution of Intermediate 88 (170 mg, 705 μmol) in CD 3 OD (5 mL) was added NaBD4 (133 mg, 3.52 mmol) at 0° C. under N 2 . The mixture was stirred at 25° C. for 16 h under N 2 and quenched with D 2 O (0.5 mL) and IN HCl (0.5 mL) at 0° C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜4% of MeOH in dichloromethane) to give the title compound (120 mg, 84% yield) as a colorless oil. MS: m/z=202.2 [M+H] +.

Step 2: ((1R,2R,7a'S)-2-Fluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizin]-7a′(5′H)-yl) methan-d 2 -ol

To a solution of (1R,2R,7a'S)-2-fluoro-7a′-(hydroxymethyl-dz)tetrahydro-3′H,5′H-spiro[cyclopropane-1,2′-pyrrolizin]-5′-one (120 mg, 596 μmol) in THE (2 mL) was added LiAlH4 (715 μL, 2.5 M in THF) dropwise at 0° C. under N 2 . The mixture was stirred at 65° C. for 2 h under N 2 . The reaction mixture was cooled to 0° C. and quenched with H 2 O (0.1 mL), 15 wt % NaOH aq. (0.1 mL) and H 2 O (0.3 mL). The reaction mixture was diluted with THE (10 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Dichloromethane: MeOH=5: 1) to give the title compound (Intermediate 148, 80 mg, 72% yield) as a colorless oil. MS: m/z=188.2 [M+H].

Step 1: (1S,7S,8S)-8-Fluoro-2-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4 (3H)-one (2.14 g. 7.47 mmol) and DIPEA (3.94 mL, 22.64 mmol) in ACN (5 mL) was added a solution of Intermediate 153 (1.6 g, 7.55 mmol, HBr salt) in ACN (5 mL) at 0° C. under N 2 . The mixture was stirred at 0° C. for 0.5 h under N 2 . The reaction mixture was quenched with H 2 O (100 mL) and extracted with CH 2 Cl 2 (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜3% of MeOH in CH 2 Cl 2 ) to give the title compound (1.4 g, 41% yield over 2 steps) as a yellow solid. MS: m/z=381.0 [M+H] +.

Step 2: (15,7S,8S)-2-(5,7-Dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1/-pyrrolizin-7a (5H)-yl) methoxy-d 2 )pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

A mixture of (1S,7S,8S)-8-fluoro-2-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (1.3 g, 2.86 mmol), Intermediate 17 (923 mg, 5.72 mmol) and DIPEA (1.50 mL, 8.59 mmol) in 1,4-dioxane (20 mL) was degassed and purged with N 2 three times. The mixture was stirred at 110° C. for 16 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜5% of MeOH in CH 2 Cl 2 ) to give a crude product. The crude product was further purified by reversed-phase column (column: C 18 ; mobile phase: [water (0.1% NH 3 ·H 2 O)-ACN]; B %: 0%˜74%, 40 min) to give the title compound (Intermediate 149, 770 mg, 53% yield) as a yellow solid. MS: m/z=506.1 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 5.41-5.15 (m, 1H), 4.52-4.21 (m, 4H), 4.02-3.88 (m, 1H), 3.69-3.56 (m, 2H), 3.11-2.96 (m, 3H), 2.84-2.67 (m, 2H), 2.23-1.72 (m, 7H). 19 F NMR (376 MHZ, Dimethylsulfoxide-d 6 ) δ −139.60, −172.20, −206.10.

To a stirred solution of methyl 2-amino-4-bromo-5-fluorobenzoate (4.5 g, 18.14 mmol) and Ag2SO 4 (9.05 g, 29.02 mmol) in methanol (43.2 mL) and H 2 O (36 mL) was added dropwise a solution of iodine (7.37 g, 29.02 mmol) in THF (43.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hour. The resulting mixture was concentrated under reduced pressure to remove MeOH & THF, filtered and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE/EA (15: 1)) to afford the title compound (6.2 g, 91% yield) as an off-white solid. MS: m/z=373.95, 375.95 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) § 7.72-7.75 (m, 1H), 3.90 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ −111.95 (s, 1F).

To a stirred solution of methyl 2-amino-4-bromo-5-fluoro-3-iodobenzoate (6 g, 16.04 mmol) and methylboronic acid (5762.73 mg, 96.27 mmol) in 1,2-dimethoxyethane (87.6 mL) and H 2 O (15 mL) were added Pd (PPh 3 ) 2 Cl 2 (1126.20 mg, 1.60 mmol) and K 2 CO 3 (4.43 g, 32.09 mmol) at room temperature under N 2 . The reaction mixture was heated at 90° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE/EA (15: 1)) to afford the title compound (2.2 g, 52% yield) as an off-white solid. MS: m/z=261.95, 263.95 [M+H] + . 1II NMR (400 MHz, Chloroform-d) δ 7.55-7.53 (m, 1H), 3.88 (s, 3H), 2.33 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ −118.82 (s, IF).

To a stirred solution of methyl 2-amino-4-bromo-5-fluoro-3-methylbenzoate (2 g, 7.63 mmol) in THF (25 mL) was added trichloroethanecarbonyl isocyanate (2.16 g, 11.44 mmol) at room temperature under N 2 . The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (3×25 mL) to give the title compound (3.5 g, crude) as an off-white solid. MS: m/z=470.75 and 472.75 [M+Na] +.

To a stirred solution of methyl 4-bromo-5-fluoro-3-methyl-2-(3-(2,2,2-trichloroacetyl) ureido)benzoate (3.5 g, crude) in methanol (120 mL) was added NH 3 MeOH (7 M in MeOH, 3.11 mL, 21.75 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (3×40 mL) to give the title compound (1.9 g, crude) as an off-white solid. MS: m/z=272.85, 274.85 [M+H] +.

To a stirred solution of POCl (665.36 mg, 4.33 mmol) and DIEA (3.08 g, 23.80 mmol) was added 7-bromo-6-fluoro-8-methylquinazoline-2,4-diol (1.3 g, crude) in an ice bath under N 2 . The reaction mixture was heated at 110° C. for 16 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was quenched with sat. NaHCO 3 aq. (15 mL) in an ice bath, diluted with water (100 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE/EA (10: 1)) to afford the title compound (700 mg, 43% yield for three steps) as an off-white solid. 1 H NMR (300 MHz, Chloroform-d) δ 7.82-7.79 (m, 1H), 2.89 (d, J=0.6 Hz, 3H). 19 F NMR (282 MHz, Chloroform-d) δ −97.76 (s, 1F).

Step 6: (15,7S,8S)-2-(7-Bromo-2-chloro-6-fluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 7-bromo-2,4-dichloro-6-fluoro-8-methylquinazoline (300 mg, 0.96 mmol) and Intermediate 153 (205.25 mg, 0.96 mmol) in DCM (5 mL) was added DIEA (375.29 mg, 2.90 mmol) dropwise at room temperature under N 2 . The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC(PE/EA 5: 1) to afford the title compound (300 mg, 76% yield) as an off-white solid. MS: m/z=403.90, 405.90 [M+H] + . 1 H NMR (300 MHZ, Chloroform-d)δ 7.94-7.91 (m, 1H), 4.54-4.39 (m, 2H), 4.29-4.08 (m, 1H), 3.99-3.96 (m, 2H), 3.89-3.80 (m, 1H), 3.66-3.57 (m, 1H), 3.23-3.07 (m, 1H), 2.82 (s, 3H), 2.35-2.23 (m, 1H). 19 F NMR (282 MHz, Chloroform-d) δ −104.30 (s, 1F), —207.16 (s, IF).

Step 7: (1S,7S,8S)-2-(7-Bromo-2,6-difluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of (IS,7S,85)-2-(7-bromo-2-chloro-6-fluoro-8-methylquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (320 mg, 0.79 mmol) in DMSO (0.5 mL) under N 2 was added KF (321.61 mg, 5.53 mmol) at room temperature. The reaction mixture was heated at 120° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC(PE/EA 6: 1) to afford the title compound (Intermediate 150, 170 mg, 55% yield) as an off-white solid. MS: m/z=388.00, 390.00 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 8.00-7.98 (m, 1H), 4.53-4.41 (m, 2H), 4.30-4.15 (m, 1H), 3.98-3.83 (m, 3H), 3.67-3.60 (m, 1H), 3.23-3.07 (m, 1H), 2.80 (s, 3H), 2.35-2.26 (m, 1H). 19 F NMR (376 MHz, Chloroform-d) δ −46.78 (s, IF), —106.04 (s, IF), —207.06 (s, 1F).

To a stirred solution of ethyl 4-amino-6-chloronicotinate (80 g, 398.76 mmol) and Ag2SO 4 (198.93 g, 638.02 mmol) in MeOH (768 mL) and H 2 O (640 mL) was added a solution of iodine (323.8 g, 1.27 mol) in THF (768 mL) at room temperature. The reaction mixture was heated at 65° C. for 16 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting mixture was diluted with DCM (600 mL), poured into cold sat. NaHISOs aq. (1800 mL), and extracted with DCM (3×800 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was triturated with EA (80 mL). The precipitated solids were collected by filtration and washed with EA (3×20 mL) to give the title compound (80 g, 245.0 mmol, 61% yield) as a light yellow solid. MS: m/z=326.85 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 4.35-4.29 (m, 2H), 1.32 (t, J=7.2 Hz, 3H).

To a stirred solution of ethyl 4-amino-6-chloro-5-iodonicotinate (10 g, 30.62 mmol) in THE (100 mL) under N 2 was added trichloroethanecarbonyl isocyanate (5.77 g, 30.62 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (80 mL). The precipitated solids were collected by filtration and washed with MTBE (20 mL) to give the title compound (12 g, 76% yield) as an off-white solid. MS: m/z=513.95, 515.95 [M+H] +.

To a stirred solution of ethyl 6-chloro-5-iodo-4-(3-(2,2,2-trichloroacetyl) ureido) nicotinate (12 g, 23.30 mmol) in methanol (180 mL) was added NH 3 a MeOH (7 M in MeOH, 9.32 mL, 65.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with MTBE (150 mL) to give the title compound (10 g, crude used through) as an off-white solid. 1H NMR (400 MHZ, DMSO-d 6 ) δ 8.35 (s, 1H).

To an ice-cooled stirred solution of POCl 3 (100 mL) and DIEA (19.98 g, 154.57 mmol) was added 7-chloro-8-iodopyrido[4,3-d]pyrimidine-2,4-diol (10 g, crude) under nitrogen atmosphere. The ice bath was removed, and the reaction mixture was heated at 110° C. for 16 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted EA (50 mL), poured into cold sat. NaHCO 3 aq. (100 mL) slowly, and extracted with EtOAc (3×200 mL). The combined organic layers were washed water (100 mL) and brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE/BA (25: 1)) to afford the title compound (6.5 g, 77% yield for two steps) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H).

Step 5: (15,75,8S)-2-(2,7-Dichloro-8-iodopyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 2,4,7-trichloro-8-iodopyrido[4,3-d]pyrimidine (2.5 g, 6.93 mmol) and DIEA (2.689 g, 20.81 mmol) in DCM (30 mL) was added Intermediate 153 (1.471 g, 6.93 mmol) dropwise at −40° C. under N 2 . The reaction mixture was stirred at −40° C. for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 20% DCM in EA) to afford the title compound (Intermediate 151, 2.1 g, 66% yield) as a light yellow solid. MS: m/z=454.85, 456.85 [M+H] +.

To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 85.46 mmol) in DMF (200 mL) was added 1-iodopyrrolidine-2,5-dione (28.84 g, 128.19 mmol) at room temperature under N 2 . The reaction mixture was heated at 80° C. for 2 hours. The resulting mixture was cooled to room temperature and poured into water. The precipitate was filtered and washed with water and MeCN to afford the title compound (28 g, 93% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.34 (s, 1H), 7.99 (m, 1H), 6.91 (bs, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ −116.19 (s, IF).

A solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (28 g, 77.79 mmol) in SOCl 2 (360 mL) was heated at 50° C. for 3 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetone (140 mL). The resulting solution was added dropwise to a solution of ammonium sulfurothioate (12.68 g, 85.58 mmol) in acetone (140 mL). The mixture was stirred at room temperature for 1 hour and then filtered. The filter cake was washed with water and dissolved in 10% aq. NaOH. The resulting mixture was filtered. The pH of the filtrate was adjusted to about 2 with 1 M aq. HCl. The precipitate was filtered and washed with methanol to afford the title compound (30 g, crude, 96% yield) as a yellow solid. MS: m/z=400.75, 402.75 [M+H] + . 1 H NMR (400 MHZ, DMSO-d 6 ) § 12.91 (s, 1H), 12.73 (s, 1H), 8.13 (s, 1H). 19 F NMR (376 MHz, DMSO-d 6 ) δ −108.34 (s, 1F).

To a solution of 7-bromo-8-fluoro-6-iodo-2-mercaptoquinazolin-4-ol (20 g, 49.88 mmol) in methanol (500 mL) was added a solution of NaOH (3.99 g, 99.75 mmol) and iodomethane (14.46 g, 99.75 mmol) in H 2 O (400 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was filtered. The filter cake was washed with water and then dissolved in 10% aq. NaOH. The resulting mixture was filtered. The pH of the filtrate was adjusted to about 6 with 1 M aq. HCl. The resulting mixture was filtered again and the filter cake was washed with methanol to afford the title compound (15 g, crude) as a yellow solid. MS: m/z=414.65, 416.65 [M+H] +.

To a solution of 7-bromo-8-fluoro-6-iodo-2-(methylthio) quinazolin-4-ol (15 g, crude) in POC13 (150 mL) was added DIEA (12.59 mL, 72.28 mmol) at room temperature. The reaction mixture was heated at 100° C. for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL) and washed with water (70 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 10% EA in PE) to give the title compound (12 g, crude) as a light-yellow solid. MS: m/z=432.85, 434.85 [M+H].

Step 5: (1S,7S,8S)-2-(7-Bromo-8-fluoro-6-iodo-2-(methylthio) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a stirred solution of 7-bromo-4-chloro-8-fluoro-6-iodo-2-(methylthio) quinazoline (12 g, crude) in DMSO (120 mL) under N 2 were added DIEA (10.73 g, 83.05 mmol) and Intermediate 153 (7044.92 mg, 33.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with H 2 O (300 mL) and extracted with EA (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 20% EA in PE) to afford the title compound (13 g, 49% yield for three steps) as a light-yellow solid. MS: m/z=528.00, 530.00 [M+H] + , 1 H NMR (300 MHz, Chloroform-d) δ 8.45 (s, 1H), 4.62-4.57 (m, 1H), 4.52-4.11 (m, 2H), 4.08-3.85 (m, 3H), 3.68-3.59 (m, 3H), 3.33-3.13 (m, 1H), 2.58 (s, 3H), 2.43-2.24 (m, 1H).

Step 6: 7-Bromo-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(methylthio) quinazoline-6-carbonitrile

To a stirred solution of (15,7S,8S)-2-(7-bromo-8-fluoro-6-iodo-2-(methylthio) quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (10 g, 18.93 mmol) in DMF (100 mL) was added CuCN (3.39 g, 37.87 mmol) at room temperature under N 2 . The reaction mixture was heated at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with EA (1500 mL), washed with H 2 O (3×500 mL) and brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 25% EA in PE) to afford the title compound (6 g, 74% yield) as a light yellow solid. MS: m/z=426.95, 428.95 [M+H] +.

Step 7: 7-Bromo-8-fluoro-4-((15,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(methylsulfonyl) quinazoline-6-carbonitrile

To an ice-cooled solution of 7-bromo-8-fluoro-4-((15,75,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(methylthio) quinazoline-6-carbonitrile (5 g, 11.70 mmol) in DCM (50 mL) was added 3-chlorobenzene-1-carboperoxoic acid (5.05 g, 29.26 mmol). The reaction mixture was stirred in an ice bath for 1 hour. The resulting mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 30% EA in PE) to afford the title compound (Intermediate 152, 4 g, 74% yield) as a yellow solid. MS: m/z=459.00, 461.00 [M+H] +.

A mixture of benzyl (15,7S,8S)-8-fluoro-S-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.0 g, 102 mmol, refer to Intermediate 31 and 32 for detail procedures) and HBr (10 mL, 30% in AcOH) was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.6 g, HBr salt) as a yellow solid, which was used in the next step without further purification.

To a solution of Intermediate 113 (3 g, 4.628 mmol) in EtOH (30 mL) were added NaOAc (760 mg, 9.264 mmol) and Hydroxylamine hydrochloride (643 mg, 9.253 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. NaHCO 3 aq. (40 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 78% EA in PE) to afford a crude product (2 g). The crude product was dissolved in EA (1.4 mL), and HCl (1.0 M in EA, 8.8 mL, 8.800 mmol) was added in an ice bath. The resulting mixture was stirred in an ice bath for 30 min. The solid was collected by filtration, washed with hexane (4×50 mL), dried under reduced pressure to afford the title compound (Intermediate 154, 1.05 g, 47% yield) as an off-white solid. MS: m/z=484.20 [M+H] + . JH NMR (400 MHz, Methanol-d 4 ) δ 8.04-7.86 (m, 2H), 7.78-7.53 (m, 2H), 1.43 (d, J=5.6 Hz, 12H), 1.24-1.14 (m, 21H).

Step 1: (15,7S,8S)-2-(2,7-Dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of Intermediate 153 (1.62 g, 7.65 mmol, HBr salt) in CH 2 Cl 2 (20 mL) was added DIPEA (5.61 mL, 32.2 mmol) and 2,4,7-trichloro-8-methylpyrido[4,3-d]pyrimidine (2 g, 8.05 mmol) at −78° C. under N 2 . The mixture was stirred at −78° C. for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜15% of EtOAc in petroleum ether) to give the title compound (2.7 g, 98% yield) as a yellow solid. MS: m/z=342.9 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 9.40 (s, 1H), 4.70-4.61 (m, 1H), 4.47-4.19 (m, 2H), 4.00-3.84 (m, 3H), 3.70-3.60 (m, 1H), 3.41-3.14 (m, 1H), 2.67 (s, 3H), 2.39-2.25 (m, 1H).

Step 2: (1S,7S,8S)-2-(7-chloro-2-fluoro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of (1S,7S,8S)-2-(2,7-dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (2.6 g, 7.58 mmol) in DMSO (26 mL) was added KF (1.32 g, 22.7 mmol) under N 2 at 25° C. The mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in petroleum ether) to give the title compound (Intermediate 156, 2 g, 81% yield) as a yellow solid. MS: m/z=327.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 4.72-4.54 (m, 1H), 4.48-4.22 (m, 2H), 4.03-3.83 (m, 3H), 3.72-3.60 (m, 1H), 3.45-3.13 (m, 1H), 2.64 (s, 3H), 2.44-2.25 (m, 1H).

To a solution of Intermediate 156 (2.6 g, 7.58 mmol) in DMSO (26 mL) was added KF (1.32 g, 22.7 mmol) under N 2 at 25° C. The mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜20% of EtOAc in petroleum ether) to give the title compound (Intermediate 157, 2 g, 81% yield) as a yellow solid. MS: m/z=327.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 4.72-4.54 (m, 1H), 4.48-4.22 (m, 2H), 4.03-3.83 (m, 3H), 3.72-3.60 (m, 1H), 3.45-3.13 (m, 1H), 2.64 (s, 3H), 2.44-2.25 (m, 1H).

A mixture of ethyl 2-cyclopropylideneacetate (150 g, 1.19 mol), ethyl 2-nitroacetate (152 mL, 1.37 mol) and K 2 CO 3 (189 g, 1.37 mol) in THF (3000 mL) was degassed, purged with N 2 three times, and stirred at 80° C. for 3 h under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (1000 mL). The pH of the mixture was adjusted to around 3 with HCl aq. (1 L, 6 M in H 2 O). The mixture was extracted with CH 2 Cl 2 (1000 mL×3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound (308 g, crude) as a yellow liquid, which was used in the next step without further purification. 1 H NMR (400 MHZ, Chloroform-d)δ 5.02 (s, 1H), 4.30-4.20 (m, 2H), 4.15-4.06 (m, 2H), 2.64-2.53 (m, 1H), 1.32-1.27 (m, 3H), 1.27-1.20 (m, 3H), 1.07-0.99 (m, 1H), 0.94-0.77 (m, 3H).

To a solution of ethyl 2-(1-(2-ethoxy-2-oxoethyl)cyclopropyl)-2-nitroacetate (39.5 g, 152 mmol) in AcOH (400 mL) and EtOH (800 mL) was added Zn (99 g, 1.52 mol) in batches at 25° C. under N 2 . The mixture was stirred at 100° C. for 16 h under N 2 . The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with sat. NaHCOsaq. (500 mL) (pH was adjusted to around 8) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (cluent: 0˜1% of MeOH in CH 2 Cl 2 ) to give the title compound (31.6 g, 56% yield) as a white solid. MS: m/z=184.0 [M+H] + . 1 H NMR (400 MHZ, Dimethylsulfoxide-d 6 ) δ 8.11 (s, 1H), 4.16-4.09 (m, 2H), 3.70 (s, 1H), 2.42 (d, J=16.8 Hz, 1H) 2.01-1.95 (m, 1H), 1.20 (t, J=7.2 Hz, 3H), 0.84-0.77 (m, 1H), 0.74-0.66 (m, 1H), 0.66-0.58 (m, 2H).

To a solution of ethyl 6-oxo-5-azaspiro[2.4]heptane-4-carboxylate (20 g, 109 mmol) and 3-chloro-2-(chloromethyl) prop-1-ene (51 mL, 437 mmol) in THF (1000 mL) was added dropwise LiHMDS (229 mL, 1 M in THF) at −40° C. over 50 min under N 2 . The mixture was stirred at this temperature for 30 min, and continued to stirr at 25° C. for 15.5 h under N 2 . The reaction mixture was quenched with sat. NH 4 Cl aq. (1000 mL) at 25° C. and extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine (2000 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜35% of EtOAc in petroleum ether) to give the title compound (6.5 g, 25% yield) as a yellow oil. MS: m/z=236.1 [M+H] +.

Step 4: Ethyl(S)-6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1, l′-pyrrolizine]-7a′(5′H)-carboxylate & ethyl (R)-6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(S′H)-carboxylate

Ethyl 6′-methylene-3′-oxotetrahydrospiro[cyclopropane-1,1′-pyrrolizine]-7a′(5′H)-carboxylate (30 g) was separated by SFC(column: DAICEL CHIRALPAK AS (250 mm×50 mm, 10 μm); mobile phase: [CO 2 -i-PrOH (0.1% NH 3 H 2 O)]; gradient: 45%˜50% B over 2.5 min) to give the title compound (Intermediate 158, 13.77 g, 46% yield, SFC peak 1, retention time: 1.216 min) as a yellow oil and the other title compound (Intermediate 159, 14.4 g, 48% yield, SFC peak 1, retention time: 1.542 min) as a yellow oil. Spectra for Intermediate 158: MS: m/z=236.0 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 5.10-4.98 (m, 2H), 4.34 (br d, J=16 Hz, 1H), 4.28-4.13 (m, 2H), 3.65 (br d, J=15.6 Hz, 1H), 3.07 (d, J=16.8 Hz, 1H), 2.84 (br d, J=14.8 Hz, 1H), 2.36 (br d, J=14.8 Hz, 1H), 2.20 (d, J=16.8 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H), 0.92-0.77 (m, 2H), 0.71-0.60 (m, 2H). Spectra for Intermediate 159: MS: m/z=236.0 [M+H] + , 1 H NMR (400 MHZ, Chloroform-d) δ 5.09-4.98 (m, 2H), 4.34 (br d, J=15.6 Hz, 1H), 4.27-4.13 (m, 2H), 3.70-3.60 (m, 1H), 3.07 (d, J=16.8 Hz, 1H), 2.84 (dd, J=0.8, 14.4 Hz, 1H), 2.40-2.32 (m, 1H), 2.19 (d, J=16.8 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H), 0.91-0.78 (m, 2H), 0.70-0.61 (m, 2H).

Step 1: (R)-Ta′-(Hydroxymethyl-d 2 )-6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-3′(2′H)-one

To a solution of Intermediate 159 (500 mg, 2.13 mmol) in CD 3 OD (10 mL) was added NaBD4 (402 mg, 10.6 mmol) under N 2 . The mixture was stirred at 25° C. for 16 h under N 2 . The reaction mixture was quenched with HCl (5 mL, 1 M in H 2 O) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜8% MeOH in CH 2 Cl 2 ) to give the title compound (390 mg, 94% yield) as an off-white solid. MS: m/z=196.2 [M+H] +.

To a solution of (R)-Ta′-(hydroxymethyl-d 2 )-6′-methylenetetrahydrospiro[cyclopropane-1,1′-pyrrolizin]-3′(2′H)-one (340 mg, 1.74 mmol) in THF (15 mL) was added LiAlH4 (3.48 mL, 2.5 M in THF) at 0° C. under N 2 . The mixture was stirred at 70° C. for 3 h under N 2 , quenched with Na 2 SO 4 $10H 2 O (3 g) at 0° C. under N 2 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜30% MeOH in CH 2 Cl 2 ) to give the title compound (Intermediate 160, 230 mg, 69% yield) as a yellow oil, MS: m/z=182.2 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d) δ 4.98-4.83 (m, 2H), 3.74 (d, J=14.4 Hz, 1H), 3.37 (d, J=14.8 Hz, 1H), 3.24-3.15 (m, 1H), 2.80-2.70 (m, 1H), 2.26-2.17 (m, 2H), 2.05-1.95 (m, 1H), 1.78-1.69 (m, 1H), 0.65-0.55 (m, 2H), 0.54-0.45 (m, 2H).

Intermediate 114 (40 g) was purified by SFC(column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 .H 2 O)]; B %: 25%, isocratic elution mode) to give the title compound (Intermediate 161, SFC peak 1: 1.240 min, 20.7 g, 51% yield) as a white solid and the other title compound (Intermediate 162, SFC peak 2: 1.442 min, 17.1 g, 42% yield) as a white solid. Spectra for Intermediate 161: MS: m/z=282.1 [M+H] + . 1 H NMR (400 MHZ, Chloroform-d)δ 7.51-7.29 (m, 5H), 5.30-5.12 (m, 2H), 4.42-4.32 (m, 1H), 4.11-3.93 (m, 1H), 3.85-3.76 (m, 1H), 3.50-3.42 (m, 1H), 3.36-3.18 (m, 3H), 3.13-3.02 (m, 1H), 1.88-1.78 (m, 1H). Spectra for Intermediate 162: MS: m/z=282.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.50-7.28 (m, 5H), 5.27-5.10 (m, 2H), 4.41-4.32 (m, 1H), 4.09-3.94 (m, 1H), 3.86-3.77 (m, 1H), 3.51-3.42 (m, 1H), 3.37-3.17 (m, 3H), 3.12-3.00 (m, 1H), 1.89-1.78 (m, 1H).

To a solution of Intermediate 162 (500 mg, 1.76 mmol) was added HBr (5 mL, 30% in AcOH). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (402 mg, HBr salt) as a brown solid, which was used into the next step without further purification.

Step 2: (1S,7S,8S)-8-chloro-2-(2,7-dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane

A mixture of (1S,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octane (402 mg, 1.76 mmol, HBr salt), 2,4,7-trichloro-8-methylpyrido[4,3-d]pyrimidine (460 mg, 1.85 mmol) in CH 2 Cl 2 (8 mL) was added DIPEA (1.61 mL, 9.26 mmol) at −78° C. under N 2 . The mixture was stirred at −78° C. for 1 h under N 2 . The reaction mixture was quenched with H 2 O (7 mL) at 0° C. and extracted with CH 2 Cl 2 (10 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0˜30% of EtOAc in petroleum ether) to give the title compound (500 mg, 73% yield) as a yellow solid. MS: m/z=358.9, 360.9 [M+H] +.

Step 3: (1S,75,8S)-8-chloro-2-(7-chloro-2-fluoro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane

To a solution of (1S,7S,8S)-8-chloro-2-(2,7-dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (400 mg, 1.09 mmol) in DMSO (4 mL) was added KF (315 mg, 5.43 mmol) under N 2 . The mixture was stirred at 100° C. for 6 h. The reaction mixture was added water (8 mL) at 25° C. and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 100% of CH 2 Cl 2 ) to give the title compound (Intermediate 163, 320 mg, 79% yield) as a yellow solid. MS: m/z=342.9 [M+H] +.

Benzyl-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans) (35 g) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -MeOH (0.1% NH 3 *H 2 O)]; B %: 20%, isocratic elution mode) to give the title compound (Intermediate 164, SFC peak 2, retention time: 1.236 min, 13.7 g, 39% yield) as a colorless oil and the other title compound (Intermediate 165, SFC peak 1, retention time: 1.002 min, 14.0 g, 40% yield) as a colorless oil. Spectra for Intermediate 164: 1 H NMR (400 MHZ, Chloroform-d) δ 7.45-7.28 (m, 5H), 5.27-5.08 (m, 2H), 4.74-4.30 (m, 1H), 4.13-3.90 (m, 1H), 2.99-2.84 (m, 2H), 2