KRAS G12D INHIBITORS AND USES THEREOF

Abstract

Provided are novel compounds useful as KRAS G12D inhibitors, as well as pharmaceutical compositions comprising these compounds, and methods of treatment by administration of these compounds or pharmaceutical compositions.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE

[0001] This disclosure relates generally to novel compounds useful as inhibitors of KRAS G12D, and to pharmaceutical compositions comprising these compounds, and methods of treatment by administration of these compounds or pharmaceutical compositions. [Background technology]

[0002]

[0002] RAS is one of the best-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten rat sarcoma viral oncogene homolog) has been thoroughly studied in the past few years. KRAS and the closely related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They control diverse cellular functions by cycling between an active GTP-bound conformation and an inactive GDP-bound conformation (Hobbs, GA et al., J. Cell Sci. 129, 1287-1292. (2016)).

[0003] KRAS is a well-known oncogene that has been proven to drive tumorigenesis (GG Jinesh et al., Oncogene 37:839-846 (2018)). KRAS also modulates numerous gene regulatory mechanisms, forming a large tumorigenesis network. The KRAS gene encodes a 21 kDa protein called KRAS, which is part of the RAS / MAPK pathway. The KRAS protein is a GTPase, meaning that it can bind with high affinity to the guanine nucleotides GDP and guanosine triphosphate (GTP) and hydrolyze GTP to GDP (Dhirendra K. Simanshu et al., Cell. 2017 Jun 29;170(1):17-33). GDP / GTP cycling is tightly regulated by a diverse family of multidomain proteins: guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs stimulate the dissociation of GDP and subsequent binding of GTP, activating RAS proteins, whereas GAPs act to accelerate endogenous GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu et al., Cell. 2017 Jun 29;170(1):17-33). The GTP-bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to the GTP-bound form of KRAS. KRAS protein is turned off (inactivated) when the protein is bound to GDP and does not relay signals to the cell's nucleus.

[0004] Cancer-promoting KRAS mutations occur most frequently at codons 12, 13, or 61 (Jozsef Timar et al., Cancer and Metastasis Reviews 39, 1029-1038 (2020)). Among these mutation sites, G12 is the most frequently mutated residue (89%), most commonly mutated to aspartic acid (G12D, 36%), followed by valine (G12V, 23%) and cysteine ​​(G12C, 14%). G12 is located in the protein active site, which consists of a phosphate-binding loop (P-loop, residues 10-17) and two switch regions (switch-I (SI), residues 25-40, and switch-II (SII), residues 60-74) (Prior, IA et al., Cancer Res 72, 2457-2467, (2012)). The active site residues bind the phosphate group of GTP and are responsible for the GTPase function of KRAS. The switch regions SI and SII are further responsible for controlling the binding to effector and regulatory proteins. Mutation of glycine at position 12 to aspartic acid (G12D) in the P-loop leads to impaired GTP hydrolysis, arresting KRAS in its active (GTP-bound) state, which causes uncontrolled cell growth and avoidance of apoptotic signals (Malumbres, M. and Barbacid, M. Nat Rev Cancer 3, 459-465, (2003)). The G12D mutation causes a structural shift in the population of local conformational states of KRAS that favors conformations associated with a catalytically impaired state, particularly in the switch-II (SII) and α3-helical regions, and also anticorrelates SII movements with other regions (Sezen Vatansever et al., Sci Rep. 2019 Aug 13;9(1):11730).

[0005]

[0005] KRAS mutations are present in up to 25% of cancers, and oncogenic variants have different occurrence rates in different cancers. In the case of pancreatic ductal adenocarcinoma, the most common KRAS alteration is the G12D substitution. The G12D variant is also the focus of drug discovery efforts by Mirati, which plans to bring its lead compound MRTX1133 into clinical trials. Based on epidemiological data and per-mutation frequency reported in Globocan 2022 (accessed November 2019), KRAS G12D mutations are present in an estimated approximately 36% of pancreatic cancers, 4% of colorectal cancers, approximately 6% of endometrial cancers, and approximately 4% of NSCLCs. This is a large patient population with high unmet need. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, KRAS G12D is very commonly observed in pancreatic cancer, which can be regarded as a representative of various incurable cancers. KRAS G12D is one of the most important chemotherapy drug targets. To investigate highly selective and potent small molecule inhibitors of KRAS G12D designed to treat patients with high unmet need. [Means for solving the problem]

[0007]

[0007] Disclosed herein are novel compounds capable of inhibiting KRAS G12D protein. As a result, the compounds disclosed herein are useful in treating KRAS G12D-related diseases, such as cancer.

[0008] In one aspect, the present disclosure provides a compound represented by formula (I) or (II):

[0009] [ka]

[0010] (In the formula, Y is O or S; Ring A is heterocyclyl or heteroaryl; Each R 1 are independently oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R * , -C(O)OR * , -C(O)N(R a ) 2 , -N(R a ) 2 , -P(O)OR * OR ** , and -C(O)OC(R a ) 2 -Z 1 -Z 2 wherein alkyl, alkenyl, alkynyl and heteroaryl are selected from the group consisting of cyano, hydroxyl, halogen, -OR b , or -N(R b ) 2 and optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; R * is selected from hydrogen, alkyl, alkylaryl or aryl; R ** is selected from hydrogen, alkyl, alkenyl or alkynyl; or R * and R ** together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Z 1 -OC(O)-#, -OP(=O)(OR *** )O-#, or -OP(=O)(OR * )N(R a )-#, where # ends in Z 2 is connected to Z 2 is hydrogen or -C(O)OR aor alkyl optionally substituted with R *** is independently selected from hydrogen, alkyl, alkenyl, or alkynyl; R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R'; Each R' is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from hydroxyl, halogen, cyano, -OR a , -N(R a ) 2 and heteroaryl, Ring Q is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2 are independently hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -C(O)R * wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring W is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 3 are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; G 1 is a bond, -O-, -S(O) p -, -SS-, -N(R c )-, or -C(R d )=C(R d )-and G 2 is a bond, -[C(R d ) 2 ] u -, -C(O)- or -C(O)C(R d ) 2 - and R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl; Each R dis independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; The Two R's d together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, where the cycloalkyl and heterocyclyl are optionally substituted with cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, and alkyl; Z is C(R e ) or N, R e is absent or hydrogen, L 1 is a bond, -O-, -S-, -N(R a )-, -C(O)N(R a )-, alkenyl, alkynyl or cycloalkyl;

[0011] [ka]

[0012] is optionally substituted with hydroxyl, halogen, cyano or amino; L 2 is a bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; E is hydrogen, hydroxyl, halogen, -N(R a ) 2 , alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH 2 OC(O)-heterocyclyl, -CH 2 O C (O) N (R a ) 2 , -NHC(=NH)NH 2 , -C(O)N(R a ) 2 , -OR a , -(CH 2 OR a )(CH 2 ) p OR a , -N(R a )C(O)-aryl and -(CH 2 ) u -heterocyclyl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R″; and —N(R a )C(O)-aryl and the aryl portion of -(CH 2 ) u -heterocyclyl and -CH 2 the heterocyclyl portion of the OC(O)-heterocyclyl is optionally substituted by one or more R''', Each R″ is independently hydroxyl, halogen, —C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or —N(R a ) 2 is selected from Each R''' is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO 2 F, -N(R a ) 2 , -SO 2-F, -C(O)(alkyl), or -C(O)(haloalkyl), where alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, -O-, or -NHC(O)-; m is an integer from 0 to 6; n is an integer from 0 to 5; r is an integer from 0 to 4; s is an integer from 0 to 5; p is an integer from 0 to 2; (u is an integer from 0 to 4) or a pharma- ceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure provides a compound represented by formula (III) or (IV):

[0014] [ka]

[0015] (In the formula, Y is O or S; Ring A is heterocyclyl or heteroaryl; Each R 1 are independently oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R * , -C(O)OR * , -C(O)N(R a ) 2 , -N(R a ) 2 , -P(O)OR * OR ** , and -C(O)OC(R a )-Z 1 -Z 2 wherein alkyl, alkenyl, alkynyl and heteroaryl are selected from the group consisting of cyano, hydroxyl, halogen, -ORb , or -N(R b ) 2 and optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; R * is selected from hydrogen, alkyl, alkylaryl or aryl; R ** is selected from hydrogen, alkyl, alkenyl or alkynyl; or R * and R ** together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Z 1 -OC(O)-#, -OP(=O)(OR *** )O-#, or -OP(=O)(OR * )N(R a )-#, where # ends in Z 2 is connected to Z 2 is hydrogen or -C(O)OR a or alkyl optionally substituted with R *** is independently selected from hydrogen, alkyl, alkenyl, or alkynyl; R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R'; Each R' is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from hydroxyl, halogen, cyano, -OR a , -N(R a ) 2 and heteroaryl, Ring Q is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2 are independently hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -C(O)R * wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring W is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 3are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; U 1 is a bond, -(CH 2 ) t -, -O(CH 2 ) t -, -N(R j )-, -C(O)- or -C(O)C(R j ) 2 - selected from U 2 -O-, -S(O) p -,-[C(R j ) 2 ] t -, -C(R j )=C(R j )-, -N(R j )-, -C(O)- or -C(O)C(R j ) 2 - selected from R j is selected from the group consisting of hydrogen, cyano, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl, where alkyl, heteroalkyl, cycloalkyl, and heterocyclyl are each independently selected from the group consisting of -N(R a ) 2 or heterocyclyl, V 1 and V 2are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, and heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, or haloalkyl; V 1 and V 2 together with the carbon atom to which they are both attached form oxo, cycloalkyl, heterocyclyl, or heteroaryl, where cycloalkyl, heterocyclyl, and heteroaryl are selected from cyano, halogen, hydroxyl, amino, and heterocyclyl or -N(R a ) 2 and optionally substituted with one or more groups independently selected from the group consisting of alkyl, optionally substituted with Z is C(R e ) or N, R e is absent or hydrogen, L 1 is a bond, -O-, -S-, -N(R a )-, alkenyl, alkynyl or cycloalkyl;

[0016] [ka]

[0017] is optionally substituted with hydroxyl, halogen, cyano or amino; L 2 is a bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; E is hydrogen, hydroxyl, halogen, -N(R a ) 2 , alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH 2 OC(O)-heterocyclyl, -NHC(=NH)NH 2 , -C(O)N(R a ) 2 , -OR a , -(CH 2 OR a )(CH 2 ) p OR a , -N(R a )C(O)-aryl and -(CH 2 ) u -heterocyclyl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R″; and —N(R a )C(O)-aryl and the aryl portion of -(CH 2 ) u -heterocyclyl and -CH 2 the heterocyclyl portion of the OC(O)-heterocyclyl is optionally substituted by one or more R''', Each R″ is independently hydroxyl, halogen, —C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or —N(R a ) 2 is selected from Each R''' is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO 2 F, -N(R a ) 2 , -SO 2 -F, -C(O)(alkyl), or -C(O)(haloalkyl), where alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, -O-, or -NHC(O)-; m is an integer from 0 to 6; n is an integer from 0 to 5; r is an integer from 0 to 4; s is an integer from 0 to 5; p is an integer from 0 to 2; t is an integer from 0 to 3; (u is an integer from 0 to 4) or a pharma- ceutically acceptable salt thereof.

[0018] In another aspect, the present disclosure provides a compound of formula (Ia) or (Ib):

[0019] [ka]

[0020] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0021] In another aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising:

[0022] [ka]

[0023] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0024] In another aspect, the present disclosure provides a compound of formula (IIIa) or (IIIb):

[0025] [ka]

[0026] (In the ceremony T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0027] In another aspect, the present disclosure provides a compound represented by formula (IIIc), (IIId) or (IIIe):

[0028] [ka]

[0029] or a pharma- ceutically acceptable salt thereof.

[0030] In another aspect, the present disclosure provides a compound of formula (IVa) or (IVb):

[0031] [ka]

[0032] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0033] In another aspect, the present disclosure provides a compound of formula (IVc), (IVd) or (IVe):

[0034] [ka]

[0035] or a pharma- ceutically acceptable salt thereof.

[0036]

[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharma ceutically acceptable salt thereof, and a pharma ceutically acceptable excipient.

[0037]

[0017] In a further aspect, the present disclosure provides a method for inhibiting KRas G12D activity in a subject in need of inhibition of KRas G12D activity, the method comprising the step of administering to the subject an effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0038]

[0018] In a further aspect, the present disclosure provides a method for treating KRas G12D-associated cancer, comprising the step of administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0039] In a further aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising: (a) obtaining knowledge that cancer is associated with a KRas G12D mutation; (b) administering to the subject an effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure; The present invention provides a method comprising:

[0040]

[0020] In another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharma ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.

[0041]

[0021] In another aspect, the present disclosure provides a compound of the present disclosure or a pharma ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in the treatment of cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042]

[0022] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differ or conflict with this application, including but not limited to defined terms, term usage, described techniques, etc., the present disclosure will control. All references, patents, patent applications cited in this disclosure are hereby incorporated by reference in their entirety.

[0043]

[0023] It will be understood that certain features of the present disclosure, which are described for clarity in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are described for brevity in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms thereof unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes a plurality of compounds. definition

[0024] The definitions of certain functional groups and chemical terms are described in more detail below. For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and certain functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as certain functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004, the entire contents of each of which are incorporated herein by reference.

[0044] At various places in this disclosure, linking substituents are described. Each linking substituent is specifically intended to include both the forward and backward forms of the linking substituent. For example, -NR(CR'R'')- includes both -NR(CR'R'')- and -(CR'R'')NR-. Where a structure expressly requires a linking group, the Markush variable recited for that group will be understood to be the linking group. For example, where a structure requires a linking group and the Markush group definition for that variable recites "alkyl," it will be understood that "alkyl" represents a linking alkylene group.

[0045]

[0026] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, the substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom through which the substituent is bonded to the remainder of the compound of a given formula, the substituent may be bonded through any atom in that formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0046]

[0027] As used herein, a dash "-" at the front or end of a chemical group is used for convenience to indicate the point of attachment of a substituent. For example, -OH is attached through a carbon atom, and chemical groups may be represented with or without one or more dashes without losing their normal meaning. A wavy line drawn with a single line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named. As used herein, a solid line emanating from the center of a ring indicates that the point of attachment of a substituent on the ring may be at any ring atom. When a substituent is listed without indicating the atom through which the substituent is attached to the remainder of the compound of a given formula, the substituent may be attached through any atom in the formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0047] Any variable part (e.g., R i When any radical R occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, a radical R i When the moiety is indicated to be substituted, the group may have up to two R i Each occurrence of R i is R i Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0048]

[0029] As used herein, the term "compounds provided herein" or "compounds disclosed herein" or "compounds of the disclosure" refers to compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (Ia), Formula (Ib), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IIIe), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (IVe) and specific compounds disclosed herein.

[0049] As used herein, the term "C i~j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, where j is greater than i. For example, C 1~6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. 1~12 " denotes 1 to 12, in particular 1 to 10, in particular 1 to 8, in particular 1 to 6, in particular 1 to 5, in particular 1 to 4, in particular 1 to 3 or in particular 1 to 2 carbon atoms.

[0050]

[0031] As used herein, the term "alkyl," whether as part of another term or used independently, refers to a saturated straight or branched chain hydrocarbon group that may be independently optionally substituted with one or more of the substituents described below. i~j "Alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1~10Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~6 Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0051]

[0032] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, including groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

[0052]

[0033] As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond, which may be independently and optionally substituted with one or more substituents described herein. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkynyl group contains 2-11 carbon atoms. In some embodiments, an alkynyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0053]

[0034] As used herein, the term "alkoxy", whether as part of another term or used independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. i~j "Alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1~6 Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0054] As used herein, the term "amino" refers to -NH 2 The amino group may also be substituted with one or more groups, such as alkyl, aryl, carbonyl or other amino groups.

[0055]

[0036] As used herein, the term "aryl", whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, at least one ring in the system is aromatic, and each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused with one or more additional rings. In the case of polycyclic ring systems, only one of the rings need be aromatic (e.g., 2,3-dihydroindole), but all of the rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl groups may be optionally substituted at one or more ring positions with substituents as described above.

[0056] As used herein, the term "cyano" refers to --CN.

[0057] As used herein, the term "cyanoalkyl" refers to an alkyl, as defined above, substituted with one or more cyano.

[0058]

[0039] As used herein, the term "cycloalkyl", whether as part of another term or used independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyl can contain 3-12 ring-forming carbon atoms, 3-10 ring-forming carbon atoms, 3-9 ring-forming carbon atoms, 3-8 ring-forming carbon atoms, 3-7 ring-forming carbon atoms, 3-6 ring-forming carbon atoms, 3-5 ring-forming carbon atoms, 4-12 ring-forming carbon atoms, 4-10 ring-forming carbon atoms, 4-9 ring-forming carbon atoms, 4-8 ring-forming carbon atoms, 4-7 ring-forming carbon atoms, 4-6 ring-forming carbon atoms, 4-5 ring-forming carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated. Cycloalkyl groups can be substituted. In some embodiments, cycloalkyl groups can be saturated cyclic alkyl groups. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Fused, spiro and bridged ring systems are also included within the scope of this definition. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decanyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0059] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[0060]

[0041] As used herein, the term "haloalkyl" refers to an alkyl, as defined above, substituted by one or more halogens, as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0061] As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxide).

[0062]

[0043] As used herein, the term "heteroalkyl" refers to an alkyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. A heteroalkyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), and may be independently optionally substituted with one or more substituents described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy groups.

[0063]

[0044] As used herein, the term "heteroalkenyl" refers to an alkenyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. A heteroalkenyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), which may be independently optionally substituted with one or more substituents described herein.

[0064]

[0045] As used herein, the term "heteroalkynyl" refers to an alkynyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. The heteroalkynyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), which may be independently optionally substituted with one or more substituents described herein.

[0065]

[0046] As used herein, the term "heteroaryl", whether as part of another term or used independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the group or point of attachment is on the aromatic heterocycle. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0066]

[0047] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms may be optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in the ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of a basic nitrogen. "Heterocyclyl" also includes groups in which the heterocyclyl group is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclyl group may be carbon- or nitrogen-linked, where possible. In some embodiments, the heterocyclic ring is carbon-linked. In some embodiments, the heterocyclic ring is nitrogen-linked. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked), and a group derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0067] In some embodiments, the term "3-12 membered heterocyclyl" refers to a 3-12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl include, but are not limited to, oxetanyl, 1,1-dioxothietanyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyls include, but are not limited to, phenyl- or pyridinyl-fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolidinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl groups, and the like. Examples of spiroheterocyclyls include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclyls include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0068] As used herein, the terms "hydroxyl" or "hydroxy" refer to --OH.

[0069] As used herein, the term "hydroxyalkyl" refers to an alkyl, as defined above, substituted with one or more hydroxyls.

[0070] As used herein, the term "oxo" refers to a ═O substituent.

[0071]

[0052] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings that have multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0072]

[0053] As used herein, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. "Substituted" or "substituted with" will be understood to include the implicit proviso that such substitution is in accordance with the allowed valence of the atom being substituted, and that the substitution results in a stable or chemically feasible compound that does not naturally undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. It will be understood by those skilled in the art that the substituents may themselves be substituted, where appropriate. Unless expressly stated as "unsubstituted", references to chemical moieties herein will be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. compound In one aspect, the present disclosure provides a compound represented by formula (I) or (II):

[0073] [ka]

[0074] (In the formula, Y is O or S; Ring A is heterocyclyl or heteroaryl; Each R 1 are independently oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R * , -C(O)OR * , -C(O)N(R a ) 2 , -N(R a ) 2 , -P(O)OR * OR ** , and -C(O)OC(R a ) 2 -Z 1 -Z 2 wherein alkyl, alkenyl, alkynyl and heteroaryl are selected from the group consisting of cyano, hydroxyl, halogen, -OR b , or -N(R b ) 2 and optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; R * is selected from hydrogen, alkyl, alkylaryl or aryl; R ** is selected from hydrogen, alkyl, alkenyl or alkynyl; or R * and R ** together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Z 1 -OC(O)-#, -OP(=O)(OR *** )O-#, or -OP(=O)(OR* )N(R a )-#, where # ends in Z 2 is connected to Z 2 is hydrogen or -C(O)OR a or alkyl optionally substituted with R *** is independently selected from hydrogen, alkyl, alkenyl, or alkynyl; R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R'; Each R' is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from hydroxyl, halogen, cyano, -OR a , -N(R a ) 2 and heteroaryl, Ring Q is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2 are independently hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -C(O)R *wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring W is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 3 are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; G 1 is a bond, -O-, -S(O) p -, -SS-, -N(R c )-, or -C(R d )=C(R d )-and G 2 is a bond, -[C(R d ) 2 ] u -, -C(O)- or -C(O)C(R d ) 2 - and R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl; Each R dis independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; The Two R's d together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, where the cycloalkyl and heterocyclyl are optionally substituted with cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, and alkyl; Z is C(R e ) or N, R e is absent or hydrogen, L 1 is a bond, -O-, -S-, -N(R a )-, -C(O)N(R a )-, alkenyl, alkynyl or cycloalkyl;

[0075] [ka]

[0076] is optionally substituted with hydroxyl, halogen, cyano or amino; L 2 is a bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; E is hydrogen, hydroxyl, halogen, -N(R a ) 2 , alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH 2 OC(O)-heterocyclyl, -CH 2 O C (O) N (R a ) 2 , -NHC(=NH)NH 2 , -C(O)N(R a ) 2 , -OR a , -(CH 2 OR a )(CH 2 ) p OR a , -N(R a )C(O)-aryl and -(CH 2 ) u -heterocyclyl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R″; and —N(R a )C(O)-aryl and the aryl portion of -(CH 2 ) u -heterocyclyl and -CH 2 the heterocyclyl portion of the OC(O)-heterocyclyl is optionally substituted by one or more R''', Each R″ is independently hydroxyl, halogen, —C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or —N(R a ) 2 is selected from Each R''' is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO 2 F, -N(R a ) 2 , -SO 2-F, -C(O)(alkyl), or -C(O)(haloalkyl), where alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, -O-, or -NHC(O)-; m is an integer from 0 to 6; n is an integer from 0 to 5; r is an integer from 0 to 4; s is an integer from 0 to 5; p is an integer from 0 to 2; (u is an integer from 0 to 4) or a pharma- ceutically acceptable salt thereof.

[0077] In another aspect, the present disclosure provides a compound represented by formula (III) or (IV):

[0078] [ka]

[0079] (In the formula, Y is O or S; Ring A is heterocyclyl or heteroaryl; Each R 1 are independently oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R * , -C(O)OR * , -C(O)N(R a ) 2 , -N(R a ) 2 , -P(O)OR * OR ** , and -C(O)OC(R a ) 2 -Z 1 -Z 2wherein alkyl, alkenyl, alkynyl and heteroaryl are selected from the group consisting of cyano, hydroxyl, halogen, -OR b , or -N(R b ) 2 and optionally substituted with one or more groups independently selected from Each R a and R b are independently hydrogen, alkyl, alkenyl, or alkynyl; R * is selected from hydrogen, alkyl, alkylaryl or aryl; R ** is selected from hydrogen, alkyl, alkenyl or alkynyl; or R * and R ** together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Z 1 -OC(O)-#, -OP(=O)(OR *** )O-#, or -OP(=O)(OR * )N(R a )-#, where # ends in Z 2 is connected to Z 2 is hydrogen or -C(O)OR a or alkyl optionally substituted with R *** is independently selected from hydrogen, alkyl, alkenyl, or alkynyl; R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R'; Each R' is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl are independently selected from hydroxyl, halogen, cyano, -OR a , -N(R a ) 2 and heteroaryl, Ring Q is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 2 are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Ring W is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 3are independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; U 1 is a bond, -(CH 2 ) t -, -O(CH 2 ) t -, -N(R j )-, -C(O)- or -C(O)C(R j ) 2 - selected from U 2 -O-, -S(O) p -,-[C(R j ) 2 ] t -, -C(R j )=C(R j )-, -N(R j )-, -C(O)- or -C(O)C(R j ) 2 - selected from R j is selected from the group consisting of hydrogen, cyano, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, and heterocyclyl, where alkyl, heteroalkyl, cycloalkyl, and heterocyclyl are each independently selected from the group consisting of -N(R a ) 2 or heterocyclyl, V 1 and V 2are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, and heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, or haloalkyl; V 1 and V 2 together with the carbon atom to which they are both attached form oxo, cycloalkyl, heterocyclyl, or heteroaryl, where cycloalkyl, heterocyclyl, and heteroaryl are selected from cyano, halogen, hydroxyl, amino, and heterocyclyl or -N(R a ) 2 and optionally substituted with one or more groups independently selected from the group consisting of alkyl, optionally substituted with Z is C(R e ) or N, R e is absent or hydrogen, L 1 is a bond, -O-, -S-, -N(R a )-, alkenyl, alkynyl or cycloalkyl;

[0080] [ka]

[0081] is optionally substituted with hydroxyl, halogen, cyano or amino; L 2 is a bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl, or heteroaryl; E is hydrogen, hydroxyl, halogen, -N(R a ) 2 , alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH 2 OC(O)-heterocyclyl, -NHC(=NH)NH 2 , -C(O)N(R a ) 2 , -OR a , -(CH 2 OR a )(CH 2 ) p OR a , -N(R a )C(O)-aryl and -(CH 2 ) u -heterocyclyl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R″; and —N(R a )C(O)-aryl and the aryl portion of -(CH 2 ) u -heterocyclyl and -CH 2 the heterocyclyl portion of the OC(O)-heterocyclyl is optionally substituted by one or more R''', Each R″ is independently hydroxyl, halogen, —C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or —N(R a ) 2 is selected from Each R''' is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO 2 F, -N(R a ) 2 , -SO 2 -F, -C(O)(alkyl), or -C(O)(haloalkyl), where alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy; T is a bond, -O-, or -NHC(O)-; m is an integer from 0 to 6; n is an integer from 0 to 5; r is an integer from 0 to 4; s is an integer from 0 to 5; p is an integer from 0 to 2; t is an integer from 0 to 3; (u is an integer from 0 to 4) or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, Z is C(R e In certain embodiments, R e is absent. In certain embodiments, R e is hydrogen.

[0083] In some embodiments, Z is N.

[0084] In some embodiments, ring A is heterocyclyl. In certain embodiments, ring A is 6-12 membered heterocyclyl. In certain embodiments, ring A is 6-10 membered heterocyclyl. In certain embodiments, ring A is 8-10 membered heterocyclyl.

[0085] In some embodiments, ring A is heteroaryl. In certain embodiments, ring A is 6-12 membered heteroaryl. In certain embodiments, ring A is 6-10 membered heteroaryl. In certain embodiments, ring A is 8-10 membered heteroaryl.

[0086] In some embodiments, ring A is a bridged heterocyclyl optionally containing at least one additional heteroatom selected from the group consisting of N, S, and O. In certain embodiments, ring A is a 6-12 membered bridged heterocyclyl optionally containing at least one additional heteroatom selected from the group consisting of N, S, and O. In certain embodiments, ring A is a 6-10 membered bridged heterocyclyl optionally containing at least one additional heteroatom selected from the group consisting of N, S, and O. In certain embodiments, ring A is an 8-10 membered bridged heterocyclyl optionally containing at least one additional heteroatom selected from the group consisting of N, S, and O.

[0087] In certain embodiments, ring A is

[0088] [ka]

[0089] (In the formula,

[0090] [ka]

[0091] represents a single or double bond) is selected from the group consisting of:

[0092]

[0062] In some embodiments, ring A is a spiro or fused ring, optionally containing at least one additional heteroatom selected from the group consisting of N, S, and O.

[0093] In certain embodiments, ring A is

[0094] [ka]

[0095] (In the formula, q is an integer of 1 to 4, and q' is an integer of 0 to 4.) is selected from the group consisting of:

[0096] In some embodiments, Ring B is cycloalkyl optionally substituted with one or more R'. In certain embodiments, Ring B is C optionally substituted with one or more R'. 5~12 In certain embodiments, ring B is a C cycloalkyl group optionally substituted with one or more R′. 5~10 In certain embodiments, ring B is a C cycloalkyl group optionally substituted with one or more R′. 5~8 In certain embodiments, ring B is a C cycloalkyl group optionally substituted with one or more R′. 5~7 In certain embodiments, ring B is a C cycloalkyl group optionally substituted with one or more R′. 5~6 It is cycloalkyl.

[0097] In some embodiments, ring B is a heterocyclyl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-12 membered heterocyclyl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-10 membered heterocyclyl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-8 membered heterocyclyl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-7 membered heterocyclyl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-6 membered heterocyclyl optionally substituted with one or more R'.

[0098] In certain embodiments, Ring B is 1,2,3,6-tetrahydropyridinyl or piperidinyl, each optionally substituted with one or more R' independently selected from oxo, alkyl, alkynyl, heteroalkyl, or cyano.

[0099] In some embodiments, Ring B is aryl optionally substituted with one or more R'. In certain embodiments, Ring B is C optionally substituted with one or more R'. 5~12 In certain embodiments, ring B is C optionally substituted with one or more R′. 5~10 In certain embodiments, ring B is C optionally substituted with one or more R′. 5~8 In certain embodiments, ring B is C optionally substituted with one or more R′. 5~7 In certain embodiments, ring B is C optionally substituted with one or more R′. 5~6 It is aryl.

[0100] In certain embodiments, Ring B is phenyl optionally substituted with one or more R'.

[0101] In some embodiments, ring B is a heteroaryl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-12 membered heteroaryl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-10 membered heteroaryl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-8 membered heteroaryl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-7 membered heteroaryl optionally substituted with one or more R'. In certain embodiments, ring B is a 5-6 membered heteroaryl optionally substituted with one or more R'.

[0102] In certain embodiments, Ring B is pyridinyl or pyrimidinyl, each optionally substituted with one or more R'.

[0103] In some embodiments, ring Q is cycloalkyl. In certain embodiments, ring Q is C 5~12 In certain embodiments, ring Q is C 5~10 In certain embodiments, ring Q is C 5~8 In certain embodiments, ring Q is C 5~7 In certain embodiments, ring Q is C 5~6 It is cycloalkyl.

[0104] In some embodiments, ring Q is heterocyclyl. In certain embodiments, ring Q is 5-12 membered heterocyclyl. In certain embodiments, ring Q is 5-10 membered heterocyclyl. In certain embodiments, ring Q is 5-8 membered heterocyclyl. In certain embodiments, ring Q is 5-7 membered heterocyclyl. In certain embodiments, ring Q is 5-6 membered heterocyclyl.

[0105] In some embodiments, ring Q is aryl. In certain embodiments, ring Q is C 5~12 In certain embodiments, ring Q is C 5~10 In certain embodiments, ring Q is C 5~8 In certain embodiments, ring Q is C 5~7 In certain embodiments, ring Q is C 5~6 It is aryl.

[0106] In certain embodiments, ring Q is phenyl or naphthalenyl.

[0107] In some embodiments, ring Q is heteroaryl. In certain embodiments, ring Q is 5-12 membered heteroaryl. In certain embodiments, ring Q is 5-10 membered heteroaryl. In certain embodiments, ring Q is 5-8 membered heteroaryl. In certain embodiments, ring Q is 5-7 membered heteroaryl. In certain embodiments, ring Q is 5-6 membered heteroaryl.

[0108] In certain embodiments, ring Q is selected from benzothiophenyl, benzimidazolyl, quinazolinyl, benzotriazolyl, thiophenyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl.

[0109] In some embodiments, ring W is cycloalkyl or heterocyclyl.

[0110] In certain embodiments, ring W is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0111] In some embodiments, ring W is heterocyclyl.

[0112] In certain embodiments, Ring W is tetrahydrofuranyl, pyrrolidinyl, tetrahydro-2H-pyranyl, piperidinyl, or piperazinyl.

[0113] In some embodiments, ring W is aryl. In certain embodiments, ring Q is C 5~12 In certain embodiments, ring Q is C 5~10 In certain embodiments, ring Q is C 5~8 In certain embodiments, ring Q is C 5~7 In certain embodiments, ring Q is C 5~6 It is aryl.

[0114] In certain embodiments, ring W is phenyl or naphthalenyl.

[0115] In some embodiments, ring W is heteroaryl. In certain embodiments, ring W is 5-12 membered heteroaryl. In certain embodiments, ring W is 5-10 membered heteroaryl. In certain embodiments, ring W is 5-8 membered heteroaryl. In certain embodiments, ring W is 5-7 membered heteroaryl. In certain embodiments, ring W is 5-6 membered heteroaryl.

[0116] In certain embodiments, ring W is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, purinyl, quinolinyl, isoquinolinyl, isoquinolin-1(2H)-one group, isoindolin-1-one group, benzo[d]oxazol-2(H)-one group, and 1,3-dihydro-2H-benzo[d]imidazol-2-one group.

[0117] In some embodiments, G 1 is a bond.

[0118] In some embodiments, G 1 is -O-.

[0119] In some embodiments, G 1 -S(O) p -It is.

[0120] In some embodiments, G 1 -N(R c In certain embodiments, R c is hydrogen. In certain embodiments, R cis alkyl. In certain embodiments, R c is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 In certain embodiments, R c is methyl.

[0121] In some embodiments, G 1 is -C(O)-.

[0122] In some embodiments, G 1 -C(R d )=C(R d In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, both R d is hydrogen. In certain embodiments, both R d is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, one R d is hydrogen and the other is alkyl. In certain embodiments, one R d is hydrogen and the other is methyl.

[0123] In some embodiments, G 2 is a bond.

[0124] In some embodiments, G 2 -[C(R d ) 2 ] u In certain embodiments, each R d is independently hydrogen, hydroxyl, or alkyl. In certain embodiments, each R d are independently hydrogen, hydroxyl, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3In certain embodiments, each R d is independently hydrogen, hydroxyl or methyl.

[0125] In some embodiments, G 2 is -C(O)-.

[0126] In some embodiments, G 2 is -C(O)C(R d ) 2 In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, both R d is hydrogen. In certain embodiments, both R d is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, one R d is hydrogen and the other is alkyl. In certain embodiments, one R d is hydrogen and the other is methyl.

[0127] In some embodiments, G 1 is -O- and G 2 -[C(R d ) 2 ] u -, where u is 1 or 2. In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, each R d are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, each R d is independently hydrogen or methyl.

[0128] In some embodiments, G 1 -S(O) p- and G 2 -[C(R d ) 2 ] u -, where u is 1. In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, each R d are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, each R d are independently hydrogen or methyl. In certain embodiments, both R d is hydrogen.

[0129] In some embodiments, G 1 -N(R c )- and G 2 -C(O)-, -C(O)C(R d ) 2 -or-[C(R d ) 2 ] u -, where u is 1 or 2. In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, each R d are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, each R d is independently hydrogen or methyl.

[0130] In some embodiments, G 1 -C(R d )=C(R d )- and G 2 is -C(O)- or -[C(R d ) 2 ] u -, where u is 1. In certain embodiments, each R d are independently hydrogen, hydroxyl, C1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, each R d is independently hydrogen, hydroxyl or methyl.

[0131] In some embodiments, m is 0.

[0132] In some embodiments, m is an integer from 1 to 3, and each R 1 are independently 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 Alkyl such as alkyl.

[0133] In some embodiments, m is 1 and R 1 is -C(O)R * OR -C(O)OR * where R * is alkyl or alkylaryl. In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, R a is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R a is benzyl. In certain embodiments, m is 1 and R 1 teeth

[0134] [ka]

[0135] is selected from.

[0136] In some embodiments, m is 1 and R 1 HA-P(O)OR *OR ** In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, m is 1 and R 1 HA-P(O)OR * OR ** and R * and R ** together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl. In certain embodiments, m is 1 and R 1 is optionally substituted with aryl or haloaryl

[0137] [ka]

[0138] In certain embodiments, m is 1 and R 1 teeth,

[0139] [ka]

[0140] It is.

[0141] In some embodiments, m is 1 and R 1 is -C(O)OC(R a ) 2 -Z 1 -Z 2 and Z 1 is -OC(O)-#, and Z 2 is alkyl optionally substituted with aryl. In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, Z 2 each optionally substituted with aryl (e.g., phenyl) 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C1~3 In certain embodiments, m is 1 and R 1 teeth,

[0142] [ka]

[0143] It is.

[0144] In some embodiments, m is 1 and R 1 is -C(O)OC(R a ) 2 -Z 1 -Z 2 and Z 1 -OP(=O)(OR *** )N(R a )-# and Z 2 HA-OC(O)R a is an alkyl substituted with R *** In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, R * In certain embodiments, m is 1 and R 1 teeth,

[0145] [ka]

[0146] It is.

[0147] In some embodiments, m is 1 and R 1 is -C(O)OC(R a ) 2 -Z 1 -Z 2 and Z 1 -OP(=O)(OR *** )O-# and Z 2 is hydrogen or alkyl optionally substituted with aryl, and R ***is hydrogen, alkyl, or alkylaryl. In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, Z 2 each optionally substituted with aryl; 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 It is an alkyl.

[0148] In some embodiments, m is 1 and R 1 is -C(O)OC(R a ) 2 -Z 1 -Z 2 and Z 1 -OP(=O)(OR *** )O-# and R *** and Z 2 together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl. In certain embodiments, m is 1 and R 1 is substituted at the -NH- position of ring A. In certain embodiments, -Z 1 -Z 2 is optionally substituted with aryl or haloaryl

[0149] [ka]

[0150] In certain embodiments, -Z 1 -Z 2 teeth,

[0151] [ka]

[0152] In certain embodiments, m is 1 and R 1 teeth,

[0153] [ka]

[0154] It is.

[0155] In some embodiments, n is an integer from 1 to 4, and each R 2 is independently selected from hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, or cycloalkyl, where alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, or alkyl.

[0156] In certain embodiments, n is an integer from 1 to 4, and each R 2 are independently hydroxyl, halogen, amino, C 1~3 Alkyl, C 2~4 Alkynyl, C 1~3 Haloalkyl, or C 3~6 cycloalkyl.

[0157] In some embodiments, s is an integer from 1 to 4, and each R 3 is independently selected from hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, or cycloalkyl, where alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, or alkyl.

[0158] In certain embodiments, s is an integer from 1 to 4, and each R 3 are independently hydroxyl, halogen, amino, C 1~3 Alkyl, or C 3~6 cycloalkyl.

[0159] In some embodiments, L 1is a bond.

[0160] In some embodiments, L 1 is -O-.

[0161] In some embodiments, L 1 is -S-.

[0162] In some embodiments, L 1 -N(R a In certain embodiments, R a is hydrogen. In certain embodiments, R a is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 Alkyl such as alkyl.

[0163] In some embodiments, L 1 is alkenyl. In certain embodiments, L 1 is ethenyl.

[0164] In some embodiments, L 1 is alkynyl. In certain embodiments, L 1 is ethynyl.

[0165] In some embodiments, L 1 is cycloalkyl. In certain embodiments, L 1 is cyclopropyl.

[0166] In some embodiments, L 2 is a bond.

[0167] In some embodiments, L 2 is alkyl, cycloalkyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more of halogen or alkyl.

[0168] In certain embodiments, L 2 is selected from hexahydro-1H-pyrrolidinyl, azetidinyl, pyrrolidinyl or pyridinyl.

[0169] In some embodiments, E is hydrogen, hydroxyl, halogen, haloalkyl, heteroalkyl, or -CH 2 OC(O)-heterocyclyl.

[0170] In some embodiments, L 1 is -O- or -N(R a )- and L 2 is heterocyclyl or heteroaryl.

[0171] In some embodiments, L 1 is a bond or alkynyl, L 2 is heterocyclyl.

[0172] In some embodiments, E is hydrogen, hydroxyl, halogen, haloalkyl, heteroalkyl, -N(R a ) 2 , or -CH 2 OC(O)-heterocyclyl.

[0173] In a further aspect, the present disclosure provides a compound of formula (Ia) or (Ib):

[0174] [ka]

[0175] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0176] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0177] [ka]

[0178] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0179] In some embodiments, T 2 is C(R'), where R' is hydrogen, hydroxyl or halogen.

[0180] In some embodiments, G 1 is -O-.

[0181] In some embodiments, G 2 -[C(R d ) 2 ] u -It is.

[0182] In some embodiments, G 1 is -O- and G 2 -[C(R d ) 2 ] u -, where u is 1 or 2. In certain embodiments, each R d is independently hydrogen or alkyl. In certain embodiments, each R d is hydrogen.

[0183] In some embodiments, L 1 is -O-.

[0184] In some embodiments, T 1 is N or C(R'); T 2 is C(R'), where R' is hydrogen, hydroxyl or halogen; G 1 is -O-;G 2 -[C(R d ) 2 ] u -, where u is 1 or 2; L 1 is -O-.

[0185] In a further aspect, the present disclosure provides a compound of formula (IIIa) or (IIIb):

[0186] [ka]

[0187] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0188] In a further aspect, the present disclosure provides a compound of formula (IIIc), (IIId) or (IIIe):

[0189] [ka]

[0190] or a pharma- ceutically acceptable salt thereof.

[0191] In a further aspect, the present disclosure provides a compound of formula (IVa) or (IVb):

[0192] [ka]

[0193] (In the formula, T 1 is N or C(R'), T 2 is N or C(R'), v is an integer from 0 to 4. or a pharma- ceutically acceptable salt thereof.

[0194] In a further aspect, the present disclosure provides a compound of formula (IVc), (IVd) or (IVe):

[0195] [ka]

[0196] or a pharma- ceutically acceptable salt thereof.

[0197] In some embodiments, the present disclosure provides:

[0198] [ka]

[0199] [ka]

[0200] [ka]

[0201] [ka]

[0202] [ka]

[0203]

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[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] or a pharma- ceutically acceptable salt thereof.

[0250]

[0138] The compounds provided herein are described with reference to both the general formula and the specific compounds. In addition, the compounds of the present disclosure may exist in several different forms or derivatives, including, but not limited to, prodrugs, soft drugs, active metabolic derivatives (active metabolites), and pharma- ceutically acceptable salts thereof, all of which are within the scope of the present disclosure.

[0251]

[0139] As used herein, the term "prodrug" refers to a compound or its pharma- ceutically acceptable salt that, when metabolized under physiological conditions or converted by solvolysis, results in the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound, and during metabolism, the ester group is cleaved to yield the active drug. Also, some prodrugs are enzymatically activated to yield the active compound, or a compound that, upon further chemical reaction, yields the active compound. Prodrugs may proceed from the prodrug form to the active form in a single step, or may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACS Symposium Series, Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; Prodrugs: Challenges and Rewards, edited by V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are incorporated herein by reference in their entireties.

[0252]

[0140] As used herein, the term "soft drugs" refers to compounds that exert a pharmacological effect but degrade into inactive metabolic decomposition products such that the activity is of limited time. See, for example, "Soft drugs: Principles and methods for the design of safe drugs," Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, pp. 449-469, 1984, which is incorporated herein by reference in its entirety.

[0253]

[0141] As used herein, the term "metabolite", e.g., active metabolite, overlaps with prodrug as described above. Thus, such metabolites are compounds that are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds that are derivatives resulting from metabolic processes in the subject's body. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compounds are generally inactive or less active than the metabolites. For active metabolites, the parent compound may be an active compound or an inactive prodrug.

[0254]

[0142] Prodrugs and active metabolites can be identified using routine techniques known in the art, see, e.g., Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.

[0255]

[0143] As used herein, the term "pharmacologically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the subject to be treated therewith.

[0256]

[0144] As used herein, the term "pharmaceutical acceptable salts" includes, unless otherwise indicated, salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Contemplated pharmaceutical acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts may facilitate pharmacological use by modifying the physical characteristics of a compound without preventing the compound from exerting its physiological effects. Useful modifications in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

[0257] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts may be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0258]

[0146] Pharmaceutically acceptable salts also include base addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc, when an acidic functional group such as carboxylic acid or phenol is present. See, for example, Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth, eds., Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0259]

[0147] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then isolated by evaporating the solution. Thus, if a particular compound is a base, the desired pharma-ceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0260] Similarly, if a particular compound is an acid, the desired pharma- ceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0261]

[0149] It should also be understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and the present disclosure is intended to encompass all such forms.

[0262]

[0150] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance, where the water is H 2 It retains its molecular state as O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0263]

[0151] As used herein, the terms "crystal form", "crystalline form", "polymorphic form" and "polymorph" may be used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in various crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may favor one crystal form. Crystal polymorphs of a compound may be prepared by crystallization under different conditions.

[0264]

[0152] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide or iodine in the compounds of the present disclosure are intended to include their isotopes, such as, but not limited to, 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 Contains C.

[0265]

[0153] Those skilled in the art will understand that the compounds of the present disclosure can exist in various tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. The presence and concentration of isomeric forms depends on the environment in which the compound is found, and may vary depending on whether the compound is a solid or in an organic or aqueous solution. By way of example, proton tautomers (also known as prototropic tautomers) include interconversions by migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations, and cyclic forms in which a proton may occupy more than one position in a heterocyclic ring system. Valence tautomers include interconversions by rearrangement of some of the bonding electrons. Tautomers may be in equilibrium or sterically fixed in one form by appropriate substitution. Compounds of the disclosure that are identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compound synthesis

[0154] The compounds provided herein may be prepared using any known organic synthesis technique or may be synthesized according to any of a number of possible synthetic routes.

[0266]

[0155] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0267]

[0156] Preparation of the compounds of the present disclosure may include protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in TW Greene and P G M Huts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter G M Huts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0268]

[0157] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 The compounds may be monitored by spectroscopic means such as spectroscopy, infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds may be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, the entire contents of which are incorporated herein by reference), and normal phase silica chromatography. Use of the compound In certain aspects, the present disclosure provides compounds capable of inhibiting KRAS proteins, particularly KRAS G12D proteins.

[0269]

[0159] As used herein, the term "treatment" is intended to have its ordinary meaning of dealing with a disease to completely or partially alleviate one, some or all of the symptoms of the disease or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical result. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, attenuation of the extent of the disease, a stabilized (i.e., not worsening) state of the disease, delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of such treatment. Those in need of treatment include those already with a condition or disorder as well as those susceptible to having the condition or disorder or those in whom the condition or disorder is to be prevented. The term "treatment" also encompasses prophylaxis, unless there is specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be construed in a corresponding manner.

[0270]

[0160] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention, which prevents the development of a disease, and secondary prevention, where a disease has already developed and the patient is protected, either temporarily or permanently, against progression or worsening of the disease or the development of new symptoms associated with the disease.

[0271]

[0161] The term "treatment" is used synonymously with "therapy." Similarly, the term "treat" may also be considered as "applying therapy," as "treatment" is defined herein.

[0272]

[0162] In a further aspect, the present disclosure provides the use of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in therapy, for example, in therapy associated with KRAS protein, particularly in therapy associated with KRAS G12D protein.

[0273]

[0163] In a further aspect, the present disclosure provides the use of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.

[0274] In some embodiments, the cancer is mediated by a KRAS protein. In some embodiments, the cancer is mediated by a KRAS G12D protein. Pharmaceutical Compositions In a further aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0275]

[0166] In another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0276]

[0167] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to a subject.

[0277]

[0168] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful for preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. "Pharmaceutically acceptable excipient" as used herein includes both one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0278]

[0169] The specific excipient used depends on the means and purpose for which the compound of the present disclosure is being applied. The solvent is generally selected based on the solvent recognized by those skilled in the art as safe for administration to mammals, including humans. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof.

[0279]

[0170] In some embodiments, suitable excipients include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin, gelatin, or immunoglobulins, etc. the protein; a hydrophilic polymer such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; a chelating agent such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0280] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings, and other known additives for providing an elegant presentation of the drug (i.e., the compound of the present disclosure or a pharmaceutical composition thereof) or for aiding in the manufacture of the pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, prepared, for example, by coacervation techniques or by interfacial polymerization. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th Edition, Osol, A. (1980). "Liposomes" are small vesicles composed of various types of lipids, phospholipids and / or surfactants that are useful for delivery of drugs (e.g., compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0281]

[0172] The pharmaceutical compositions provided herein may be in any form that allows the composition to be administered to a subject, including, but not limited to, a human, and may be formulated to be compatible with the intended route of administration.

[0282]

[0173] Various routes are contemplated for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage form depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable liquid dosage forms, and powders suitable for reconstitution with an appropriate solution may be acceptable solid dosage forms. For inhalation administration, liquids, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms.

[0283] The amount of active ingredient in the composition of unit dosage form is a therapeutically effective amount and varies according to the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition containing a molecule or compound to treat, ameliorate, or prevent a specified disease or condition, or to show a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the discretion of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0284]

[0175] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for oral administration.

[0285]

[0176] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of a tablet formulation. Suitable pharma- ceutically acceptable excipients for tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or may be coated to modify their disintegration in the gastrointestinal tract and subsequent absorption of active ingredients, or to improve their stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[0286]

[0177] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or may be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0287] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension containing the active ingredient in finely divided form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum arabic; a dispersing or wetting agent, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or propyl p-hydroxybenzoate, an antioxidant, for example ascorbic acid, coloring agents, flavoring agents, and / or sweetening agents, for example, sucrose, saccharin or aspartame.

[0288]

[0179] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, generally containing the active ingredient suspended in a vegetable oil (e.g., arachis oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). The oily suspensions may also contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0289]

[0180] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or any mixture thereof. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavorings, and preservatives.

[0290]

[0181] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, demulcents, preservatives, flavoring agents and / or coloring agents.

[0291]

[0182] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for injectable administration.

[0292]

[0183] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be similarly used in the preparation of injectables.

[0293]

[0184] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for inhaled administration.

[0294] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary with the requirements of the particular compound, but typically include non-ionic surfactants (Tween, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

[0295]

[0186] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for topical or transdermal administration.

[0296]

[0187] In certain embodiments, the pharmaceutical compositions provided herein may generally be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may be obtained by formulating the active ingredient with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0297]

[0188] In certain embodiments, the pharmaceutical compositions provided herein can be formulated in the form of transdermal skin patches, which are well known to those of ordinary skill in the art.

[0298]

[0189] In addition to these representative dosage forms described above, pharma- ceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences," Mack Pub.Co., New Jersey (1991), "Remington: The Science and Practice of Pharmacy," University of the Sciences in Philadelphia, ed., 21st ed., LWW (2005), which are incorporated herein by reference.

[0299]

[0190] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated as a single dosage form. The amount of the compound provided herein in a single dosage form varies depending on the subject being treated and the particular mode of administration.

[0300]

[0191] In some embodiments, the pharmaceutical compositions of the present disclosure provide a dose of 0.001 to 1000 mg / kg body weight / day, e.g., 0.01 to 800 mg / kg body weight / day, 0.01 to 700 mg / kg body weight / day, 0.01 to 600 mg / kg body weight / day, 0.01 to 500 mg / kg body weight / day, 0.01 to 400 mg / kg body weight / day, 0.01 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day of a compound provided herein, or a pharma- ceutical acceptable salt thereof. , 0.1-150 mg / kg body weight / day, 0.1-100 mg / kg body weight / day, 0.5-100 mg / kg body weight / day, 0.5-80 mg / kg body weight / day, 0.5-60 mg / kg body weight / day, 0.5-50 mg / kg body weight / day, 1-50 mg / kg body weight / day, 1-45 mg / kg body weight / day, 1-40 mg / kg body weight / day, 1-35 mg / kg body weight / day, 1-30 mg / kg body weight / day, 1-25 mg / kg body weight / day may be administered. In some cases, dosage levels below the lower limits of the aforementioned ranges may be more than sufficient, while in other cases, even larger doses may be employed without causing adverse side effects, provided that such larger doses are first divided into several smaller doses for overall daily administration. For further information regarding routes of administration and dosage regimes, see Chapter 25.3, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0301]

[0192] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations of the present disclosure can also be formulated for controlled release or slow release.

[0302] In a further aspect, veterinary compositions are also provided that include one or more molecules or compounds of the present disclosure or pharma- ceutically acceptable salts thereof and a veterinary carrier. A veterinary carrier is a substance useful for the purpose of administering the composition, and may be a solid, liquid or gas substance that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0303]

[0194] Pharmaceutical or veterinary compositions may be packaged in a variety of ways depending on the method used to administer the drug. For example, an article for distribution may include a container into which the composition is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The containers may also include tamper-evident features to prevent indiscreet access to the contents of the package. In addition, the containers are labeled with a label describing the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier for injection, such as water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0304]

[0195] In a further aspect, there is also provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharma- ceutically acceptable salt thereof, as a first active ingredient and a second active ingredient.

[0305]

[0196] In some embodiments, the second active ingredient has complementary activities to the compounds provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the intended purpose. Methods for Treating Disease

[0197] In a further aspect, the present disclosure provides a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

[0306]

[0198] In some embodiments, the compounds provided herein or pharma- ceutically acceptable salts thereof and compositions may be used in a subject in need thereof for the treatment of a KRas G12D-associated cancer comprising the step of administering to the subject a therapeutically effective amount of a compound provided herein, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt thereof.

[0307] In some embodiments, the compounds provided herein or pharma- ceutically acceptable salts and compositions thereof can be used to treat a wide variety of cancers, including tumors, such as lung, prostate, breast, brain, skin, cervical cancer, testicular cancer, and the like. More particularly, cancers that can be treated by the compounds provided herein or pharma- ceutically acceptable salts and compositions thereof include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancer and sarcoma. More particularly, the compounds provided herein or pharma- ceutically acceptable salts and compositions thereof can be used to treat a wide variety of cancers, including tumors such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancer and sarcoma. (i) Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (ii) Lung: bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; (iii) Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (iv) genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); (v) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (vi) Biliary tract: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; (vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); (viii) Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (ix) Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphomas (malignant lymphomas); (x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigines, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and (xi) Adrenal gland: Neuroblastoma may be used to treat

[0308]

[0200] In certain embodiments, the cancer that may be treated with the compounds provided herein or pharma- ceutically acceptable salts and compositions thereof is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

[0309]

[0201] The concentration and route of administration to a subject varies depending on the cancer to be treated. In certain embodiments, administration is via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and local administration.

[0310]

[0202] The compounds, their pharma- ceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-neoplastic compounds, such as chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as pre- or post-operative adjuvants.

[0311] In some embodiments, the compounds, their pharma- ceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may be administered simultaneously, separately, or sequentially with one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from an anti-PD-1 antagonist, a MEK inhibitor, a SHP2 inhibitor, a platinum agent, or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB404. In certain embodiments, the MEK inhibitor is trametinib. In certain embodiments, the SHP2 inhibitor is RMC-4630.

[0312] In another aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising: (a) obtaining knowledge that cancer is associated with a KRAS G12D mutation; (b) administering to the subject an effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof; Also provided is a method comprising:

[0313]

[0205] In another aspect, the present disclosure provides a method for inhibiting KRAS G12D activity in a subject in need of inhibition of KRAS G12D activity, the method comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition. EXAMPLES

[0314]

[0206] For purposes of illustration, the following examples are included, however, it should be understood that these examples do not limit the disclosure and are only intended to suggest a method of practicing the disclosure.

[0315] General synthetic route

[0208] In some embodiments, compounds of Formula (Ib) provided herein can be prepared by a synthetic route as shown in Scheme 1.

[0316] [ka]

[0317] Step 1:

[0210] The starting material of formula (Ib_1) is commercially available. Compounds of formula (Ib_3) can be prepared by bromination reaction of compounds of formula (IIb_1) and formula (Ib_2) in the presence of an organolithium reagent (e.g. n-BuLi) under standard conditions.

[0318] Step 2:

[0212] Compounds of formula (Ib_4) can be prepared by the amidation reaction of compounds of formula (Ib_3) with ammonia under standard conditions.

[0319] Step 3: Compounds of formula (Ib_6) may be prepared by areneformylation of compounds of formula (Ib_4) and (Ib_5) in the presence of oxalyl chloride under standard conditions.

[0320] Step 4: Compounds of formula (Ib_7) may be prepared by intramolecular cyclization reaction of compounds of formula (Ib_6) with a base (eg KHMDS) under standard conditions.

[0321] Step 5:

[0218] Compounds of formula (Ia_8) can be prepared by methylation of compounds of formula (Ia_7) with a methylating reagent (eg MeONa).

[0322] Step 6: Compounds of formula (Ib_10) may be prepared by substitution reaction of compounds of formula (Ib_8) and compounds of formula (Ib_9) in the presence of a base (eg DIPEA) under standard conditions.

[0323] Step 7: Compounds of formula (Ib_11) may be prepared by intramolecular coupling reaction of compounds of formula (Ib_10) in the presence of a phosphonium salt (eg PyBOP) and a base (eg DBU) under standard conditions.

[0324] Step 8: Compounds of formula (Ib_12) can be prepared by reacting compounds of formula (Ib_11) with a dealkylating agent (e.g., BBr 3 ) by demethylation reaction.

[0325] Step 9: Compounds of formula (Ib_13) can be prepared by reacting compounds of formula (Ib_12) with a chloride reagent (e.g. POCl) in the presence of a base (e.g. DIPEA) under standard conditions. 3 ) by chlorination reaction.

[0326] Step 10: Compounds of formula (Ib_15) can be prepared by the reaction of a palladium catalyst (e.g. PddppfCl 2 ) and a base (e.g. Na 2 CO 3 The compound of formula (Ib_16) can be prepared by Suzuki coupling reaction of a compound of formula (Ib_13) with a compound of formula (Ib_16) in the presence of

[0327] Step 11:

[0230] Compounds of formula (Ib) may be prepared by removal of the Cbz protecting group of compounds of formula (Ib_15) with TMSI under standard conditions.

[0328]

[0231] In some embodiments, compounds of Formula (IIb) provided herein can be prepared by a synthetic route as shown in Scheme 2.

[0329] [ka]

[0330] Step 1:

[0233] The starting material of formula (IIb_1) is commercially available. Compounds of formula (IIb_2) can be prepared by electrophilic fluorination of compounds of formula (IIb_1) with a fluorine donor (e.g. Selectfluor) under standard conditions.

[0331] Step 2:

[0235] Compounds of formula (IIb_3) can be prepared by iodination of compounds of formula (IIb_2) with N-iodosuccinimide under standard conditions.

[0332] Step 3: Compounds of formula (IIb_4) can be prepared by palladium catalysis (e.g., Pd(Ph) 3 P) 4It can be prepared by the carbonylation reaction of a compound of formula (IIIb_3) with carbon monoxide in the presence of a base such as triethylamine.

[0333] Step 4:

[0239] Compounds of formula (IIb_6) can be prepared by trichloroacetylisocyanate reaction of compounds of formula (IIb_4) and compounds of formula (IIb_5) under standard conditions.

[0334] Step 5:

[0241] Compounds of formula (IIa_7) can be prepared by pyrimidinedione cyclization reaction of compounds of formula (IIa_6) with ammonia under standard conditions.

[0335] Step 6:

[0243] Compounds of formula (IIa_8) can be prepared by methylation of compounds of formula (IIa_7) with a methylating reagent (eg MeONa).

[0336] Step 7: Compounds of formula (IIb_9) can be prepared by reacting compounds of formula (IIb_8) with a chloride reagent (e.g., POCl) in the presence of a base (e.g., DIPEA) under standard conditions. 3 ) by chlorination reaction.

[0337] Step 8:

[0247] Compounds of formula (IIb_11) can be prepared by substitution reaction with compounds of formula (IIb_9) and (IIb_10) in the presence of a base (eg DIPEA) under standard conditions.

[0338] Step 9: Compounds of formula (IIb_12) can be prepared by intramolecular cyclization reaction of compounds of formula (IIb_11) with a base (eg KF) under standard conditions.

[0339] Step 10: Compounds of formula (IIb_14) can be prepared by nucleophilic substitution reaction of compounds of formula (IIb_12) with compounds of formula (IIb_13) in the presence of a base (eg DIPEA) under standard conditions.

[0340] Step 11: Compounds of formula (IIb_15) can be prepared by reacting compounds of formula (IIb_14) with a dealkylating agent (e.g., BBr 3 ) by demethylation reaction.

[0341] Step 12: Compounds of formula (IIb_16) can be prepared by reacting compounds of formula (IIb_15) with a chloride reagent (e.g., POCl) in the presence of a base (e.g., DIPEA) under standard conditions. 3 ) by chlorination reaction.

[0342] Step 13: Compounds of formula (IIb) can be prepared by the reaction of a palladium catalyst (e.g. PddppfCl 2 ) and a base (e.g. Na 2 CO 3 The compound of formula (IIb_16) can be prepared by Suzuki coupling reaction of a compound of formula (IIb_17) with a compound of formula (IIb_18) in the presence of

[0343]

[0258] In some embodiments, compounds of Formula (IIIb) provided herein can be prepared by a synthetic route as shown in Scheme 3.

[0344] [ka]

[0345] Step 1:

[0260] The starting material of formula (IIIb_1) is commercially available. The compound of formula (IIIb_2) can be prepared by Curtius rearrangement reaction with the compound of formula (IIIb_1) in the presence of diphenylphosphoryl azide (DPPA) under standard conditions.

[0346] Step 2:

[0262] Compounds of formula (IIIb_3) can be prepared by removal of the Boc protecting group with an acid (eg TFA) under standard conditions.

[0347] Step 3:

[0264] Compounds of formula (IIIb_4) can be prepared by iodination reaction of compounds of formula (IIIb_3) with N-iodosuccinimide (NIS) under standard conditions.

[0348] Step 4: Compounds of formula (IIIb_5) can be prepared by palladium catalysis (e.g. Pd(Ph) 3 P) 4 It can be prepared by the carbonylation reaction of a compound of formula (IIIb_4) with carbon monoxide in the presence of a base such as triethylamine.

[0349] Step 5: Compounds of formula (IIIb_6) can be prepared by reacting compounds of formula (IIIb_5) with a diazotization reagent (e.g., NaNO 2 ) and an iodinating agent (e.g. CuI) to prepare iodinating agents.

[0350] Step 6: Compounds of formula (IIIb_8) can be prepared by the reaction of a palladium catalyst (e.g. Pd(OAc) 2 ), a ligand (e.g., BINAP) and a base (e.g., Cs 2 CO 3 The compound of formula (IIIb_6) can be prepared by the Buchwald reaction of a compound of formula (IIIb_7) in the presence of

[0351] Step 7: Compounds of formula (IIIb_9) can be prepared by acylation of compounds of formula (IIIb_8) with acetyl chloride under standard conditions.

[0352] Step 8: Compounds of formula (IIIb_10) can be prepared by intramolecular cyclization of compounds of formula (IIIb_9) in the presence of a base (eg t-BuOK) under standard conditions.

[0353] Step 9:

[0276] Compounds of formula (IIIb_11) can be prepared by nitration reaction of compounds of formula (IIIb_10) with nitric acid under standard conditions.

[0354] Step 10: Compounds of formula (IIIb_12) can be prepared by reacting compounds of formula (III_11) with a chloride reagent (e.g., POCl) in the presence of a base (e.g., DIPEA) under standard conditions. 3 ) by chlorination reaction.

[0355] Step 11: Compounds of formula (IIIb_14) can be prepared under standard conditions with a base (e.g., DIPEA, NaHCO 3 It can be prepared by a substitution reaction with a compound of formula (III_12) and a compound of formula (IIIb_13) in the presence of

[0356] Step 12: Compounds of formula (IIIb_15) can be prepared by standard reduction conditions (e.g. Fe / NH 4 Cl) to prepare a compound of formula (IIIb_14).

[0357] Step 13:

[0284] Compounds of formula (IIIb_16) can be prepared by methylation reaction of compounds of formula (IIIb_15) with a methylating reagent (eg MeI) under standard conditions.

[0358] Step 14: Compounds of formula (IIIb_18) can be prepared by the reaction of a palladium catalyst (e.g. PddppfCl 2 ) and a base (e.g. Na 2 CO 3 The compound of formula (IIIb_16) can be prepared by Suzuki coupling reaction of a compound of formula (IIIb_17) with a compound of formula (IIIb_18) in the presence of

[0359] Step 15: Compounds of formula (IIIb) may be prepared by removal of the Boc protecting group with an acid (eg TFA) under standard conditions.

[0360]

[0289] In some embodiments, compounds of Formula (IVa) provided herein can be prepared by a synthetic route as shown in Scheme 4.

[0361] [ka]

[0362] Step 1: The starting material of formula (IVa_1) is commercially available. Compounds of formula (IVa_2) can be prepared by reacting them with acids (e.g. H 2 SO 4 It can be prepared by esterification of a compound of formula (IVa_1) with ethanol in the presence of

[0363] Step 2:

[0293] Compounds of formula (IVa_3) can be prepared by pyridone cyclization reaction of compounds of formula (IVa_2) with diethyl malonate in the presence of a base (eg EtONa) under standard conditions.

[0364] Step 3:

[0295] Compounds of formula (IVa_4) can be prepared by decarboxylation of compounds of formula (IVa_3) with concentrated HCl under standard conditions.

[0365] Step 4:

[0297] Compounds of formula (IVa_5) can be prepared by nitration reaction of compounds of formula (IVa_4) with nitric acid under standard conditions.

[0366] Step 5: Compounds of formula (IVa_6) can be prepared by reacting compounds of formula (IVa_5) with a chloride reagent (e.g. POCl) in the presence of a base (e.g. TEBAC) under standard conditions. 3 ) by chlorination reaction.

[0367] Step 6: Compounds of formula (IVa_8) can be prepared under standard conditions with a base (e.g., DIPEA, NaHCO 3 The compound of formula (IVa_6) may be prepared by a substitution reaction with a compound of formula (IVa_7) in the presence of

[0368] Step 7:

[0303] Compounds of formula (IVa_10) can be prepared by Mitsunobu reaction of compounds of formula (IVa_8) and compounds of formula (IVa_9) in the presence of triphenylphosphine and an azodicarboxylate (eg DIAD) under standard conditions.

[0369] Step 8: Compounds of formula (IVa_11) can be prepared by reacting compounds of formula (IVa_10) with a reducing agent (e.g., NaBH 4 ) by reduction reaction.

[0370] Step 9: Compounds of formula (IVa_12) can be prepared by standard reduction conditions (e.g. Fe / NH 4 Cl) to prepare a compound of formula (IVa_11).

[0371] Step 10:

[0309] Compounds of formula (IVa_13) can be prepared by methylation reaction of compounds of formula (IVa_12) with a methylating reagent (eg MeI) under standard conditions.

[0372] Step 11:

[0311] Compounds of formula (IVa_14) may be prepared by removal of the Boc protecting group of compounds of formula (IVa_13) with an acid (eg HCl) under standard conditions.

[0373] Step 12: Compounds of formula (IVa_16) can be prepared by the reaction of a palladium catalyst (e.g. Pd(OAc) 2 ), a ligand (e.g., BINAP) and a base (e.g., Cs 2 CO 3 The compound of formula (IVa_14) can be prepared by Buchwald reaction of a compound of formula (IVa_15) in the presence of

[0374] Step 13:

[0315] Compounds of formula (IVa) may be prepared by removal of the Cbz protecting group of compounds of formula (IVa_16) with TMSI under standard conditions.

[0375]

[0316] In some embodiments, intermediate INT1 useful in the present disclosure can be prepared by a synthetic route as shown in Scheme 5.

[0376] [ka]

[0377] Step 1:

[0318] The starting racemic mixture (V-1) is commercially available. Compounds of formula (V-2) can be prepared by methylation of compounds of formula (V-1) in the presence of trimethyloxonium tetrafluoroborate under standard conditions.

[0378] Step 2: Formula (V-3) as an E / Z mixture can be prepared via condensation reaction of V-2 with ethyl 2-nitroacetate under standard conditions.

[0379] Step 3: Formula (V-4) as a mixture of four diastereomers can be prepared via Pd / C catalyzed hydrogenation / condensation reaction under standard conditions. The two minor diastereomeric pairs are removed by column chromatography and the two major diastereomeric pairs are carried forward to the next step.

[0380] Step 4: Formula (V-5) as a 1:1 diastereomeric mixture can be prepared via Boc protection of formula (V-4) under standard conditions.

[0381] Step 5: INT1, as a 1:1 diastereomeric mixture, can be prepared by the reaction of INT1 with a reducing agent (e.g., LiAlH 4 ) can be prepared via reduction of formula (V-5).

[0382]

[0327] In some embodiments, compounds of Formula (IIb) provided herein can be prepared by a synthetic route as shown in Scheme 6.

[0383] [ka]

[0384] Step 1: Compounds of formula (VI-2) can be prepared via fluorination of commercially available compounds of formula (VI-1) with a fluorinating agent (eg Selectfluor) under standard conditions.

[0385] Step 2: Compounds of formula (VI-3) can be prepared via iodination of compounds of formula (VI-2) with an iodinating reagent (eg, NIS) under standard conditions.

[0386] Step 3: Formula (VI-4) can be prepared under standard conditions in methanol with carbon monoxide, a base (e.g., TEA) and a palladium catalyst (e.g., Pd(dppf)Cl 2 The aryl iodides of formula (VI-3) can be prepared via palladium catalyzed alkoxycarbonylation with

[0387] Step 4: Compounds of formula (VI-5) can be prepared via hydrolysis of the methyl ester of formula (VI-4) under standard conditions.

[0388] Step 5: Formula (VI-6) can be prepared by reacting a chlorinating agent (e.g., POCl) under standard conditions. 3 ) via chlorination of the carboxylic acid formula (VI-5).

[0389] Step 6: Formula (VI-7) can be prepared via cyclocondensation of Formula (VI-6) with ammonium thiocyanate under standard conditions.

[0390] Step 7: Compounds of formula (VI-8) can be prepared via methylation of compounds of formula (VI-7) with methyl iodide under standard conditions.

[0391] Step 8: Compounds of formula (VI-9) as a 1:1 diastereomeric mixture can be prepared via the SNAr reaction of compounds of formula (VI-8) with INT1 in the presence of a base (eg NaH) under standard conditions.

[0392] Step 9: Formula (VI-10) as a 1:1 diastereomeric mixture can be prepared via intramolecular cyclization of Formula (VI-9) in the presence of a peptide coupling reagent (e.g., PyBOP) and a base (e.g., DBU) under standard conditions.

[0393] Step 10:

[0347] Formula (VI-12) as a 1:1 diastereomeric mixture can be prepared by palladium catalysis (e.g., XPhos-Pd-G 2 ) and a base (e.g., K 2 CO 3 can be prepared via Suzuki coupling reaction of arylboronic esters of formula (VI-11) and formula (VI-10) in the presence of arylboronic acid ester (VI-12).

[0394] Step 11: Formula (VI-13) as a 1:1 diastereomeric mixture can be prepared via sulfur oxidation of Formula (VI-12) with an oxidizing agent such as mCPBA under standard conditions.

[0395] Step 12: Formula (VI-15) as a 1:1 diastereomeric mixture can be prepared via SNAr reaction of Formula (VI-13) with alcohol Formula (VI-14) in the presence of base (eg NaH) under standard conditions.

[0396] Step 13: Compounds of formula (IIb) as a 1:1 diastereomeric mixture can be prepared by deprotection of compounds of formula (VI-15) with acid (eg HCl) under standard conditions.

[0397] Step 14:

[0355] Formula (IIb-Peak 1) and Formula (IIb-Peak 2) as single diastereomers can be prepared by SFC separation of the diastereomeric mixture (IIb) on a suitable column under standard conditions.

[0398]

[0356] In some embodiments, the intermediate of formula (VI-8) in Scheme 6 can also be prepared by a synthetic route as shown in Scheme 7.

[0399] [ka]

[0400] Step 1: Formula (VII-2) can be prepared via bromination of commercially available formula (VI-1) with 1,2-dibromo-1,1,2,2-tetrachloroethane in the presence of methyllithium under standard conditions.

[0401] Step 2: Compounds of formula (VII-3) can be prepared via condensation reaction of acid chlorides of formula (VII-2) with 2-methyl-2-thiopseudourea sulfate in the presence of a base (eg NaOH) under standard conditions.

[0402] Step 3: Formula (VI-8) can be prepared by the addition of a base (e.g., Cs) under standard conditions. 2 CO 3 can be prepared via intramolecular SNAr cyclization of formula (VII-3) in the presence of

[0403]

[0362] In some embodiments, intermediate INT2 provided herein can be prepared by a synthetic route as shown in Scheme 8.

[0404] [ka]

[0405] Step 1:

[0364] The starting material methyl (R)-5-oxopyrrolidine-2-carboxylate (VIII-1) is commercially available. Compounds of formula (VIII-2) can be prepared by methylation of compounds of formula (VIII-1) in the presence of trimethyloxonium tetrafluoroborate under standard conditions.

[0406] Step 2: Formula (VIII-3) as an E / Z mixture can be prepared via condensation reaction of VIII-2 with ethyl 2-nitroacetate under standard conditions.

[0407] Step 3:

[0368] Formula (VIII-4) as a mixture of two diastereomers can be prepared via Pd / C catalyzed hydrogenation / condensation reaction under standard conditions. The minor diastereomer is removed by column chromatography and the major diastereomer is carried forward to the next step.

[0408] Step 4: Compound (VIII-5) can be prepared via Boc protection of compound (VIII-4) under standard conditions.

[0409] Step 5:

[0372] INT2 as a single diastereomer can be prepared by the reaction of INT2 with a reducing agent (e.g. LiAlH 4 The compound of formula (VIII-5) can be prepared by reduction of the compound of formula (VIII-6) with

[0410]

[0373] In some embodiments, compounds of formula (IX-7) provided herein can be prepared by a synthetic route as shown in Scheme 9.

[0411] [ka]

[0412] Step 1: Compounds of formula (IX-2) can be prepared by displacement of the sulfone group of formula (IX-1) with sodium cyanate under standard conditions.

[0413] Step 2: Compounds of formula (IX-3) can be prepared by hydrolysis of the cyanide of formula (IX-2) to the acid and in situ formation of the methyl ester in the presence of methanol under acidic conditions.

[0414] Step 3: Compounds of formula (IX-4) can be prepared by Boc protection of formula (IX-3) under standard conditions.

[0415] Step 4: Compounds of formula (IX-5) can be prepared by hydrolysis of the methyl ester of formula (IX-4) under standard conditions.

[0416] Step 5: Compounds of formula (IX-6) can be prepared by HATU coupling of compounds of formula (IX-5) with appropriate primary amines under standard conditions.

[0417] Step 6: Compounds of formula (IX-7) can be prepared by Boc deprotection of compounds of formula (IX-6) under acidic conditions.

[0418]

[0386] In some embodiments, compounds of formula (X-3) provided herein can be prepared by a synthetic route as shown in Scheme 10.

[0419] [ka]

[0420] Step 1: The compound of formula (X-2) can be prepared by the reaction of CD in DMF. 3 It can be prepared by treatment of formula (X-1) with CSF in the presence of OD.

[0421] Step 2:

[0390] Compounds of formula (X-3) can be prepared by Boc deprotection of formula (X-2) under acidic conditions.

[0422]

[0391] In some embodiments, compounds of Formula (II'a) provided herein can be prepared by a synthetic route as shown in Scheme 11.

[0423] [ka]

[0424]

[0392] Step 1: Compounds of formula (XI-2) can be prepared by treatment of compounds of formula (XI-1) with a brominating reagent such as 1,2-dibromotetrachloroethane under standard conditions.

[0425] Step 2: Formula (XI-3) can be prepared by the reaction of PMBNH 2 It can be prepared by substitution of the bromine of formula (XI-2) with

[0426] Step 3: Compounds of formula (XI-4) can be prepared by amide coupling of acid chlorides with amines of formula (XI-3) under standard conditions.

[0427]

[0398] Step 4: Formula (XI-5) can be prepared by intermolecular cyclization of formula (XI-4) in the presence of thionyl chloride and a base such as TEA.

[0428] Step 5: Formula (XI-6) can be prepared by decarboxylation of formula (XI-5) in the presence of sodium chloride under microwave heating conditions.

[0429] Step 6: Compounds of formula (XI-7) can be prepared by displacement of the chlorine of compound (XI-6) with an alcohol under basic conditions.

[0430] Step 7:

[0405] Formula (XI-8) can be prepared by intermolecular cyclization of formula (XI-7) under Mitsunobu reaction conditions.

[0431] Step 8: Formula (XI-9) can be prepared by PMB deprotection of formula (XI-8) under acidic conditions.

[0432] Step 9: Compounds of formula (XI-10) can be prepared by Boc protection of the secondary amine of formula (XI-9) under standard conditions.

[0433] Step 10:

[0411] Formula (XI-11) can be prepared by Mitsunobu coupling of an alcohol with formula (XI-10).

[0434] Step 11: Compounds of formula (XI-12) can be prepared by Suzuki coupling of compounds of formula (XI-11) with a boronic ester under standard conditions.

[0435] Step 12: Formula (XI-13) can be prepared by Boc deprotection of formula (XI-12) under acidic conditions.

[0436] Step 13:

[0417] Formula (II'a) can be prepared by TIPS deprotection of formula (XI-13) in the presence of CsF under standard conditions.

[0437]

[0418] In some embodiments, compounds of formula (XII-13) provided herein can be prepared by a synthetic route as shown in Scheme 12.

[0438] [ka]

[0439]

[0419] Step 1: Compounds of formula (XII-2) can be prepared under standard conditions by deprotonation of compounds of formula (XII-1) with a base such as n-BuLi, followed by CO 2 It can be prepared by the addition of

[0440]

[0421] Step 2: Compounds of formula (XII-3) can be prepared by coupling of acid chlorides of formula (XII-2) with 2-methyl-2-thio-pseudourea hydrogen sulfate under basic conditions.

[0441] Step 3:

[0424] Compounds of formula (XII-4) can be prepared by intramolecular cyclization of compounds of formula (XII-3) under basic conditions.

[0442] Step 4: Compounds of formula (XII-5) can be prepared by treatment of compounds of formula (XII-4) with POCl 3 under standard conditions.

[0443] Step 5:

[0428] Compounds of formula (XII-6) can be prepared by the SNAr reaction of compounds of formula (XII-5) with tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate under basic conditions.

[0444] Step 6: Compounds of formula (XII-7) can be prepared under standard conditions using a palladium(II) catalyst, i.e., Pd(OAc) 2 and in the presence of a ligand, ie, BINAP, by intramolecular coupling of formula (XII-6).

[0445] Step 7: Compounds of formula (XII-8) can be prepared by demethylation of compounds of formula (XII-7) with TMSI under standard conditions.

[0446] Step 8: Compounds of formula (XII-9) can be prepared by Boc protection of compounds of formula (XII-8) under standard conditions.

[0447] Step 9: The compound of formula (XII-10) can be prepared by the reaction of a copper(II) catalyst, i.e., Cu(OAc) 2 The compound (XII-9) can be prepared by Chan-Lam coupling of an aromatic boronic ester with the compound (XII-9) in the presence of

[0448] Step 10: Compounds of formula (XII-11) can be prepared by sulfur oxidation of compounds of formula (XII-10) with m-CPBA under standard conditions.

[0449] Step 11:

[0440] Compounds of formula (XII-12) can be prepared by the SNAr reaction of compounds of formula (XII-11) with alcohols under basic conditions.

[0450] Step 12: Compounds of formula (XII-13) can be prepared by Boc deprotection of formula (XII-12) under standard conditions.

[0451]

[0443] In some embodiments, compounds of formula (XIII-11) provided herein can be prepared by a synthetic route as shown in Scheme 13.

[0452] [ka]

[0453] Step 1: Compounds of formula (XIII-2) can be prepared under standard conditions by deprotonation of compounds of formula (XIII-1) with a base such as n-BuLi, followed by CO 2 It can be prepared by the addition of

[0454] Step 2: Compounds of formula (XIII-3) can be prepared by coupling of acid chlorides of formula (XIII-2) with 2-methyl-2-thio-pseudourea hydrogen sulfate under basic conditions.

[0455] Step 3:

[0449] Compounds of formula (XIII-4) can be prepared by intramolecular cyclization of compounds of formula (XIII-3) under basic conditions.

[0456] Step 4:

[0451] Compounds of formula (XIII-5) can be prepared by the SNAr reaction of compounds of formula (XIII-4) with tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate under basic conditions.

[0457] Step 5: Compounds of formula (XIII-6) can be prepared by intramolecular cyclization of compounds of formula (XIII-5) in the presence of PyBOP under basic conditions.

[0458] Step 6: Compounds of formula (XIII-7) can be prepared by Suzuki coupling of boronic esters with compounds of formula (XIII-6) under standard conditions.

[0459] Step 7: Compounds of formula (XIII-8) can be prepared by sulfur oxidation of compounds of formula (XIII-7) with m-CPBA under standard conditions.

[0460] Step 8:

[0459] Compounds of formula (XIII-9) can be prepared by the SNAr reaction of compounds of formula (XIII-8) with alcohols under basic conditions.

[0461] Step 9: Compounds of formula (XIII-10) can be prepared by Boc deprotection of formula (XIII-9) under standard conditions.

[0462] Step 10:

[0463] Atropisomers I and II of formula (XIII-11) can be prepared by SFC separation of formula (XIII-10) under standard chiral SFC separation conditions.

[0463]

[0464] In some embodiments, compounds of formula (XIV-2) provided herein can be prepared by a synthetic route as shown in Scheme 14.

[0464] [ka]

[0465] Compounds of formula (XIV-2) can be prepared by reacting compounds of formula (XIV-1) with a carbonate reagent in the presence of a base under standard conditions.

[0466] Example 1 Preparation of intermediate tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT1)

[0467] [ka]

[0468]

[0466] Intermediate INT1 was prepared according to the synthetic route as shown in Scheme 5. Methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate

[0469] [ka]

[0470] To a solution of methyl 5-oxopyrrolidine-2-carboxylate (42 mL, 349 mmol) in DCM (300 mL) was added trimethyloxonium tetrafluoroborate (57 g, 384 mmol) and the reaction was stirred at room temperature for 18 h. The reaction was diluted with saturated NaHCO 3 The mixture was quenched with a solution of saturated NaHCO 3 The solution was washed with water and concentrated in vacuo. The residue was purified using silica gel column chromatography to give the title compound methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (21 g, 38%) as a yellow oil.

[0471]

[0468] LC / MS ESI(m / z):158[M+H] +

[0469] 1 H NMR (400 MHz, CDCl 3) δ 4.55 (dd, J = 7.7, 6.5 Hz, 1H), 4.55 (dd, J = 7.7, 6.5 Hz, 1H), 3.87 (s, 3H), 3.77 (d, J = 11.8 Hz, 3H), 2.65 - 2.47 (m, 2H), 2.39 - 2.29 (m, 1H), 2.24 - 2.15 (m, 1H). Methyl (Z)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate and methyl (E)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate

[0472] [ka]

[0473] To a flask containing methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (27.5 g, 175 mmol) was added ethyl 2-nitroacetate (39 mL, 349.9 mmol) at room temperature. The mixture was stirred at 60° C. for 18 hours. The resulting mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography to give the title compound (Z)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate and methyl (E)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate (16 g, 62 mmol, 35.4%) as a yellow gum.

[0474]

[0471] LC / MS ESI(m / z):259[M+H] + .

[0475]

[0472] 1 H NMR (400 MHz, DMSO-d 6) δ 10.19 (s, 1H), 4.63 (dd, J = 9.3, 4.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 14.4 Hz, 3H), 3.06 (s, 2H), 2.44 - 2.34 (m, 1H), 2.05 (dt, J = 18.6, 6.5 Hz, 1H), 1.28 - 1.20 (m, 3H). Ethyl-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0476] [ka]

[0477] To a solution of (Z)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate and methyl (E)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate in EtOH (300 mL) was added Pd / C (131 mmol). The reaction was diluted with H 2 The mixture was stirred at room temperature under atmosphere (20 atm) for 3 days. The reaction was filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol (0-10%) in chloroform to give the title compound (1:1 major diastereomeric mixture) ethyl-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (4 g, 20 mmol, 37%) as a yellow solid and the minor diastereomeric mixture ethyl-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (170.0 mg, 1.6%) as a white solid (discarded).

[0478]

[0474] Major diastereomer mixture: LC / MS ESI (m / z): 199 [M+H] + .

[0479]

[0475] 1 H NMR (400 MHz, DMSO-d6 ) δ 7.25 (s, 1H), 4.25 (d, J = 4.4 Hz, 1H), 4.19 - 4.08 (m, 2H), 3.74 (t, J = 5.1 Hz, 1H), 3.38 (d, J = 6.6 Hz, 1H), 1.86 - 1.65 (m, 3H), 1.51 - 1.39 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H). 8-(tert-butyl) 2-ethyl-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0480] [ka]

[0481]

[0476] THF (20 mL) and H 2 A solution of ethyl-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (2 g, 10 mmol) in HO (5 mL) was added to NaHCO 3 (1.7 g, 20 mmol) and (Boc) 2 HO (2.2 mL, 10 mmol) was added and the reaction was stirred at room temperature for 24 h. The reaction was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The residue was purified using silica gel column chromatography to give the title compound (1:1 major diastereomeric mixture) 8-tert-butyl 2-ethyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (2.45 g, 81%) as a white solid.

[0482]

[0477] LC / MS ESI(m / z):299[M+H] + .

[0483]

[0478] 1 H NMR (400 MHz, DMSO-d 6) δ 7.64 (s, 1H), 4.43 (s, 2H), 4.22 - 4.13 (m, 2H), 4.10 (d, J = 6.6 Hz, 1H), 2.12 - 1.97 (m, 2H), 1.81 (t, J = 9.2 Hz, 1H), 1.57 (t, J = 8.6 Hz, 1H), 1.41 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H). tert-Butyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0484] [ka]

[0485] LiAlH in THF (20 mL) 4 (1.22 g, 32 mmol) in THF (20 mL) was added dropwise to 8-tert-butyl 2-ethyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1.2 g, 4.0 mmol) at 0° C. The reaction was then cooled to 5° C. with 5% CO. 2 The reaction mixture was stirred at 0° C. for 5 hours under reduced pressure. 2 SO 4 The mixture was quenched with a solution of 1,2-dichloromethane. The mixture was filtered and the filtrate was washed with DCM / MeOH (10 / 1). The combined organic phase was concentrated in vacuo to give the title compound (1:1 major diastereomeric mixture) tert-butyl 2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 82%) as a yellow oil, which was used directly without further purification.

[0486]

[0480] LC / MS ESI(m / z):243[M+H] + .

[0487]

[0481] 1 H NMR (400 MHz, DMSO-d 6) δ 4.53 (d, J = 60.7 Hz, 1H), 3.95 (s, 2H), 3.35 (s, 1H), 3.19 (d, J = 6.4 Hz, 2H), 2.73 (d, J = 11.4 Hz, 2H), 2.56 (d, J = 11.5 Hz, 1H), 1.82 - 1.62 (m, 3H), 1.56 (s, 1H), 1.40 (s, 9H). Example 2 Preparation of intermediate 4-bromo-2,6-dichloro-5-fluoronicotinic acid (VI-8)

[0488] [ka]

[0489]

[0482] Intermediates of formula (VI-8) were prepared according to the synthetic route as shown in Scheme 7. 4-Bromo-2,6-dichloro-5-fluoronicotinic acid

[0490] [ka]

[0491] To a cooled solution of 2,6-dichloro-5-fluoronicotinic acid (6.0 mL, 47.6 mmol) in anhydrous THF (100 mL) was added MeLi (76.0 mL, 98.8 mmol, 1.3 M in THF) at -78 °C over 30 min. The reaction was warmed to -20 to -30 °C for 2 h. The reaction mixture was cooled to -78 °C, followed by the addition of 1,2-dibromo-1,1,2,2-tetrachloroethane (6.30 mL, 52 mmol) in anhydrous THF (30 mL). The reaction mixture was stirred at 0 °C for 1.5 h. The reaction solution was diluted with ice water (150 mL) followed by extraction with chloroform (30 mL). The aqueous layer was separated and adjusted to pH = 2 by the addition of 1N hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with Na 2 SO 4The mixture was dried at rt, filtered and concentrated to give the title compound 4-bromo-2,6-dichloro-5-fluoronicotinic acid (12 g, 87%) as a white solid, which was used in the next step without further purification.

[0492]

[0484] LC / MS ESI(m / z):288[M+H] + . Methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)carbamimidothioate

[0493] [ka]

[0494] To a solution of 4-bromo-2,6-dichloro-5-fluoronicotinic acid (6.65 g, 23 mmol) in DCM (60 mL) was added oxalyl dichloride (4.38 g, 34.5 mmol) 2 The addition was carried out at 0° C. under atmospheric conditions and the reaction was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo to give crude 4-bromo-2,6-dichloro-5-fluoronicotinoyl chloride as a red-brown oil. 2 2-Methyl-2-thiopseudourea sulfate (8.0 g, 42.6 mmol) was added in small batches to a solution of NaOH (4.26 g, 106.6 mmol) in 0 (80 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 30 min. The above mixture was added to a solution of 4-bromo-2,6-dichloro-5-fluoronicotinoyl chloride in DCM (20 mL) at 0° C., and the reaction was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with EA (2×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography to give the title compound methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)carbamimidothioate (2.6 g, 31.3%) as a white solid.

[0495]

[0486] LCMS(ESI)m / z:361[M+H] + . 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0496] [ka]

[0497] A solution of methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)carbamimidothioate (2.6 g, 7.2 mmol) in DMF (30 mL) was added to Cs 2 CO 3 (3.52 g, 10.8 mmol) was added and the reaction was stirred at 90 °C for 1 h. The reaction was cooled to room temperature and poured into ice water (20 mL). The pH of the aqueous phase was adjusted to 2-3 and a solid precipitated. The solid was collected by filtration and washed with water. The residue was dried in a vacuum oven to give 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.8 g, 89%) as a white solid.

[0498]

[0488] LC / MS ESI(m / z):280[M+H] + .

[0499] The following examples may be prepared according to the synthetic route as shown in Scheme 6.

[0500] Example 3 Preparation of 5-chloro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (Compound 1)

[0501] [ka]

[0502] 2,6-Dichloro-3-fluoropyridin-4-amine

[0503] [ka]

[0504] To a solution of 2,6-dichloropyridin-4-amine (6 g, 36.8 mmol) in DMF (20 mL) and MeCN (20 ml) was added Selectfluor (15.6 g, 44.2 mmol) in one portion. The mixture was stirred at 80° C. for 4 h. The crude reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was further purified by silica gel column chromatography to give 2,6-dichloro-3-fluoropyridin-4-amine (3.2 g, 48% yield) as a white solid.

[0505]

[0491] LC / MS(ESI)m / z:181[M+H] + . 2,6-Dichloro-3-fluoro-5-iodopyridin-4-amine

[0506] [ka]

[0507] To a mixture of 2,6-dichloro-3-fluoropyridin-4-amine (3.2 g, 17.68 mmol) in MeCN (20 mL) was added N-iodosuccinimide (3.67 g, 21.21 mmol), p-toluenesulfonic acid (0.17 g, 0.88 mmol). The mixture was stirred at 70° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was further purified by silica gel column chromatography to give 2,6-dichloro-3-fluoro-5-iodopyridin-4-amine as a white solid.

[0508]

[0493] LC / MS(ESI)m / z:307[M+H] + . Methyl 4-amino-2,6-dichloro-5-fluoronicotinate

[0509] [ka]

[0510] 2,6-Dichloro-3-fluoro-5-iodopyridin-4-amine (4.6 g, 15 mmol), Pd(dppf)Cl in MeOH (50 mL) 2 A mixture of (2.19 g, 3 mmol) and TEA (12.7 mL, 90 mmol) was stirred under carbon monoxide atmosphere (15 psi) at 65° C. for 12 h. The mixture was filtered through Celite, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give methyl 4-amino-2,6-dichloro-5-fluoropyridine-3-carboxylate (2.5 g, 10.46 mmol, 70%) as a pink powder.

[0511]

[0495] LC / MS(ESI)m / z:239[M+H] + .

[0512]

[0496] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.31 (s, 2H), 3.87 (s, 3H). 4-Amino-2,6-dichloro-5-fluoronicotinic acid

[0513] [ka]

[0514] To a solution of methyl 4-amino-2,6-dichloro-5-fluoropyridine-3-carboxylate (1.5 g, 6.28 mmol) in MeOH (30 mL) was added THF (10 mL) followed by H 2A solution of NaOH (0.75 g, 18.83 mmol) in 2H2O (10 mL) was added. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was treated with ethyl acetate and water. The aqueous layer was separated, washed with petroleum ether and then acidified to pH=5 with aqueous HCl (3N). The resulting aqueous layer was then concentrated to dryness and coevaporated twice with EtOH to give crude 4-amino-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.9 g, crude) containing NaCl as a white solid, which was carried forward without further purification.

[0515]

[0498] LC / MS ESI(m / z):225[M+H] + 4-Amino-2,6-dichloro-5-fluoronicotinoyl chloride

[0516] [ka]

[0517]

[0499] POCl 3 A mixture of crude 4-amino-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.9 g, 6.3 mmol) containing NaCl in (20 mL, 214.6 mmol) was stirred at 90° C. for 3 h. After cooling to room temperature, the mixture was filtered. The resulting filtrate was concentrated in vacuum on an oil pump to give crude 4-amino-2,6-dichloro-5-fluoronicotinoyl chloride (2.1 g, crude) as a yellow oil, which was used directly in the following step.

[0518]

[0500] LC / MS ESI(m / z):243[M+H] + 5,7-Dichloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one

[0519] [ka]

[0520]

[0499] Crude 4-amino-2,6-dichloro-5-fluoronicotinoyl chloride (2.1 g, 6.3 mmol) was dissolved in dry THF (20 mL) followed by NH 4 A solution of SCN (1.44 g, 18.9 mmol) was added over 10 min at 0° C. The resulting mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was treated with ethyl acetate and water. The organic layer was separated, washed with brine and added Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo to give crude 5,7-dichloro-8-fluoro-2-sulfanylidene-1H,2H,3H,4H-pyrido[4,3-d]pyrimidin-4-one (2.1 g, 100.10%) as a yellow solid which was used for the next step without further purification.

[0521]

[0502] LC / MS ESI(m / z):264[MH] - 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0522] [ka]

[0523] To a solution of crude 5,7-dichloro-8-fluoro-2-sulfanylidene-1H,2H,3H,4H-pyrido[4,3-d]pyrimidin-4-one (2.1 g, 6.3 mmol) in dry DMF (30 mL) was added EtONa (0.43 g, 6.3 mmol) at 0° C. The resulting mixture was stirred at room temperature for 10 min, and then iodomethane (0.47 mL, 7.6 mmol) was added dropwise at 0° C. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was treated with ethyl acetate and ice water. The organic layer was separated, washed with brine and diluted with Na 2 SO 4The residue was purified by silica gel column chromatography, followed by trituration with a small amount of EtOH to give pure 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3H,4H-pyrido[4,3-d]pyrimidin-4-one (400 mg, 23%) as a yellow solid.

[0524]

[0504] LC / MS ESI(m / z):280[M+H] + tert-Butyl 2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0525] [ka]

[0526] To a solution of INT1 tert-butyl 2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (207.6 mg, 0.86 mmol) (1:1 major diastereomeric mixture) in dry THF (20 mL) was added NaH (68 mg, 1.71 mmol, 60% in mineral oil) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h before 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3H,4H-pyrido[4,3-d]pyrimidin-4-one (200 mg, 0.71 mmol) was added in one portion at 0° C. The reaction mixture was then stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with cold saturated NH 4The mixture was quenched with Cl and then extracted twice with DCM. The combined extracts were concentrated and purified by flash column chromatography on silica gel to give 2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (225 mg, 64.8%) as a white solid (1:1 major diastereomeric mixture).

[0527]

[0506] LC / MS ESI(m / z):486[M+H] + tert-Butyl 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0528] [ka]

[0529] To a solution of 2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.45 mmol) in dry MeCN (20 mL) was added PyBOP (471 mg, 0.91 mmol). After cooling to 0° C., DBU (0.27 mL, 1.81 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction mixture was diluted with aqueous saturated NaHCO 3The mixture was poured into a 50 ml aliquot of 100 ml of ethyl acetate and then extracted twice with ethyl acetate. The combined extracts were concentrated in vacuo and the residue was purified by flash column chromatography on silica gel to give tert-butyl 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (130 mg, 61.4%) (1:1 major diastereomeric mixture) as a colorless gum.

[0530]

[0508] LC / MS ESI(m / z):468[M+H] + tert-Butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0531] [ka]

[0532]

[0493] tert-Butyl 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (100 mg, 0.2 mmol) and 2-[8-chloro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97 mg, 0.28 mmol) in THF (1 mL) and water (0.3 mL), K 2 CO 3 (59 mg, 0.43 mmol) was mixed with N 2 The mixture was degassed three times with XPhos-Pd-G 2 (16.8 mg, 0.02 mmol). The reaction tube was filled with N 2Degas the mixture for 10 min with N 2 The mixture was stirred at 60° C. for 2.5 h under reduced pressure. After completion, the mixture was diluted with ethyl acetate (5 mL) and water (2 mL). The aqueous phase was extracted with ethyl acetate (2×2 mL). The combined organic layers were washed with saturated brine (5 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by column chromatography to give the title compound (70 mg, 50%) (1:1 major diastereomeric mixture) as a brown solid.

[0533]

[0510] LC / MS ESI(m / z):654[M+H] + . tert-Butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0534] [ka]

[0535] To a flask containing tert-butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (45 mg, 0.07 mmol) was added DCM (3 mL) at 0° C., followed by m-CPBA (23 mg, 0.14 mmol). The mixture was stirred at 0° C. for 5 min. The resulting mixture was diluted with NaHCO 3 (aqueous). The mixture was extracted with DCM (3×3 mL). 2 Cl 2 Combine the layers and add Na 2 SO 4The crude material was purified by preparative TLC plate to give the title compound tert-butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (42 mg, 89%) (1:1 major diastereomeric mixture).

[0536]

[0512] LCMS(ESI)m / z:686[M+H] + . tert-Butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0537] [ka]

[0538] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (8 mg, 0.05 mmol) in dry THF (3 mL) was added NaH (4 mg, 0.1 mmol, 60% in mineral oil) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, and then a solution of tert-butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (35 mg, 0.05 mmol) in dry THF (1 mL) was added dropwise at 0° C. LCMS showed that the starting material was completely consumed. The reaction mixture was diluted with saturated NH 4 The mixture was poured into Cl and extracted twice with DCM. The combined extracts were concentrated in vacuo and the residue was purified by preparative TLC to give tert-butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 51%) as a white solid (1:1 major diastereomeric mixture).

[0539]

[0514] LC / MS ESI(m / z):765[M+H] + 5-Chloro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0540] [ka]

[0541] To a flask containing tert-butyl (6R,9S)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 0.03 mmol) was added DCM (3 mL) followed by HCl / dioxane (4 M, 1 mL). The mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated and the residue was purified by preparative HPLC to give the title compound 5-chloro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (6 mg, 37%) (1:1 major diastereomeric mixture).

[0542]

[0516] LC / MS ESI(m / z):621[M+H] + .

[0543]

[0517] 1 HNMR (400 MHz, methanol-d 4) δ 8.45 (s, 1H), 7.78 - 7.70 (m, 1H), 7.40 - 7.29 (m, 3H), 7.16 (dd, J = 52.4, 2.0 Hz, 1H), 5.45 (d, J = 52.5 Hz, 1H), 5.09 (t, J = 15.3 Hz, 1H), 4.67 - 4.44 (m, 4H), 4.21 (d, J = 8.3 Hz, 1H), 3.88 - 3.55 (m, 5H), 3.27 (s, 2H), 2.62 - 2.38 (m, 2H), 2.31 (s, 1H), 2.25 - 2.15 (m, 2H), 2.11 - 1.78 (m, 5H). The following compounds may be prepared in a similar manner to compound 1, except using other appropriate aryl boronic esters and alcohols. Compound 2: 5-chloro-4-((6R,9S)-1-fluoro-12-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0544] [ka]

[0545]

[0519] LC / MS(ESI)m / z:603[M+H] + .

[0546]

[0520] 1 H NMR (400 MHz, methanol-d 4) δ 8.41 (s, 2H), 7.77 - 7.71 (m, 1H), 7.37 - 7.31 (m, 3H), 7.17 (dd, J = 52.5, 2.5 Hz, 1H), 5.08 (d, J = 17.5 Hz, 1H), 4.64 (d, J = 3.7 Hz, 2H), 4.56 - 4.50 (m, 1H), 4.23 (d, J = 8.4 Hz, 1H), 3.84 (d, J = 23.3 Hz, 2H), 3.71 - 3.62 (m, 2H), 3.30 - 3.24 (m, 4H), 2.31 (dd, J = 12.1, 6.8 Hz, 2H), 2.24 - 2.07 (m, 6H), 2.00 - 1.84 (m, 4H). (1:1 major diastereomeric mixture) Compound 3: 6-fluoro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0547] [ka]

[0548]

[0521] LC / MS(ESI)m / z:605[M+H] + .

[0549]

[0522] 1 H NMR (400 MHz, methanol-d 4) δ 7.80 (dd, J = 8.9, 5.7 Hz, 1H), 7.35 - 7.20 (m, 4H), 5.50 (d, J = 52.4 Hz, 1H), 5.13 (d, J = 13.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.58 - 4.51 (m, 2H), 4.25 (d, J = 6.5 Hz, 1H), 3.95 - 3.67 (m, 5H), 3.34 (m, 2H), 2.68 - 2.45 (m, 2H), 2.36 (m, 1H), 2.27 (d, J = 5.5 Hz, 2H), 2.14 - 1.88 (m, 5H).(1:1 major diastereomeric mixture) Compound 4: (6R,9S)-2-(8-ethyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0550] [ka]

[0551]

[0523] LC / MS(ESI)m / z:617[M+H] + .

[0552]

[0524] 1 H NMR (400 MHz, methanol-d 4) δ 8.04 (d, J = 8.1 Hz, 1H), 7.91 (dd, J = 8.8, 6.1 Hz, 1H), 7.55 - 7.33 (m, 3H), 5.50 (d, J = 52 Hz, 1H), 5.16 (m, 1H), 4.68 - 4.51 (m, 4H), 4.29 (m, 1H), 3.98 (m, 2H), 3.80 - 3.62 (m, 3H), 3.43 - 3.32 (m, 2H), 2.60 (d, J = 9.7 Hz, 1H), 2.55 - 2.47 (m, 2H), 2.38 - 2.20 (m, 4H), 2.14 - 1.91 (m, 5H), 0.88 (dt, J = 32.8, 7.3 Hz, 3H). (1:1 major diastereomeric mixture) Compound 5: 5-ethynyl-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0553] [ka]

[0554]

[0525] LC / MS(ESI)m / z:611[M+H] + .

[0555]

[0526] 1 H NMR (400 MHz, methanol-d 4) δ 8.09 - 7.47 (m, 3H), 7.44 - 7.07 (m, 2H), 5.46 (d, J = 53.0 Hz, 1H), 5.08 (d, J = 13.7 Hz, 1H), 4.68 - 4.38 (m, 4H), 4.19 (m, 1H), 3.81 (d, J = 18.7 Hz, 2H), 3.62 (m, 3H), 3.33 (m, 1H), 3.22 (d, J = 2.5 Hz, 2H), 2.56 (m, 1H), 2.45 (m, 1H), 2.29 (m, 1H), 2.20 (d, J = 6.0 Hz, 2H), 2.08 - 1.85 (m, 5H).(1:1 major diastereomeric mixture) Compound 6: 5-fluoro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0556] [ka]

[0557]

[0527] LC / MS(ESI)m / z:605[M+H] + .

[0558]

[0528] 1 H NMR (400 MHz, methanol-d 4) δ 7.57 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.20 - 7.06 (m, 1H), 6.92 (d, J = 7.5 Hz, 1H), 5.47 (d, J = 52.1 Hz, 1H), 5.07 (m, 1H), 4.63 (m, 1H), 4.58 (m, 3H), 4.48 (m, 2H), 4.19 (m, 1H), 3.82 (m, 1H), 3.76 (m, 1H), 3.65 (m, 3H), 2.50 (m, 2H), 2.32 (m, 1H), 2.21 (m, 2H), 2.03 (m, 1H), 1.89 (m, 4H). (1:1 major diastereomeric mixture) Compound 7: 5-ethynyl-6-fluoro-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0559] [ka]

[0560]

[0529] LC / MS ESI(m / z):629[M+H] + .

[0561]

[0530] 1 HNMR (400 MHz, methanol-d 4) δ 7.88 - 7.80 (m, 1H), 7.36 - 7.28 (m, 2H), 7.28 - 7.11 (m, 1H), 5.47 (d, J = 52.9 Hz, 1H), 5.10 (d, J = 13.2 Hz, 1H), 4.67 - 4.46 (m, 4H), 4.21 (m, 1H), 3.90 - 3.54 (m, 6H), 3.47 (d, J = 4.3 Hz, 1H), 2.63 - 2.42 (m, 2H), 2.33 (m, 1H), 2.22 (m, 2H), 2.09 - 1.85 (m, 5H).(1:1 major diastereomer mixture) Compound 8: (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0562] [ka]

[0563]

[0531] LC / MS(ESI)m / z:613[M+H] + .

[0564]

[0532] 1 H NMR (400 MHz, methanol-d 4) δ 8.10 (td, J = 7.5, 6.7, 2.4 Hz, 2H), 7.71 - 7.57 (m, 2H), 7.44 (td, J = 8.9, 4.4 Hz, 1H), 5.50 (d, J = 52.5 Hz, 1H), 5.16 (d, J = 13.7 Hz, 1H), 4.72 - 4.51 (m, 4H), 4.30 (s, 1H), 4.08 - 3.92 (m, 2H), 3.92 - 3.68 (m, 3H), 3.66 - 3.55 (m, 1H), 3.46 - 3.32 (m, 2H), 2.70 - 2.45 (m, 2H), 2.36 (s, 1H), 2.25 (d, J = 9.6 Hz, 2H), 2.16 - 1.90 (m, 5H). (1:1 major diastereomeric mixture) A 1:1 diastereomeric mixture of (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene (60 mg) was purified using a ChiralPak IB, 250 x 21.2 mm (ID, 5 μm) and cooled to 37°C. 2 Mobile phase A and EtOH+0.1%NH 3 H 2Further separation with 0.1% B afforded the faster eluting diastereomer (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene (peak 1, compound 9, 26 mg, 86%) and the slower eluting diastereomer (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene (peak 2, compound 10, 25 mg, 83%). Compound 9: (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0565] [ka]

[0566]

[0534] LC / MS(ESI)m / z:613.5[M+H] + .

[0567]

[0535] 1 H NMR (400 MHz, methanol-d 4) δ 8.08 (tt, J = 6.0, 3.1 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.42 (td, J = 8.9, 5.3 Hz, 1H), 5.30 (d, J = 54.9 Hz, 1H), 5.05 (ddd, J = 13.5, 7.8, 2.2 Hz, 1H), 4.63 - 4.56 (m, 1H), 4.49 - 4.40 (m, 1H), 4.29 (dd, J = 10.5, 3.7 Hz, 1H), 4.20 (dd, J = 10.5, 7.6 Hz, 1H), 4.15 - 4.10 (m, 1H), 3.72 (m, 1H), 3.63 (d, J = 2.9 Hz, 2H), 3.29 - 3.18 (m, 4H), 3.07 - 2.97 (m, 1H), 2.39 - 2.18 (m, 2H), 2.12 (d, J = 9.6 Hz, 1H), 2.03 - 1.80 (m, 7H). Compound 10: (6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0568] [ka]

[0569]

[0536] LC / MS(ESI)m / z:613.5[M+H] + .

[0570]

[0537] 1 H NMR (400 MHz, methanol-d 4) δ 8.08 (tt, J = 6.0, 2.9 Hz, 2H), 7.66 - 7.56 (m, 2H), 7.43 (td, J = 8.9, 5.3 Hz, 1H), 5.32 (d, J = 53.8 Hz, 1H), 5.06 (ddd, J = 13.5, 6.6, 2.3 Hz, 1H), 4.61 (ddd, J = 13.2, 6.8, 2.0 Hz, 1H), 4.45 (dt, J = 13.5, 6.7 Hz, 1H), 4.35 - 4.22 (m, 2H), 4.14 (d, J = 5.8 Hz, 1H), 3.73 (d, J = 2.9 Hz, 1H), 3.68 - 3.61 (m, 2H), 3.42 - 3.32 (m, 1H), 3.24 (d, J = 21.8 Hz, 3H), 3.10 - 3.01 (m, 1H), 2.41 - 2.23 (m, 2H), 2.21 - 2.14 (m, 1H), 2.06 - 1.99 (m, 2H), 1.97 - 1.80 (m, 5H). Compound 11: (6R,9S)-2-(8-chloro-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0571] [ka]

[0572]

[0538] LC / MS(ESI)m / z:623.0[M+H] + .

[0573]

[0539] 1 H NMR (400 MHz, methanol-d 4) δ 8.14 (dd, J = 6.6, 3.2 Hz, 1H), 8.10 - 8.03 (m, 1H), 7.70 - 7.57 (m, 2H), 7.52 (td, J = 8.9, 5.3 Hz, 1H), 5.47 (d, J = 52.0 Hz, 1H), 5.11 (t, J = 14.1 Hz, 1H), 4.65 (d, J = 13.0 Hz, 1H), 4.58 - 4.45 (m, 3H), 4.22 (dd, J = 16.5, 6.5 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.77 - 3.46 (m, 4H), 3.27 (d, J = 11.3 Hz, 1H), 2.62 - 2.42 (m, 2H), 2.41 - 1.85 (m, 10H). (1:1 major diastereomeric mixture) Compound 12: (6R,9S)-2-(8-chloronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0574] [ka]

[0575]

[0540] LC / MS(ESI)m / z:605.1[M+H] + .

[0576]

[0541] 1 H NMR (400 MHz, methanol-d 4) δ 8.15 - 8.10 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.60 - 7.46 (m, 2H), 5.50 (d, J = 52.5 Hz, 1H), 5.15 (t, J = 15.1 Hz, 1H), 4.59 (tt, J = 26.3, 13.3 Hz, 4H), 4.30 (d, J = 5.0 Hz, 1H), 4.00 - 3.89 (m, 2H), 3.87 - 3.62 (m, 4H), 3.36 (d, J = 11.0 Hz, 1H), 2.67 - 2.46 (m, 2H), 2.35 (s, 1H), 2.30 - 2.21 (m, 2H), 2.14 - 1.90 (m, 5H). (1:1 major diastereomeric mixture) Compound 13: (6R,9S)-1-fluoro-2-(7-fluoro-8-methylnaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0577] [ka]

[0578]

[0542] LC / MS(ESI)m / z:603.2[M+H] + .

[0579]

[0543] 1 H NMR (400 MHz, methanol-d 4) δ 8.02 (d, J = 7.5 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.49 (dd, J = 24.8, 7.3 Hz, 1H), 7.35 (dt, J = 14.6, 7.3 Hz, 1H), 5.30 (d, J = 53.8 Hz, 1H), 5.05 (t, J = 14.5 Hz, 1H), 4.60 (d, J = 13.2 Hz, 1H), 4.53 - 4.42 (m, 1H), 4.29 (m, 1H), 4.22 (d, J = 10.5 Hz, 1H), 4.14 (d, J = 9.0 Hz, 1H), 3.72 (d, J = 5.5 Hz, 1H), 3.63 (m, 1H), 3.24 (m, 2H), 3.19 (d, J = 7.5 Hz, 2H), 3.01 (d, J = 5.4 Hz, 1H), 2.42 - 2.25 (m, 1H), 2.22 (d, J = 10.9 Hz, 1H), 2.19 - 2.12 (m, 1H), 2.05 (s, 1H), 2.03 - 1.97 (m, 2H), 1.94 (m, 3H), 1.87 (m, 2H), 1.84 (m, 2H) (1:1 major diastereomer mixture) Compound 14: (6R,9S)-2-(7,8-difluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0580] [ka]

[0581]

[0544] LC / MS(ESI)m / z:607.1[M+H] + .

[0582]

[0545] 1H NMR (400 MHz, methanol-d 4 ) δ 8.10 (d, J = 7.3 Hz, 1H), 7.94 - 7.81 (m, 1H), 7.72 - 7.46 (m, 3H), 5.50 (d, J = 59.6 Hz, 1H), 5.21 - 5.02 (m, 1H), 4.69 - 4.49 (m, 4H), 4.23 (s, 1H), 3.95 - 3.59 (m, 6H), 2.65 - 2.31 (m, 3H), 2.26 - 2.21 (m, 2H), 2.13 - 1.84 (m, 5H), 1.39 - 1.23 (m, 1H).(1:1 major diastereomer mixture) Compound 15: (6R,9S)-1-fluoro-2-(8-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0583] [ka]

[0584]

[0546] LC / MS(ESI)m / z:589.3[M+H] + .

[0585]

[0547] 1 H NMR (400 MHz, methanol-d 4) δ 8.08 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.2, 2.1 Hz, 1H), 7.67 (q, J = 7.8 Hz, 1H), 7.63 - 7.52 (m, 1H), 7.51 (dd, J = 5.6, 3.0 Hz, 1H), 7.18 (td, J = 12.3, 7.2 Hz, 1H), 5.30 (d, J = 54.0 Hz, 1H), 5.05 (dd, J = 13.6, 2.5 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 4.46 (ddd, J = 13.3, 9.6, 7.6 Hz, 1H), 4.30 (ddd, J = 10.3, 5.2, 2.5 Hz, 1H), 4.22 (dd, J = 10.5, 4.1 Hz, 1H), 4.13 (t, J = 7.0 Hz, 1H), 3.72 (d, J = 5.9 Hz, 1H), 3.63 (d, J = 5.4 Hz, 1H), 3.25 (m, 2H), 3.19 (m, 2H), 3.02 (m, 1H), 2.40 - 2.20 (m, 2H), 2.17 - 2.12 (m, 1H), 2.01 (dd, J = 13.0, 7.0 Hz, 2H), 1.90 (m, 2H), 1.88 - 1.83 (m, 2H), 1.82 (m, 1H). (1:1 major diastereomeric mixture) Compound 16: (6R,9S)-1-fluoro-2-(7-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0586] [ka]

[0587]

[0548] LC / MS(ESI)m / z:589(M+H) + .

[0588]

[0549] 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.81 (m, 2H), 7.70 (d, J = 7.1 Hz, 1H), 7.60 - 7.43 (m, 2H), 7.33 - 7.27 (m, 1H), 5.45 - 5.32 (m, 1H), 5.06 (d, J = 12.8 Hz, 1H), 4.88 - 4.74 (m, 4H), 4.57 - 4.41 (m, 3H), 4.39 - 4.19 (m, 2H), 3.90 (s, 1H), 3.81 - 3.58 (m, 3H), 3.44 - 3.22 (m, 2H), 3.18 - 3.03 (m, 1H), 2.56 - 2.28 (m, 3H), 2.17 - 2.03 (m, 3H). (1:1 major diastereomeric mixture) Compound 17: (6R,9S)-1-fluoro-12-(((2R,7As)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2-(7-methoxynaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0589] [ka]

[0590]

[0550] MS(ESI) m / z:601(M+H) + .

[0591]

[0551] 1 H NMR (400 MHz, CDCl 3) δ 7.89 - 7.83 (m, 1H), 7.80 (d, J = 9.7 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.19 - 7.14 (m, 2H), 5.34 - 5.22 (m, 1H), 5.06 (d, J = 13.3 Hz, 1H), 4.48 (d, J = 13.0 Hz, 1H), 4.31 - 4.25 (m, 2H), 4.13 (dd, J = 19.1, 8.8 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 1H), 3.59 (s, 1H), 3.32 - 3.23 (m, 2H), 3.20 - 3.12 (m, 2H), 3.02 - 2.95 (m, 1H), 2.31 - 2.17 (m, 3H), 1.98 - 1.93 (m, 2H), 1.88 - 1.84 (m, 3H), 1.82 - 1.76 (m, 3H). (1:1 major diastereomeric mixture) Compound 18: (6R,9S)-2-(3,8-difluoroisoquinolin-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0592] [ka]

[0593]

[0552] LC / MS(ESI)m / z:608.6[M+H] + .

[0594]

[0553] 1 H NMR (400 MHz, methanol-d 4) δ 7.92 (d, J = 8.2 Hz, 1H), 7.81 (dt, J = 12.9, 6.4 Hz, 1H), 7.71 (s, 1H), 7.35 - 7.25 (m, 1H), 5.50 (d, J = 52.2 Hz, 1H), 5.14 (d, J = 13.6 Hz, 1H), 4.69 - 4.53 (m, 4H), 4.28 (d, J = 5.9 Hz, 1H), 3.97 - 3.87 (m, 2H), 3.82 - 3.67 (m, 3H), 3.39 - 3.32 (m, 2H), 2.65 - 2.43 (m, 2H), 2.40 -2.32 (m, 1H), 2.29 -2.21 (m, 2H), 2.13 - 2.06 (m, 1H), 2.03 - 1.87 (m, 4H). (1:1 major diastereomeric mixture) Compound 19: (6R,9S)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0595] [ka]

[0596]

[0554] LC / MS(ESI)m / z:595.2[M+H] + .

[0597]

[0555] 1 H NMR (400 MHz, methanol-d 4) δ 8.07 (dd, J = 17.9, 8.1 Hz, 2H), 7.79 - 7.71 (m, 1H), 7.70 - 7.46 (m, 3H), 5.49 (d, J = 52.0 Hz, 1H), 5.13 (d, J = 14.4 Hz, 1H), 4.66 (dd, J = 13.3, 6.4 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.52 (dt, J = 13.6, 6.4 Hz, 2H), 4.25 (s, 1H), 3.93 (s, 1H), 3.87 (d, J = 6.1 Hz, 1H), 3.83 (s, 1H), 3.72 - 3.61 (m, 2H), 3.37 (s, 2H), 3.22 (s, 1H), 2.69 - 2.51 (m, 1H), 2.48 (d, J = 5.1 Hz, 1H), 2.35 (s, 1H), 2.24 (s, 2H), 2.03 (d, J = 9.4 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.92 (s, 1H).(1:1 major diastereomer mixture) Compound 20: 8-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-1-naphthonitrile

[0598] [ka]

[0599]

[0556] LC / MS ESI(m / z):596.3[M+1] +

[0557] 1 H NMR (400 MHz, methanol-d 4) δ 8.36 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 8.10 - 7.99 (m, 1H), 7.82 - 7.65 (m, 3H), 5.39 (d, J = 54.0 Hz, 1H), 5.10 (d, J = 13.4 Hz, 1H), 4.60 (s, 1H), 4.47 (dd, J = 18.3, 9.1 Hz, 2H), 4.37 (d, J = 11.1 Hz, 1H), 4.19 (s, 1H), 3.81 - 3.67 (m, 2H), 3.47 (s, 3H), 3.21 (d, J = 28.1 Hz, 2H), 2.51 - 2.22 (m, 3H), 2.12 (s, 2H), 2.02 - 1.81 (m, 5H). (1:1 major diastereomeric mixture) Compound 21: (6R,9S)-2-(2-cyclopropyl-3-fluorophenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0600] [ka]

[0601]

[0558] LCMS ESI(m / z):579[M+H] +

[0559] 1 HNMR (400 MHz, methanol-d 4) δ 7.39 - 7.31 (m, 1H), 7.18 (dd, J = 17.0, 7.8 Hz, 2H), 5.53 (d, J = 52.2 Hz, 1H), 5.18 (d, J = 13.4 Hz, 1H), 4.70 - 4.52 (m, 4H), 4.32 (d, J = 6.1 Hz, 1H), 4.03 (dd, J = 16.7, 5.1 Hz, 2H), 3.94 - 3.70 (m, 3H), 3.39 (d, J = 14.8 Hz, 2H), 2.70 - 2.47 (m, 2H), 2.38 (d, J = 4.4 Hz, 1H), 2.28 (td, J = 12.2, 6.6 Hz, 2H), 2.12 (d, J = 10.9 Hz, 1H), 2.01 (td, J = 13.9, 6.4 Hz, 4H), 1.84 (t, J = 5.4 Hz, 1H), 0.67 (d, J = 8.6 Hz, 2H), 0.38 (t, J = 4.9 Hz, 2H).(1:1 major diastereomer mixture) Compound 22: 2-amino-4-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)benzo[b]thiophene-3-carbonitrile

[0602] [ka]

[0603]

[0560] MS(ESI)m / z:617.4[M+H] + .

[0604]

[0561] 1 H NMR (400 MHz, methanol-d 4) δ 7.69 (dd, J = 7.9, 1.0 Hz, 1H), 7.36 (d, J = 6.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 5.47 (d, J = 51.1 Hz, 1H), 5.11 (d, J = 13.7 Hz, 1H), 4.60 (ddd, J = 18.6, 12.7, 4.4 Hz, 3H), 4.49 (dd, J = 9.2, 4.4 Hz, 2H), 4.20 (d, J = 6.7 Hz, 1H), 3.85 - 3.74 (m, 3H), 3.71 - 3.65 (m, 2H), 2.59 - 2.20 (m, 6H), 2.04 (d, J = 11.6 Hz, 1H), 1.91 (dt, J = 21.0, 6.4 Hz, 4H). (1:1 major diastereomeric mixture) Compound 23: (6R,9S)-2-(3-chloro-2-cyclopropylphenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0605] [ka]

[0606]

[0562] MS(ESI):m / z=595[M+1] + .

[0607]

[0563] 1 H NMR (400 MHz, methanol-d 4) δ 7.53 (dd, J = 6.2, 3.1 Hz, 1H), 7.38 - 7.31 (m, 2H), 5.52 (d, J = 52.5 Hz, 1H), 5.22 - 5.08 (m, 1H), 4.64 (dd, J = 13.5, 11.5 Hz, 2H), 4.58 - 4.49 (m, 2H), 4.26 (d, J = 6.9 Hz, 1H), 3.99 - 3.72 (m, 5H), 3.42 - 3.34 (m, 2H), 2.69 - 2.49 (m, 2H), 2.37 (s, 1H), 2.27 (dq, J = 12.1, 6.3 Hz, 2H), 2.17 - 1.90 (m, 6H), 0.74 (s, 2H), 0.24 - 0.10 (m, 2H). (1:1 major diastereomeric mixture) Compound 24: 3-chloro-4-cyclopropyl-5-((6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)phenol

[0608] [ka]

[0609]

[0564] LC / MS(ESI):m / z=611[M+1] + .

[0610]

[0565] 1 H NMR (400 MHz, methanol-d 4) δ 6.95 (d, J = 2.6 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 5.53 (d, J = 52.6 Hz, 1H), 5.18 (d, J = 14.2 Hz, 1H), 4.70 - 4.59 (m, 3H), 4.58 - 4.51 (m, 1H), 4.29 (d, J = 5.5 Hz, 1H), 4.01 (dd, J = 16.0, 6.1 Hz, 2H), 3.96 - 3.77 (m, 3H), 3.46 - 3.33 (m, 2H), 2.72 - 2.52 (m, 2H), 2.38 (s, 1H), 2.30 (dt, J = 10.9, 6.2 Hz, 2H), 2.15 (s, 1H), 2.08 - 1.93 (m, 4H), 1.88 - 1.79 (m, 1H), 0.64 (s, 2H), 0.11 (d, J = 5.1 Hz, 2H). (1:1 major diastereomeric mixture) Example 4 Preparation of single diastereomeric tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT2)

[0611] [ka]

[0612] Methyl (2R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate

[0613] [ka]

[0614] To a solution of methyl (2R)-5-oxopyrrolidine-2-carboxylate (88 g, 0.61 mol) in DCM (1 L) was added trimethyloxonium tetrafluoroborate (100 g, 0.67 mol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 The mixture was quenched with a solution of 100 ml of ethyl acetate at 0° C. The layers were separated. The organic layer was washed with saturated aqueous NaHCO 3 Wash with solution and brine, and add anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give methyl (2R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (69 g, 71% yield) as a yellow oil. MS ESI (m / z): 158 (M+H). + . Methyl (R)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate

[0615] [ka]

[0616] A mixture of methyl (2R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (69 g, 0.44 mol) and ethyl 2-nitroacetate (38.9 mL, 0.35 mol) was stirred at 60° C. for 18 h. The mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give methyl (R)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate (37 g, 33% yield) as a yellow oil. MS ESI (m / z): 259 (M+H). + . Ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0617] [ka]

[0618] To a solution of methyl (R)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate (32 g, 0.12 mol) in EtOH (200 mL) was added Pd / C (10 g, 10% wt). The reaction mixture was cooled to 5° C. 2 Degassed three times under atmospheric pressure and 2 The mixture was stirred under a balloon at 50° C. for 20 h and then at 80° C. for 48 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (10 g, 41% yield) as a white solid. MS ESI (m / z): 199 (M+H). + . 8-tert-Butyl 2-ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0619] [ka]

[0620] To a solution of ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (1.54 g, 7.77 mmol) in THF (20 mL) and water (5 mL) was added NaHCO 3 (2.20 g, 10.1 mmol) and Boc 2 O (2.2 g, 10.1 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc, washed with water and brine, and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give 8-tert-butyl 2-ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1.9 g, 81% yield) as a white solid. MS ESI (m / z): 299 (M+H).+ . tert-Butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0621] [ka]

[0622] LiAlH in THF (20 mL) 4 To a suspension of (1.91 g, 50.4 mmol) was added a solution of 8-tert-butyl 2-ethyl (1R,2R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1.88 g, 6.30 mmol) in THF (20 mL) dropwise at 0 °C, and the mixture was cooled to N 2 The mixture was stirred at 0° C. under atmosphere for 5 h. The reaction was quenched with water (1.9 mL), aqueous NaOH (1.9 mL, 15% wt) and water (5.7 mL) successively at 0° C. The mixture was stirred at 0° C. for 30 min and filtered. The filter cake was washed with DCM / MeOH (2×50 mL, 10 / 1). The filtrate was diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) to give tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900 mg, 59% yield) as a yellow oil.

[0623]

[0571] MS(ESI) m / z:243(M+H) + .

[0624]

[0572] 1H NMR (400 MHz, DMSO) δ 4.60 (t, J = 5.3 Hz, 1H), 3.95 (s, 2H), 3.21 - 3.17 (m, 2H), 2.73 (d, J = 10.8 Hz, 2H), 2.55 (d, J = 11.4 Hz, 1H), 1.82 - 1.51 (m, 4H), 1.43 - 1.38 (m, 9H). The following compounds can be prepared according to the procedures described in Scheme 6 from the single diastereomer INT2 and the appropriate boronic ester. Compound 25: (5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0625] [ka]

[0626]

[0574] LC / MS(ESI)m / z:595.5[M+H] + .

[0627]

[0575] 1 H NMR (400 MHz, methanol-d 4) δ 8.07 (dd, J = 17.5, 8.3 Hz, 2H), 7.78 - 7.71 (m, 1H), 7.66 (q, J = 7.6 Hz, 1H), 7.62 - 7.49 (m, 2H), 5.48 (d, J = 52.6 Hz, 1H), 5.12 (dd, J = 13.9, 2.3 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.63 - 4.56 (m, 1H), 4.50 (dt, J = 13.3, 4.9 Hz, 2H), 4.23 (s, 1H), 3.91 (s, 1H), 3.87 - 3.65 (m, 4H), 3.34 (d, J = 3.9 Hz, 2H), 3.21 (s, 1H), 2.64 - 2.43 (m, 2H), 2.34 (s, 1H), 2.25 (d, J = 6.7 Hz, 2H), 1.97 (ddd, J = 29.7, 14.4, 4.5 Hz, 5H). Compound 26: 1-(8-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-6-hydroxynaphthalen-1-yl)ethan-1-one

[0628] [ka]

[0629]

[0576] LC / MS ESI(m / z):629[M+H] + .

[0630]

[0577] 1 H NMR (400 MHz, methanol-d 4) δ 8.04 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 5.44 (d, J = 52.8 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.08 (s, 1H), 3.80 (s, 1H), 3.74 (d, J = 11.5 Hz, 1H), 3.65 (d, J = 2.5 Hz, 1H), 3.57 (d, J = 15.0 Hz, 3H), 3.34 (s, 2H), 3.30 (s, 4H), 2.54 (d, J = 7.3 Hz, 2H), 2.46 - 2.40 (m, 1H), 2.30 - 2.23 (m, 1H), 2.16 (dd, J = 11.1, 6.2 Hz, 2H), 2.05 - 1.87 (m, 5H). Compound 27: 5-chloro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0631] [ka]

[0632]

[0578] LC / MS(ESI)m / z:621.4[M+H] + .

[0633]

[0579] 1 H NMR (400 MHz, methanol-d 4) δ 7.80 - 7.69 (m, 1H), 7.40 - 7.30 (m, 3H), 7.15 (dd, J = 34.3, 2.5 Hz, 1H), 5.50 (d, J = 52.1 Hz, 1H), 5.20 - 5.08 (m, 1H), 4.70 - 4.44 (m, 5H), 4.30 - 4.20 (m, 1H), 3.98 - 3.67 (m, 5H), 3.36 (s, 1H), 2.66 - 2.22 (m, 5H), 2.12 - 1.88 (m, 5H). Compound 28: 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0634] [ka]

[0635]

[0580] LC / MS(ESI)m / z:633.5[M+H] + .

[0636]

[0581] 1 H NMR (400 MHz, methanol-d 4) δ 7.69 - 7.63 (m, 1H), 7.25 (ddd, J = 14.6, 7.0, 3.9 Hz, 2H), 7.04 (dd, J = 38.2, 2.5 Hz, 1H), 5.45 (d, J = 52.6 Hz, 1H), 5.09 (dd, J = 18.8, 14.6 Hz, 1H), 4.63 (dd, J = 12.3, 6.0 Hz, 1H), 4.56 - 4.43 (m, 3H), 4.19 (dd, J = 15.1, 7.0 Hz, 1H), 3.83 (d, J = 5.8 Hz, 1H), 3.79 - 3.58 (m, 4H), 3.27 (s, 1H), 2.61 - 1.76 (m, 13H), 0.85 (dt, J = 36.9, 7.4 Hz, 3H). Compound 29: (5aS,6S,9R)-2-(1-ethynylisoquinolin-8-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0637] [ka]

[0638]

[0582] LC / MS(ESI)m / z:596[M+H] + .

[0639]

[0583] 1 H NMR (400 MHz, methanol-d 4) δ 8.50 (t, J = 5.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.00 (dd, J = 5.6, 2.9 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.77 (dd, J = 28.1, 6.6 Hz, 1H), 5.49 (d, J = 52.3 Hz, 1H), 5.15 (dd, J = 14.0, 2.1 Hz, 1H), 4.70 - 4.49 (m, 5H), 4.28 (s, 1H), 3.95 - 3.87 (m, 2H), 3.77 - 3.67 (m, 3H), 3.36 (d, J = 11.8 Hz, 2H), 2.52 (dd, J = 30.3, 15.0 Hz, 2H), 2.35 (d, J = 5.7 Hz, 1H), 2.25 (d, J = 10.7 Hz, 2H), 2.04 - 1.91 (m, 5H). Compound 30: 6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0640] [ka]

[0641]

[0584] LC / MS(ESI)m / z:605.4[M+H] + .

[0642]

[0585] 1 H NMR (400 MHz, methanol-d 4) δ 7.78 (dd, J = 9.6, 5.7 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.23 (s, 1H), 5.33 (d, J = 54.0 Hz, 1H), 5.06 (d, J = 11.4 Hz, 1H), 4.60 (s, 2H), 4.48 (dd, J = 13.3, 7.4 Hz, 1H), 4.30 (dd, J = 28.0, 10.6 Hz, 2H), 4.15 (d, J = 7.5 Hz, 1H), 3.76 - 3.72 (m, 2H), 3.68 - 3.64 (m, 3H), 3.23 (d, J = 19.1 Hz, 2H), 3.06 (d, J = 5.6 Hz, 1H), 2.28 - 2.17 (m, 2H), 2.07 - 1.79 (m, 8H). Compound 31: 5-ethynyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0643] [ka]

[0644]

[0586] LC / MS(ESI)m / z:611.5[M+H] + .

[0645]

[0587] 1 H NMR (400 MHz, methanol-d 4) δ 8.39 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.42 - 7.35 (m, 1H), 7.31 (s, 1H), 7.14 (dd, J = 31.9, 2.5 Hz, 1H), 5.47 (d, J = 52.3 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 4.64 - 4.45 (m, 5H), 4.20 (s, 1H), 3.74 (dd, J = 61.3, 20.6 Hz, 5H), 3.48 (s, 1H), 3.18 (d, J = 37.4 Hz, 1H), 2.63 - 2.42 (m, 2H), 2.33 (s, 1H), 2.22 (s, 2H), 1.94 (dd, J = 34.4, 22.0 Hz, 5H). Compound 32: (5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0646] [ka]

[0647]

[0588] LC / MS(ESI)m / z:587.4[M+H] + .

[0648]

[0589] 1 H NMR (400 MHz, methanol-d 4) δ 8.08 (tt, J = 6.0, 2.9 Hz, 2H), 7.65 - 7.55 (m, 2H), 7.42 (td, J = 9.0, 5.1 Hz, 1H), 5.18 (d, J = 55.5 Hz, 1H), 5.09 - 5.01 (m, 1H), 4.60 (ddd, J = 13.3, 7.0, 2.1 Hz, 1H), 4.50 (dd, J = 5.2, 2.4 Hz, 2H), 4.48 - 4.41 (m, 1H), 4.13 (d, J = 7.3 Hz, 1H), 3.72 (s, 1H), 3.66 - 3.61 (m, 1H), 3.57 - 3.43 (m, 2H), 3.24 (t, J = 12.1 Hz, 1H), 3.16 - 3.11 (m, 1H), 2.72 - 2.60 (m, 1H), 2.55 (s, 3H), 2.31 (d, J = 18.4 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.96 - 1.81 (m, 4H). Compound 36: (5aS,6R,9S)-2-(3-chloro-2-cyclopropyl-5-fluorophenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0649] [ka]

[0650]

[0590] LC / MS(ESI)m / z:613(M+H) + .

[0651]

[0591] 1 H NMR (400 MHz, CDCl 3) δ 7.05 - 7.01 (m, 1H), 6.98 - 6.96 (m, 1H), 5.22 - 5.08 (m, 2H), 4.88 (dd, J = 13.3, 2.1 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.17 - 4.01 (m, 4H), 3.95 (d, J = 7.6 Hz, 1H), 3.62 (s, 1H), 3.45 (s, 1H), 3.24 - 2.99 (m, 5H), 2.87 - 2.86 (m, 1H), 2.22 - 2.01 (m, 5H), 1.17 - 1.10 (m, 7H). Compound 37: (7a-((((5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate (trans mixture)

[0652] [ka]

[0653]

[0592] LC / MS(ESI)m / z:696(M+H) + .

[0654]

[0593] 1 H NMR (400 MHz, CDCl 3) δ 7.93 - 7.88 (m, 2H), 7.56 - 7.53 (m, 2H), 7.33 - 7.29 (m, 1H), 5.08 - 4.98 (m, 1H), 4.47 - 4.44 (m, 1H), 4.35 - 4.24 (m, 5H), 4.13 - 4.05 (m, 1H), 3.78 (s, 1H), 3.56 - 3.53 (m, 2H), 3.20 (t, J = 12.5 Hz, 1H), 3.07 - 2.73 (m, 9H), 2.28 - 2.23 (m, 2H), 1.85 - 1.79 (m, 10H). Compound 38: (7a-((((5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate (cis mixture)

[0655] [ka]

[0656]

[0594] LC / MS(ESI)m / z:696(M+H) + .

[0657]

[0595] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 - 7.88 (m, 2H), 7.62 - 7.55 (m, 2H), 7.33 - 7.28 (m, 1H), 5.17 - 5.08 (m, 1H), 4.63 - 4.34 (m, 5H), 4.18 - 4.01 (m, 4H), 3.64 - 3.40 (m, 1H), 3.32 - 3.03 (m, 4H), 2.90 (s, 6H), 2.42 - 2.13 (m, 5H), 1.95 - 1.54 (m, 7H). Compound 39: (5aS,6R,9S)-2-(3-chloro-2-cyclopropyl-4-fluorophenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0658] [ka]

[0659]

[0596] LC / MS(ESI)m / z:613(M+H) + .

[0660]

[0597] 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 5.28 (d, J = 53.0 Hz, 1H), 5.00 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.28 - 4.15 (m, 3H), 4.06 (d, J = 7.1 Hz, 1H), 3.74 - 3.58 (m, 2H), 3.32 - 3.10 (m, 4H), 3.02-2.96 (m, 1H), 2.31 - 2.19 (m, 5H), 1.92 - 1.81 (m, 7H), 1.09 - 1.06 (m, 2H), 0.76 - 0.74 (m, 2H). Compound 40: (5aS)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0661] [ka]

[0662]

[0598] LC / MS(ESI)(m / z):625.8(M+H) + .

[0663]

[0599] 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 - 7.95 (m, 2H), 7.59 - 7.54 (m, 2H), 7.34 - 7.28 (m, 1H), 5.08 - 5.02 (m, 1H), 4.53 - 4.48 (m, 3H), 4.31 - 4.29 (m, 1H), 4.17 - 4.12 (m, 1H), 3.82 (s, 1H), 3.71 - 3.68 (m, 5H), 3.28 - 3.26 (m, 1H), 2.98 (d, J = 19.8 Hz, 1H), 2.55 - 2.48 (m, 6H), 1.96 - 1.83 (m, 4H), 0.73 (s, 0.51 (s, 2H). Compound 41: (5aS)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((R)-2-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0664] [ka]

[0665]

[0600] LC / MS(ESI)m / z:639(M+H) + .

[0666]

[0601] 1 H NMR (400 MHz, CDCl 3) δ 7.95 - 7.92 (m, 2H), 7.66 - 7.51 (m, 2H), 7.35 - 7.29 (m, 1H), 5.04 - 4.99 (m, 1H), 4.52 - 4.35 (m, 3H), 4.32 - 4.22 (m, 1H), 4.13 - 4.04 (m, 1H), 3.81 - 3.78 (m, 2H), 3.67 - 3.60 (m, 3H), 3.24 - 3.18 (m, 1H), 2.98 - 2.84 (m, 3H), 2.42 - 2.31 (m, 2H), 1.93 - 1.72 (m, 6H), 1.14 - 1.09 (m, 3H), 0.73 - 0.70 (s, 2H), 0.48 - 0.45 (s, 2H). Compound 42: (5aS)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0667] [ka]

[0668]

[0602] LC / MS(ESI)m / z:639(M+H) + .

[0669]

[0603] 1 H NMR (400 MHz, CDCl 3) δ 7.94 - 7.89 (m, 2H), 7.67 - 7.55 (m, 2H), 7.34 - 7.29 (m, 1H), 5.07 - 4.99 (m, 1H), 4.73 - 4.45 (m, 3H), 4.26 - 4.06 (m, 3H), 3.76 - 3.74 (m, 2H), 3.63 - 3.60 (m, 3H), 3.35 (d, J = 12.7 Hz, 1H), 3.23 - 3.19 (m, 2H), 3.04 - 2.90 (m, 2H), 2.40 (s, 1H), 2.26 - 2.18 (m, 1H), 1.90 - 1.78 (m, 4H), 0.97 - 0.90 (m, 3H), 0.75 - 0.61 (m, 2H), 0.56 - 0.36 (m, 2H). Compound 46: (5aS,6R,9S)-12-((1-((4-oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0670] [ka]

[0671]

[0604] LC / MS(ESI)m / z:651(M+H) + .

[0672]

[0605] 1 H NMR (400 MHz, CDCl 3) δ 7.88 - 7.82 (m, 2H), 7.59 - 7.45 (m, 2H), 7.27 - 7.22 (m, 1H), 4.93 (t, J = 12.2 Hz, 1H), 4.45 - 4.35 (m, 2H), 4.32 - 4.30 (m, 1H), 4.29 - 4.26 (m, 1H), 4.10 - 3.99 (m, 1H), 3.75 - 3.68 (m, 3H), 3.58 (s, 1H), 3.17 (t, J = 13.5 Hz, 1H), 2.95 - 2.91 (m, 1H), 2.60 - 2.45 (m, 7H), 1.86 - 1.82 (m, 3H), 0.69 - 0.66 (m, 4H), 0.56 - 0.54 (m, 2H), 0.45 - 0.43 (m, 2H). Compound 47: (7a-((((5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methylmorpholine-4-carboxylate

[0673] [ka]

[0674]

[0606] LC / MS(ESI)m / z:738(M+H) + .

[0675]

[0607] 1 H NMR (400 MHz, CDCl 3) δ 7.97 - 7.87 (m, 2H), 7.66 - 7.50 (m, 2H), 7.34 - 7.27 (m, 1H), 5.03 (dd, J = 11.9, 7.9 Hz, 1H), 4.52 - 4.35 (m, 2H), 4.31 - 4.14 (m, 4H), 4.08 (dd, J = 18.1, 7.3 Hz, 1H), 3.75 - 3.59 (m, 6H), 3.49 - 3.47 (m, 5H), 3.17 (dd, J = 20.1, 9.6 Hz, 1H), 2.96 - 2.91 (m, 2H), 2.74 (dd, J = 16.2, 8.3 Hz, 1H), 2.26 - 2.24 (m, 1H), 2.02 - 1.75 (m, 10H), 1.58 - 1.51 (m, 1H). Compound 48: (7a-((((5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol

[0676] [ka]

[0677]

[0608] LC / MS(ESI)m / z:625(M+H) + .

[0678]

[0609] 1 H NMR (400 MHz, CDCl 3) δ 7.97 - 7.89 (m, 2H), 7.57 - 7.52 (m, 2H), 7.33 - 7.26 (m, 1H), 4.98 - 4.95 (m, 1H), 4.57 - 4.49 (m, 3H), 4.30 - 4.25 (m, 3H), 4.02 - 4.01 (m, 1H), 3.93 - 3.90 (m, 2H), 3.73 - 3.70 (m, 2H), 3.41 - 3.32 (m, 1H), 3.13 - 3.07 (m, 2H), 2.49 - 2.43 (m, 2H), 1.92 - 1.78 (m, 10H). Compound 49: (5aS,6R,9S)-12-((1-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)cyclopropyl)methoxy)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0679] [ka]

[0680]

[0610] LC / MS(ESI)m / z:651(M+H) + .

[0681]

[0611] 1 H NMR (400 MHz, CD 3 OD) δ 8.12 - 8.09 (m, 2H), 7.66 - 7.59 (m, 2H), 7.47 - 7.41 (m, 1H), 5.26 - 5.21 (m, 1H), 4.87 - 4.49 (m, 6H), 4.35 - 4.22 (m, 5H), 3.86 - 3.83 (m, 2H), 3.58 - 3.50 (m, 2H), 3.31 - 3.25 (m, 2H), 2.31 - 2.03 (m, 8H), 0.96 - 0.94 (m, 2H), 0.93- 0.90 (m, 2H). Compound 50: (R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,8,10a,11,13-pentaazabenzo[4,5]cycloocta[1,2,3-de]naphthalene

[0682] [ka]

[0683]

[0612] MS(ESI) m / z:601[M+H] + .

[0684]

[0613] 1 H NMR (400 MHz, MeOD) δ 8.14 - 8.01 (m, 2H), 7.72 - 7.52 (m, 2H), 7.42 (dd, J = 16.2, 8.9 Hz, 1H), 6.31 (d, J = 4.7 Hz, 1H), 5.35 - 5.21 (m, 1H), 4.56 (d, J = 14.5 Hz, 4H), 4.45 - 4.24 (m, 3H), 3.67 (s, 1H), 3.58 (s, 2H), 3.43 (s, 2H), 3.08 (d, J = 35.6 Hz, 2H), 2.30 - 2.10 (m, 4H), 1.98 (dd, J = 34.6, 28.6 Hz, 6H). Compound 51: (6aR,7S,10R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene

[0685] [ka]

[0686]

[0614] MS(ESI) m / z:627[M+H] + . Compound 52: 5-Ethyl-6-fluoro-4-((6aR,7S,10R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol

[0687] [ka]

[0688]

[0615] MS(ESI) m / z:647[M+H] + . Compound 53: 6-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0689] [ka]

[0690]

[0616] MS(ESI) m / z:619[M+H] + .

[0691]

[0617] 1 H NMR (400 MHz, CDCl 3) δ 6.43 (s, 1H), 5.52 - 5.39 (m, 1H), 5.01 - 4.92 (m, 3H), 4.68 (d, J = 11.2 Hz, 1H), 4.53 - 4.48 (m, 2H), 4.29 - 4.24 (m, 2H), 4.01 - 3.81 (m, 4H), 3.55 -3.42 (m, 1H), 3.34 (d, J = 13.8 Hz, 1H), 3.22 - 3.20 (m, 1H), 2.69 - 2.45 (m, 5H), 2.43 (s, 3H), 2.00 - 1.90 (m, 5H). Compound 54: (5aS,6R,9S)-2-(5-(difluoromethyl)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0692] [ka]

[0693]

[0618] MS(ESI) m / z:653[M+H] + . Compound 55: (5aS,6R,9S)-2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0694] [ka]

[0695]

[0619] MS(ESI) m / z:645[M+H] + . Compound 56: (5aS,6R,9S)-2-(5-chloro-4-cyclopropylpyridin-3-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0696] [ka]

[0697]

[0620] MS(ESI) m / z:596[M+H] + . Compound 57: 5-chloro-6-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-methylpyridin-2-amine

[0698] [ka]

[0699]

[0621] MS(ESI) m / z:585[M+H] + .

[0700]

[0622] 1 H NMR (400 MHz, CDCl 3) δ 6.48 (s, 1H), 5.44 - 5.28 (m, 1H), 4.98 (d, J = 12.6 Hz, 1H), 4.62 - 4.42 (m, 3H), 4.36 (s, 2H), 4.27 -4.22 (m, 1H), 4.13 - 4.10 (m, 1H), 3.80 (s, 1H), 3.65 (s, 1H), 3.54 - 3.44 (m, 2H), 3.36 - 3.28 (m, 1H), 3.20 (d, J = 13.1 Hz, 1H), 3.11 - 3.05 (m, 1H), 2.46 - 2.36 (m, 2H), 2.33 (s, 3H), 2.28 - 2.22 (m, 1H), 2.06 - 2.04 (m, 3H), 1.90 - 1.82 (m, 4H). Compound 58: 5-(difluoromethyl)-6-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-methylpyridin-2-amine

[0701] [ka]

[0702]

[0623] MS(ESI) m / z:601[M+H] + . Compound 71: 6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-methylnaphthalen-2-ol

[0703] [ka]

[0704]

[0624] MS(ESI) m / z:619[M+H] + . Compound 72: 5-chloro-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0705] [ka]

[0706]

[0625] MS(ESI) m / z:639[M+H] + . Compound 73: 5,6-difluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0707] [ka]

[0708]

[0626] MS(ESI) m / z:623[M+H] + .

[0709] Example 5 Preparation of (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide (compound 33)

[0710] [ka]

[0711] tert-Butyl (5aS,6R,9S)-12-cyano-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0712] [ka]

[0713] To a mixture of tert-butyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (100 mg, 0.13 mmol) in DMSO (2 mL) was added NaCN (12.4 mg, 0.25 mmol) and the mixture was stirred at 85° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine, and diluted with anhydrous Na 2 SO 4The mixture was dried at 400 rpm and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give tert-butyl (5aS,6R,9S)-12-cyano-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (40 mg, 43% yield) as a red solid. LCMS (ESI) m / z: 737 (M+H) + . Methyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylate

[0714] [ka]

[0715]

[0628] To a solution of tert-butyl (5aS,6R,9S)-12-cyano-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (30 mg, 0.04 mmol) in MeOH (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at 70° C. for 2 h. The mixture was concentrated to dryness under reduced pressure to give methyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylate (26 mg, 95% yield) as a red solid. LCMS (ESI) m / z: 670 (M+H). + . 14-(tert-butyl)12-methyl(5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12,14-dicarboxylate

[0716] [ka]

[0717] Methyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylate (26 mg, 0.04 mmol) in THF (1 mL) and saturated aqueous NaHCO 3To the mixture of solution (1 mL) 2 O (13 mg, 0.06 mmol) was added and the mixture was stirred at 25° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. for 1 hour, filtered, and concentrated to dryness under reduced pressure to give crude 14-(tert-butyl)12-methyl(5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12,14-dicarboxylate (39 mg, 100% yield) as a yellow solid. LCMS (ESI) m / z: 770 (M+H). + . (5aS,6R,9S)-14-(tert-butoxycarbonyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylic acid

[0718] [ka]

[0719] To a mixture of 14-(tert-butyl)12-methyl(5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12,14-dicarboxylate (39 mg, 0.04 mmol) in THF (0.5 mL), MeOH (0.5 mL) and water (0.5 mL) was added LiOH. 20 (7 mg, 0.15 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give crude (5aS,6R,9S)-14-(tert-butoxycarbonyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylic acid (40 mg, 100% yield) as a yellow solid. LCMS (ESI) m / z: 756 (M+H) + . tert-Butyl (6R,9S)-12-(((R)-1-(dimethylamino)propan-2-yl)carbamoyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0720] [ka]

[0721] A mixture of crude (5aS,6R,9S)-14-(tert-butoxycarbonyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxylic acid (39 mg, 0.045 mmol), HATU (19.8 mg, 0.05 mmol), DIPEA (0.04 mL, 0.2 mmol) and [(2R)-2-aminopropyl]dimethylamine hydrochloride (7 mg, 0.05 mmol) in DMF (0.5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (5 mL), washed with water and brine, and then washed with anhydrous Na 2 SO 4The mixture was dried at 40° C. for 1 hour, filtered, and concentrated to give crude tert-butyl (5aS,6R,9S)-12-(((R)-1-(dimethylamino)propan-2-yl)carbamoyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 53.2% yield) as a yellow solid. MS(ESI) m / z: 840 (M+H) + . (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide

[0722] [ka]

[0723] To a mixture of tert-butyl (5aS,6R,9S)-12-(((R)-1-(dimethylamino)propan-2-yl)carbamoyl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 0.02 mmol) in DCM (0.3 mL) was added HCl / 1,4-dioxane (0.3 mL, 4 M) and the mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure to give (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide (15 mg, 85% yield) as a yellow solid. MS(ESI) m / z: 740 (M+H). + . (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide

[0724] [ka]

[0725] To a solution of (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide (15 mg, 0.02 mmol) in DMF (0.5 mL) was added CsF (15 mg, 0.1 mmol) and the mixture was stirred at 25° C. for 1.5 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give (5aS,6R,9S)-N-((R)-1-(dimethylamino)propan-2-yl)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-12-carboxamide (1.78 mg, 15% yield) as a red solid.

[0726]

[0634] LC / MS(ESI)m / z:584(M+H) + .

[0727]

[0635] 1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (d, J = 7.8 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.68 - 7.54 (m, 2H), 7.35 - 7.30 (m, 1H), 5.30 - 5.25 (m, 1H), 4.55 - 4.27 (m, 4H), 4.19 - 4.13 (m, 1H), 3.83 (s, 1H), 3.67 (s, 1H), 3.29 (t, J = 12.0 Hz, 1H), 2.98 - 2.93 (m, 2H), 2.47 (s, 6H), 2.02 - 1.81 (m, 5H), 1.36 (d, J = 6.4 Hz, 3H). Example 6 Preparation of (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene (compound 34)

[0728] [ka]

[0729] tert-Butyl (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0730] [ka]

[0731] To a solution of tert-butyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (50 mg, 0.06 mmol) in DMF (2 mL) was added CsF (535 mg, 3.5 mmol), CD 3OD (4 mL) was added and the reaction was stirred at room temperature for 6 h. LCMS monitored the reaction. The crude product was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give tert-butyl (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (30 mg, 73%) as a pink solid.

[0732]

[0637] LC / MS(ESI)m / z:714[M+H] + . (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene

[0733] [ka]

[0734] To a solution of tert-butyl (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (30 mg, 0.04 mmol) in DCM (5 mL) was added HCl / dioxane (3 mL) and the reaction was stirred at room temperature for 1 h. LCMS monitored the reaction. Filtration and concentration gave the crude product, which was purified by preparative HPLC to give (5aS,6R,9S)-2-(8-(ethynyl-d)-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene (4 mg, 16%) as a white solid.

[0735]

[0639] LC / MS(ESI)m / z:614[M+H] + .

[0736]

[0640] 1H NMR (400 MHz, MeOD) δ 8.08 (dq, J = 9.2, 3.1 Hz, 2H), 7.66 - 7.56 (m, 2H), 7.42 (td, J = 8.9, 5.5 Hz, 1H), 5.37 - 5.21 (m, 1H), 5.05 (ddd, J = 13.5, 7.3, 2.2 Hz, 1H), 4.62 - 4.57 (m, 1H), 4.48 - 4.40 (m, 1H), 4.27 (dd, J = 10.4, 7.5 Hz, 1H), 4.20 (dd, J = 10.4, 4.5 Hz, 1H), 4.13 (d, J = 7.0 Hz, 1H), 3.72 (d, J = 5.6 Hz, 1H), 3.65 - 3.61 (m, 1H), 3.20 (d, J = 21.4 Hz, 4H), 3.06 - 2.95 (m, 1H), 2.32 - 2.11 (m, 3H), 2.02 - 1.81 (m, 7H). Example 7 Preparation of (5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine (compound 35)

[0737] [ka]

[0738] 4-Bromo-2,6-dichloro-5-fluoronicotinic acid

[0739] [ka]

[0740] To a cold solution of 2,6-dichloro-5-fluoropyridine-3-carboxylic acid (10.0 g, 47.6 mmol) in anhydrous THF (100 mL) was added MeLi (1.3 mol / L, 76 mL) at -78 °C over 30 min, then the reaction was warmed to -20 to -30 °C and stirred for 2 h. The reaction mixture was cooled to -78 °C. Then 1,2-dibromo-1,1,2,2-tetrachloroethane (17.0 g, 52 mmol) in anhydrous THF (100 mL) was added. The reaction mixture was then stirred at 0 °C for 1.5 h. LCMS showed the reaction had gone well. The reaction solution was diluted with ice water (150 mL), the reaction was cleaned with chloroform, adjusted to PH=2 by adding 1M hydrochloric acid in water, extracted with ethyl acetate (50 mL x 3), the organic layers were combined and diluted with Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated to give 4-bromo-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (11.5 g, 83.5%) as a white solid which was not further purified for the next step. MS (ESI) m / z: 288 [M+H] + . 2,6-Dichloro-5-fluoro-4-((4-methoxybenzyl)amino)nicotinic acid

[0741] [ka]

[0742] To a flask containing 4-bromo-2,6-dichloro-5-fluoronicotinic acid (5.0 g, 17.3 mmol) was added DMF (70 mL), followed by PMBNH 2 (2.8 g, 20.7 mmol) and DIEA (8.5 mL, 51.9 mmol) were added. The mixture was stirred at 50° C. overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in (MeCN, H 2 Preparative HPLC on a 200 / 250 Hz (O / FA) column gave the title compound 2,6-dichloro-5-fluoro-4-((4-methoxybenzyl)amino)nicotinic acid (1.1 g, 18.4%). MS(ESI)m / z: 345[M+H] + . 2,6-Dichloro-4-(3-ethoxy-N-(4-methoxybenzyl)-3-oxopropanamido)-5-fluoronicotinic acid

[0743] [ka]

[0744] To a solution of 2,6-dichloro-5-fluoro-4-((4-methoxybenzyl)amino)nicotinic acid (1.2 g, 3.5 mmol) in DCM (20 mL) was added TEA (0.9 mL, 6.9 mmol) and ethyl 3-chloro-3-oxopropanoate (0.6 mL, 5.2 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo. The residue was washed with further HCl solution (1 M). The aqueous layer was back extracted with EA (3 x 15 mL). The organic layers were combined and washed with Na 2 SO 4 The mixture was dried by filtration and concentrated to give the crude compound 2,6-dichloro-4-(3-ethoxy-N-(4-methoxybenzyl)-3-oxopropanamido)-5-fluoronicotinic acid (1.4 g, 87.6%). MS(ESI) m / z: 459[M+H] + . Ethyl 5,7-dichloro-8-fluoro-1-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxylate

[0745] [ka]

[0746] A solution of 2,6-dichloro-4-(3-ethoxy-N-(4-methoxybenzyl)-3-oxopropanamido)-5-fluoronicotinic acid (1.4 g, 3.0 mmol) in DCE (20 mL) was diluted with TEA (0.8 mL, 6.1 mmol) and SOCl 2 (0.3 mL, 4.6 mmol) was added at 0° C. and the reaction was stirred at room temperature for 3 h. The reaction was diluted with DCM and saturated NaHCO3 The organic layer was separated and concentrated in vacuo. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=10:1 to give the title compound ethyl 5,7-dichloro-8-fluoro-1-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxylate (1.0 g, 74.3%). MS(ESI) m / z: 441[M+H] + . 5,7-Dichloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-1,6-naphthyridin-2(1H)-one

[0747] [ka]

[0748] To a solution of ethyl 5,7-dichloro-8-fluoro-1-(4-methoxybenzyl)-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.45 mmol) in DMSO (5 mL) was added water (0.5 mL, 27.0 mmol) and sodium chloride (316 mg, 5.45 mmol). After heating at 200° C. under microwave irradiation for 40 min, the mixture was transferred to a separatory funnel, diluted with EA and washed with water. The organic layer was separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by flash silica gel column chromatography (EA / PE 1:4) to give 5,7-dichloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-1,6-naphthyridin-2(1H)-one (50.0 mg, 29.8%) as a yellow solid. MS(ESI) m / z: 367[MH] - . tert-Butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0749] [ka]

[0750] To a flask containing tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (102 mg, 0.42 mmol) was added THF (5 mL) at 0° C., followed by NaH (16.0 mg, 0.40 mmol, 60% in oil). The mixture was stirred at room temperature for 20 min. To the mixture was added 5,7-dichloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-1,6-naphthyridin-2(1H)-one (130 mg, 0.35 mmol). The mixture was stirred at room temperature for 1 h. The reaction was diluted with saturated NH 4 The aqueous layer was back-extracted with EA (3×5 mL). The EA layers were combined and washed with Na 2 SO 4 The mixture was dried by filtration, filtered and concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=10:1 to give the title compound tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 22.2%). MS(ESI) m / z: 575[M+H] + . tert-Butyl (5aS,6S,9R)-2-chloro-1-fluoro-14-(4-methoxybenzyl)-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate

[0751] [ka]

[0752] To a solution of tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.08 mmol) in MeCN (1 mL) was added PyBOP (81 mg, 0.16 mmol) and DBU (0.06 mL, 0.39 mmol) and the reaction was stirred at 60° C. for 2 h. The reaction was concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=20:1 to give the title compound tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-14-(4-methoxybenzyl)-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (20 mg, 45.8%). MS(ESI) m / z: 557[M+H] + . (5aS,6S,9R)-2-Chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridin-13(14H)-one

[0753] [ka]

[0754] To a flask containing tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-14-(4-methoxybenzyl)-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (10 mg, 0.018 mmol) was added TFA (0.5 mL), followed by CF3 SO 3 H (1 drop) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the title compound (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridin-13(14H)-one (6 mg, 99.9%). MS(ESI) m / z: 337[M+H] + . tert-Butyl (5aS,6S,9R)-2-chloro-1-fluoro-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate

[0755] [ka]

[0756]

[0649] THF (1 mL), H 2 A solution of (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridin-13(14H)-one (6 mg, 0.018 mmol) in 2H2O (0.2 mL) was added to the reaction mixture with NaHCO. 3 (8 mg, 0.045 mmol) and Boc 2 0 (5 mg, 0.01 mmol) was added and the reaction was stirred at room temperature for 1.5 h. The reaction was diluted with EA and water. The organic layer was separated and concentrated in vacuo to give the title compound tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (7 mg, 97.6%). MS(ESI) m / z: 437[M+H] + . tert-Butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate

[0757] [ka]

[0758] To a solution of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-13-oxo-5a,6,7,8,9,10,13,14-octahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (10 mg, 0.023 mmol) in toluene (1.5 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (5 mg, 0.030 mmol) and CMBP (17 mg, 0.069 mmol) and the reaction was stirred at 110° C. for 5 h. The mixture was concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=10:1 to give the title compound tert-butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (10 mg, 75.5%). MS(ESI) m / z: 578[M+H] + . tert-Butyl (8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate

[0759] [ka]

[0760]

[0651] THF (1 mL), H 2 To a solution of tert-butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (10 mg, 0.017 mmol) in 0 (0.2 mL) ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (12 mg, 0.026 mmol), X-Phos Pd G2 (2 mg, 0.002 mmol), and K 3 PO 4 (11 mg, 0.051 mmol) 2and the reaction was stirred at 60° C. for 1 h. The reaction was diluted with EA and water. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM:MeOH=10:1 to give the title compound tert-butyl (8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2′,1′:3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (7 mg, 46.6%). MS(ESI)m / z:868[M+H] + . (8aS,9S,12R)-4-Fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine

[0761] [ka]

[0762] To a flask containing tert-butyl (8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine-15-carboxylate (7 mg, 0.008 mmol) was added DCM (1.5 mL) followed by 0.5 mL of HCl / dioxane (4 M, 0.3 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound (8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine (6 mg, 96.8%). MS(ESI)m / z:768[M+H] + . (5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine

[0763] [ka]

[0764] To a flask containing (8aS,9S,12R)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine (6 mg, 0.008 mmol) was added DMF (1 mL) followed by CsF (24 mg, 0.156 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with (MeCN, H 2 0), and preparative HPLC was performed to obtain the title compound (5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridine (1.3 mg, 27.2%).

[0765]

[0654] MS(ESI) m / z:612[M+H] + .

[0766]

[0655] 1 H NMR (400 MHz, MeOD) δ 8.14 - 8.01 (m, 2H), 7.72 - 7.52 (m, 2H), 7.42 (dd, J = 16.2, 8.9 Hz, 1H), 6.31 (d, J = 4.7 Hz, 1H), 5.35 - 5.21 (m, 1H), 4.56 (d, J = 14.5 Hz, 4H), 4.45 - 4.24 (m, 3H), 3.67 (s, 1H), 3.58 (s, 2H), 3.43 (s, 2H), 3.08 (d, J = 35.6 Hz, 2H), 2.30 - 2.10 (m, 4H), 1.98 (dd, J = 34.6, 28.6 Hz, 6H).

[0656] Compounds 59-60 can be prepared in a similar manner to compound 35, except using other appropriate aryl boronic esters and alcohols. Compound 59: 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridin-2-yl)naphthalen-2-ol

[0767] [ka]

[0768]

[0657] MS(ESI) m / z:628[M+H] + . Compound 60: 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de][1,6]naphthyridin-2-yl)naphthalen-2-ol

[0769] [ka]

[0770]

[0658] MS(ESI) m / z:632[M+H] + .

[0771] Example 8 Preparation of (5aS,6S,9R)-2-(8-chloro-7-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-2,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-1(2H)-one (compound 43)

[0772] [ka]

[0773] 5-Bromo-3-fluoro-2-methoxyisonicotinic acid

[0774] [ka]

[0775] To a solution of 5-bromo-3-fluoro-2-methoxypyridine (20 g, 97 mmol) in dry THF (200 ml) was added a solution of n-BuLi (2.5 M in hexane, 1.5 equiv.) dropwise at -78°C over 10 min and stirred at the same temperature for 30 min. After 30 min, crushed solid dry ice was added in small portions to the above solution at -78°C. The reaction mixture was then allowed to warm to room temperature over 2 h. The reaction mixture was then cooled to 0°C and neutralized with concentrated HCl. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in 5 M NaOH solution, washed with ether, the aqueous layer was cooled to 0°C and acidified to pH 5-6 with concentrated HCl. A precipitate formed. The precipitate was filtered and washed with ether to obtain 5-bromo-3-fluoro-2-methoxyisonicotinic acid (18 g, 74.16%) as a white solid.

[0776]

[0660] MS(ESI) m / z:250[M+H] + . Methyl (5-bromo-3-fluoro-2-methoxyisonicotinoyl)carbamimidothioate

[0777] [ka]

[0778] To a solution of 5-bromo-3-fluoro-2-methoxyisonicotinic acid (18 g, 72 mmol) in DCM (200 mL) (COCl) 2 (10 mL) 2 The addition was carried out under atmosphere at 0° C. and the reaction was stirred at room temperature for 3 hours. TLC showed the reaction was complete. The reaction was concentrated in vacuo to give the crude product as a red-brown oil which was used in the next step.

[0779]

[0662] H 2 To a solution of NaOH (11.5 g, 288 mmol) in 2H2O (100 mL) was added 2-methyl-2-thio-pseudourea hydrogen sulfate (13.1 g, 133.2 mmol) in batches at 0° C. and the reaction was stirred at 0° C. for 30 min. To this mixture was added a solution of the crude acyl chloride product in DCM (50 mL) at 0° C. and the reaction was stirred at room temperature for 1 h. TLC monitored the reaction and it was complete. The organic layer was separated and the aqueous layer was extracted with EA (300 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to give the title methyl (5-bromo-3-fluoro-2-methoxyisonicotinoyl)carbamimidothioate (6.4 g, 27.6%) as a white solid.

[0780]

[0663] MS(ESI) m / z:322[M+H] + .

[0781]

[0664] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H), 3.95 (s, 3H), 2.39 (s, 3H). 5-Bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4(3H)-one

[0782] [ka]

[0783] Methyl (5-bromo-3-fluoro-2-methoxyisonicotinoyl)carbamimidothioate (6.4 g, 19.8 mmol) and Cs in DMF (60 mL). 2 CO 3 (9.7 g, 29.8 mmol). The mixture was stirred at 90 °C for 3 h. LCMS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. Water was added and the aqueous layer was cooled to 0 °C and acidified to pH 3-4 with concentrated HCl. A precipitate formed. The precipitate was filtered and washed with water to give 5-bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4(3H)-one (3 g, 50%) as a white solid.

[0784]

[0666] MS(ESI) m / z:302[M+H] + .

[0785]

[0667] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.05 (s, 1H), 8.15 (s, 1H), 3.97 (s, 3H), 2.57 (s, 3H). 5-Bromo-4-chloro-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine

[0786] [ka]

[0787] DIEA (1.5 mL, 9 mmol) and POCl 3To a solution of 5-bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 1.65 mmol) in 1,2-dichloro-1,2-diphenyl-2,4-diphenyl-2,5-diaminetetraacetate (30 mL). The reaction mixture was stirred at 110° C. for 3 h. The reaction was monitored by LCMS. The mixture was concentrated to give the crude product. Saturated NaHCO 3 The EA layer was washed with Na 2 SO 4 It was dried by filtration, filtered and concentrated and used directly in the next reaction step.

[0788]

[0669] MS(ESI) m / z:320[M+H] + .

[0789]

[0670] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 4.13 (s, 3H), 2.65 (s, 3H). tert-Butyl (1S,2S,5R)-3-(5-bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0790] [ka]

[0791] To a solution of 5-bromo-4-chloro-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine (500 mg, 1.56 mmol) and tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (378 mg, 1.56 mmol) in MeCN (30 mL), the mixture was heated at 80° C. for 4 h until the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. The residue was poured into water and extracted with EtOAc (60 mL). The organic layer was concentrated to 100% by weight, and the mixture was cooled to 100° C. for 4 h. 2 SO 4The residue was purified using silica gel column chromatography eluting with PE / EtOAc 1:1 to give tert-butyl (1S,2S,5R)-3-(5-bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 48.7%) as a solid.

[0792]

[0672] MS(ESI) m / z:526[M+H] + . tert-Butyl (8aS,9S,12R)-4-methoxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0793] [ka]

[0794] tert-Butyl (1S,2S,5R)-3-(5-bromo-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.43 mmol) and Pd(OAc) in toluene (20 mL). 2 (39mg, 0.17mmol), BINAP (108mg, 0.17mmol), Cs 2 CO 3 (213 mg, 0.65 mmol) was added to the solution, and the mixture was heated to 80° C. and stirred for 12 h until the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. The residue was poured into water and extracted with EtOAc (60 mL). The organic layer was concentrated with Na 2 SO 4The residue was purified using silica gel column chromatography eluting with PE / EtOAc 1:1 to give tert-butyl (8aS,9S,12R)-4-methoxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (85 mg, 43.67%) as a solid.

[0795]

[0674] MS(ESI) m / z:446[M+H] + .

[0796]

[0675] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 4.53 (d, J = 13.9 Hz, 1H), 4.33 (dd, J = 13.7, 4.7 Hz, 2H), 4.10 (d, J = 6.9 Hz, 3H), 3.39 (d, J = 31.1 Hz, 2H), 2.98 (dd, J = 10.9, 2.1 Hz, 1H), 2.65 (s, 3H), 2.49 (t, J = 9.0 Hz, 1H), 1.98 - 1.88 (m, 2H), 1.71 (dd, J = 23.7, 16.8 Hz, 2H), 1.50 (d, J = 8.0 Hz, 9H). (8aS,9S,12R)-2-(Methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4-ol

[0797] [ka]

[0798] To a solution of tert-butyl (8aS,9S,12R)-4-methoxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (85 mg, 0.19 mmol) in MeCN (5 mL) was added TMSI (0.13 mL, 0.57 mmol) and the reaction was stirred at 0° C. for 2 h. The reaction was monitored by LCMS. Filtration and concentration gave (8aS,9S,12R)-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4-ol (60 mg, 94.9%) as a white solid.

[0799]

[0677] MS(ESI) m / z:332[M+H] + . tert-Butyl (8aS,9S,12R)-4-hydroxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0800] [ka]

[0801]

[0678] THF (8 mL) and H 2 A solution of (8aS,9S,12R)-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4-ol (60 mg, 0.18 mmol) in 2H2O (2 mL) was added to the flask. 3 (30.42 mg, 0.36 mmol), (Boc) 20 (39.5 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 3 h. LCMS showed complete consumption of starting material. The reaction was concentrated in vacuo. The crude product was chromatographed on silica gel (DCM / MeOH 10:1) to give the title compound tert-butyl (8aS,9S,12R)-4-hydroxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (60 mg, 76.8%) as a white solid.

[0802]

[0679] MS(ESI) m / z:432[M+H] + .

[0803]

[0680] 1 H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H), 6.68 (s, 1H), 4.50 (d, J = 13.7 Hz, 1H), 4.32 (dd, J = 13.6, 4.1 Hz, 2H), 3.75 - 3.70 (m, 1H), 3.67 (dd, J = 5.8, 3.5 Hz, 1H), 3.63 - 3.56 (m, 2H), 3.46 (t, J = 6.7 Hz, 1H), 3.20 (d, J = 30.2 Hz, 2H), 2.85 - 2.77 (m, 1H), 2.64 (s, 3H), 2.46 (t, J = 9.2 Hz, 1H), 1.49 (s, 9H). tert-Butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0804] [ka]

[0805] To a solution of tert-butyl (8aS,9S,12R)-4-hydroxy-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (70 mg, 0.16 mmol) in pyridine (5 mL), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (147 mg, 0.32 mmol), Cu(OAc) 2 (59 mg, 0.32 mmol) and molecular sieves 4 Å (30 mg) were added and the reaction was stirred at room temperature for 40 h. LCMS showed complete consumption of starting material. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM / MeOH (10:1) to give tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (30 mg, 24.5%) as a white solid.

[0806]

[0682] MS(ESI) m / z:756[M+H] + . tert-Butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfinyl)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0807] [ka]

[0808] To a flask containing tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (40 mg, 52.9 pmol) was added DCM (3 mL) at 0° C., followed by m-CPBA (18 mg, 106 pmol). The mixture was stirred at 0° C. for 10 min. The mixture was diluted with NaHCO 3 (aqueous). The aqueous layer was extracted with DCM (3×5 mL). The organic layers were combined and washed with Na 2 SO 4 The mixture was dried by filtration, filtered and concentrated to give the crude title compound tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfinyl)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (40 mg, 100%) as a white foam, which was used directly in the next reaction without further purification.

[0809]

[0684] MS(ESI) m / z:772[M+H] + . tert-Butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0810] [ka]

[0811] To an oven-dried flask was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (12.0 mg, 78 pmol), sodium tert-butoxide (5.0 mg, 52 pmol) and molecular sieves 4Å (30 mg), then the flask was heated to 40-50°C with a hot air gun simultaneously with a vacuum pump and then N 2 The mixture was degassed three times at 30° C. and the solid material in the flask was cooled to room temperature, followed by the addition of toluene (5 mL) and stirring at room temperature for 20 minutes and continued to cool to 0° C. To the mixture was added tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfinyl)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (40 mg, 52 pmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at this temperature for 20 minutes. The reaction was filtered and concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=15:1 to give the title compound tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 45%).

[0812]

[0686] MS(ESI) m / z:867[M+H] + . (8aS,9S,12R)-5-(7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4(5H)-one

[0813] [ka]

[0814] To a flask containing tert-butyl (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-oxo-4,5,8a,9,10,11,12,13-octahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalene-14-carboxylate (20 mg, 23 pmol) was added DCM (1 mL) followed by HCl / dioxane (4 M, 0.5 mL). The mixture was stirred at room temperature for 30 min. The mixture was concentrated to give the crude title compound (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4(5H)-one (approximately 30 mg, 100%) as a white foam, which was used directly in the next reaction step.

[0815]

[0688] MS(ESI) m / z:767[M+H] + . (5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-2,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-1(2H)-one

[0816] [ka]

[0817] To a flask containing (8aS,9S,12R)-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,5,13a,14-pentaaza-9,12-methanonaphtho[1,8-ab]heptalen-4(5H)-one (30 mg, 23 pmol, crude) was added DMF (1 mL) followed by CsF (7 mg, 46 pmol). The mixture was stirred at room temperature for 20 min. (MeCN, H 2 The mixture was purified by preparative HPLC with 1H-hexanediaminetetraacetate to give the title compound (5aS,6S,9R)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-2,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-1(2H)-one (1.4 mg, 9.5%).

[0818]

[0690] MS(ESI) m / z:611[M+H] + .

[0819]

[0691] 1H NMR (400 MHz, MeOD) δ 8.50 (s, 2H), 8.16 (s, 1H), 7.67 (d, J = 25.0 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 5.47 (s, 1H), 5.33 (d, J = 4.6 Hz, 2H), 4.76 (s, 2H), 4.58 (s, 2H), 3.68 (s, 1H), 3.67 (s, 1H), 3.66 (s, 1H), 3.63 (s, 1H), 3.48 (s, 2H), 3.13 (s, 2H), 2.18 (s, 2H), 2.14 (s, 4H), 2.02 (s, 2H), 1.96 (s, 2H).

[0692] Compounds 61-62 can be prepared in a similar manner to compound 43, except using other appropriate aryl boronic acid esters and alcohols. Compound 61: (5aS,6S,9R)-2-(8-acetyl-7-fluoronaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-2,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-1(2H)-one

[0820] [ka]

[0821]

[0693] LC / MS(ESI)m / z:629[M+H] + .

[0822]

[0694] 1H NMR (400 MHz, MeOD) δ 8.14 (d, J = 8.7 Hz, 2H), 7.69 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.07 (d, J = 20.6 Hz, 1H), 5.34 (s, 2H), 4.32 (d, J = 8.0 Hz, 2H), 3.74 (d, J = 11.1 Hz, 2H), 3.65 (d, J = 5.3 Hz, 2H), 3.48 - 3.46 (m, 2H), 3.22 (d, J = 8.7 Hz, 2H), 3.15 - 3.12 (m, 2H), 2.22 - 2.12 (m, 6H), 2.03 (d, J = 5.3 Hz, 7H). Compound 62: (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-2,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-1(2H)-one

[0823] [ka]

[0824]

[0695] MS(ESI) m / z:631[M+H] + .

[0825] Example 9 Preparation of (5aS)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (compound 44)

[0826] [ka]

[0827] 4-Bromo-2,3,5,6-tetrafluorobenzoic acid

[0828] [ka]

[0829] 1,4-Dibromo-2,3,5,6-tetrafluorobenzene (25 g, 81.2 mmol) was added to an oven-dried, single-necked, round-bottom flask containing a stir bar under a stream of Ar, and the flask was sealed with a rubber septum. Dry, freshly distilled THF (500 ml) was added to the flask via cannula. The solution was cooled to -78 °C by immersion in a dry ice-acetone bath for 10-15 min. n-Butyllithium (1.6 M solution in hexanes, 53.0 ml, 85.0 mmol) was then added slowly to the solution over 20 min. After 20 min, carbon dioxide gas was purged into the reaction mixture for 10 min, followed by the addition of excess solid dry ice to the reaction mixture. The reaction mixture was slowly warmed to 0 °C and carefully quenched with 2 M HCl. The solvent was removed on a rotary evaporator, and the product was extracted into methylene chloride. The organic phase was washed with saturated sodium thiosulfate solution, brine solution and dried using anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator to give the crude product, which was triturated with cold hexane and filtered to give pure 4-bromo-2,3,5,6-tetrafluorobenzoic acid (9.8 g, 43% yield). Methyl (4-bromo-2,3,5,6-tetrafluorobenzoyl)carbamimidothioate

[0830] [ka]

[0831] To a mixture of 4-bromo-2,3,5,6-tetrafluorobenzoic acid (3.4 g, 12.5 mmol) in DCM (50 mL) (COCl) 2 (6.35 g, 50 mmol) and DMF (0.1 mL) were dissolved in N 2 The mixture was added under atmosphere at 0° C. and the reaction was stirred at room temperature for 3 hours. TLC showed the reaction was complete. The reaction was concentrated in vacuo to give 4-bromo-2,3,5,6-tetrafluorobenzoyl chloride (3.5 g, crude) as a yellow oil, which can be used directly in the next step.

[0832] To a solution of NaOH (2.3 g, 57.5 mmol) in water (100 mL) and THF (50 mL) was added 2-methyl-2-thio-pseudourea hydrogen sulfate (3.5 g, 12.5 mmol) in batches at 0° C., and the reaction was stirred at 0° C. for 30 min. Then, a solution of 4-bromo-2,3,5,6-tetrafluorobenzoyl chloride (3.5 g, crude) in DCM (20 mL) was added at 0° C., and the reaction was stirred at room temperature for 1 h. TLC (PE:EA=3:1) showed the reaction was complete. The reaction was extracted with EA (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=3:1) to give methyl (4-bromo-2,3,5,6-tetrafluorobenzoyl)carbamimidothioate (2.5 g, yield 58%) as a yellow solid.

[0833]

[0699] LC / MS(ESI)(m / z):345 / 347[M+H] + . 7-Bromo-5,6,8-trifluoro-2-(methylthio)quinazolin-4(3H)-one

[0834] [ka]

[0835] A solution of methyl (4-bromo-2,3,5,6-tetrafluorobenzoyl)carbamimidothioate (2.45 g, 7.10 mmol) in DMF (30 mL) was stirred at 120° C. for 3 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc=3:1) to give 7-bromo-5,6,8-trifluoro-2-(methylthio)quinazolin-4(3H)-one (1.66 g, 72% yield) as a yellow solid. LC / MS(ESI)(m / z):325 / 327[M+H] + . tert-Butyl (1R,5S)-2-(((7-bromo-6,8-difluoro-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0836] [ka]

[0837] To a solution of tert-butyl (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82 mg, 0.34 mmol) in dry DMF (1 mL) was added NaH (14 mg, 0.34 mmol, 60% in mineral oil) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h and then 7-bromo-5,6,8-trifluoro-2-(methylthio)quinazolin-4(3H)-one (100 mg, 0.31 mmol) was added at 0° C. The reaction mixture was stirred at 65° C. for 2 h. LCMS showed that the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (5 mL×3). The combined organic phase was washed with brine (10 mL) and diluted with anhydrous Na 2 SO 4The residue was purified by column chromatography on silica gel (EtOAc) to give tert-butyl (1R,5S)-2-(((7-bromo-6,8-difluoro-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 47.6% yield) as a yellow solid.

[0838]

[0702] LC / MS ESI(m / z):547 / 549[M+H] + . tert-Butyl 2-bromo-1,3-difluoro-13-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate

[0839] [ka]

[0840] To a solution of tert-butyl (1R,5S)-2-(((7-bromo-6,8-difluoro-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (320 mg, 0.59 mmol) and PyBOP (371 mg, 0.7 mmol) in dry MeCN (10 mL) was added TEA (180 mg, 1.77 mmol) and the resulting mixture was stirred at 80° C. for 2 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL×2). The combined extracts were washed with anhydrous Na 2 SO 4The residue was purified using silica gel column chromatography eluting with EA / PE=1 / 1 to give tert-butyl 2-bromo-1,3-difluoro-13-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (200 mg, 71% yield) as a white solid.

[0841]

[0704] LC / MS ESI(m / z):529 / 531[M+H] + . tert-Butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate

[0842] [ka]

[0843]

[0705] Dioxane (5 mL), H 2 To a solution of tert-butyl 2-bromo-1,3-difluoro-13-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (190 mg, 0.35 mmol) in 2H2O (1 mL), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (240 mg, 0.53 mmol), Pd(PPh 3 ) 4 (42 mg, 30 pmol) and Na 2 CO 3 (115 mg, 1.07 mmol) was added and the reaction was diluted with N 2The mixture was stirred under reduced pressure at 100° C. for 5 h. The mixture was extracted with EA (3×5 mL). The EA layers were combined and washed with Na 2 SO 4 The crude material was dried by filtration, filtered and concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using PE:EA=3:1 to give the title compound tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (80 mg, 28.7%).

[0844]

[0706] MS(ESI) m / z:775[M+H] + . tert-Butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate

[0845] [ka]

[0846] To a flask containing tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (75 mg, 0.09 mmol) was added DCM (4 mL) at 0° C., followed by m-CPBA (33 mg, 0.19 mmol). The mixture was stirred at 0° C. for 20 min. The reaction was diluted with NaHCO 3The mixture was extracted with DCM (3×3 mL) and 2 SO 4 The extract was dried by filtration to give the title compound tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (78 mg, 99.8%).

[0847]

[0708] MS(ESI) m / z:807[M+H] + . tert-Butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate

[0848] [ka]

[0849] To an oven-dried flask containing [(2R,7aS)-2-fluoro-2,3,5,6,7,7a-hexahydro-1H-pyrrolidin-7a-yl]methanol (27 mg, 0.17 mmol) was added toluene (4 mL) at 0° C., followed by 4 Å MS and t-BuONa (16 mg, 0.17 mmol). The mixture was stirred at room temperature for 10 min. To the mixture was added tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (70 mg, 0.08 mmol). The mixture was stirred at room temperature for 0.5 hours. The reaction solution was diluted with saturated NH 4 The mixture was quenched with Cl solution and filtered. The aqueous layer was back-extracted with EA (3×5 mL). The EA layers were combined and washed with Na 2 SO 4 The mixture was dried by filtration, filtered and concentrated. The crude material was loaded onto a silica gel plate. The plate was developed using DCM:MeOH=10:1 to give the title compound tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (60 mg, 78.0%).

[0850]

[0710] MS(ESI) m / z:886[M+H] + . 4,6-Difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0851] [ka]

[0852] To a flask containing tert-butyl 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (55 mg, 0.06 mmol) was added DCM (3 mL) followed by HCl / dioxane (1 mL, 4M in dioxane). The mixture was stirred at room temperature for 1 h. The resulting material was concentrated under vacuum to give the title compound 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (48 mg, 98.3%).

[0853]

[0712] MS(ESI) m / z:786[M+H] + . (5aS)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0854] [ka]

[0855] To a flask containing 4,6-difluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (48 mg, 0.06 mmol) was added DMF (3 mL) followed by CsF (185 mg, 1.22 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was analyzed by preparative HPLC (column: UniHybrid 5-120 C4 150*21.2mm 5um; H 2 O(0.1%NH 4 OH) / CH 3 CN) to give the title compound 5-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,6-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (21 mg, 54.6%). LC-MS(ESI):m / z630[M+H] + . 1H NMR (400 MHz, MeOD) δ 8.12 - 8.05 (m, 2H), 7.63 (td, J = 7.7, 2.6 Hz, 1H), 7.53 (t, J = 7.0 Hz, 1H), 7.43 (td, J = 8.9, 2.5 Hz, 1H), 5.30 (d, J = 54.0 Hz, 1H), 5.07 (ddd, J = 29.7, 13.4, 2.4 Hz, 1H), 4.63 - 4.54 (m, 2H), 4.38 - 4.23 (m, 2H), 4.20 - 4.08 (m, 2H), 3.69 (s, 1H), 3.56 (d, J = 4.1 Hz, 1H), 3.29 - 3.11 (m, 4H), 3.01 (td, J = 9.6, 5.7 Hz, 1H), 2.34 - 2.10 (m, 3H), 2.04 - 1.79 (m, 7H)). The following compounds may be prepared in a similar manner to compound 44, except using other appropriate aryl boronic esters and alcohols. Compound 63: 4-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0856] [ka]

[0857]

[0715] LC / MS(ESI)m / z:650[M+H] + . Compound 64: 4-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0858] [ka]

[0859]

[0716] LC / MS(ESI)m / z:646[M+H] + . Compound 65: 4-((5aS,6S,9R)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0860] [ka]

[0861]

[0717] LC / MS(ESI)m / z:666[M+H] + . Compound 66: 4-((5aS,6S,9R)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0862] [ka]

[0863]

[0718] LC / MS(ESI)m / z:662[M+H] + . Compound 74: 4-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoro-5-methylnaphthalen-2-ol

[0864] [ka]

[0865]

[0719] LC / MS(ESI)m / z:636[M+H] + . Compound 75: 5-chloro-4-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoronaphthalen-2-ol

[0866] [ka]

[0867]

[0720] LC / MS(ESI)m / z:656[M+H] + . Compound 76: 4-((5aS,6S,9R)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5,6-difluoronaphthalen-2-ol

[0868] [ka]

[0869]

[0721] LC / MS(ESI)m / z:640[M+H] + . Compound 77: 4-((5aS,6S,9R)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoro-5-methylnaphthalen-2-ol

[0870] [ka]

[0871]

[0722] LC / MS(ESI)m / z:652[M+H] + . Compound 78: 5-chloro-4-((5aS,6S,9R)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoronaphthalen-2-ol

[0872] [ka]

[0873]

[0723] LC / MS(ESI)m / z:672[M+H] + . Compound 79: 4-((5aS,6S,9R)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5,6-difluoronaphthalen-2-ol

[0874] [ka]

[0875]

[0724] LC / MS(ESI)m / z:656[M+H] + . Compound 80: (5aS,6S,9R)-3-chloro-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0876] [ka]

[0877]

[0725] LC / MS(ESI)m / z:646[M+H] + . Compound 81: 6-((5aS,6R,9S)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0878] [ka]

[0879]

[0726] LC / MS(ESI)m / z:636[M+H] + . Compound 82: (5aS,6R,9S)-2-(5-(difluoromethyl)-3-methyl-2-(trifluoromethyl)phenyl)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0880] [ka]

[0881]

[0727] LC / MS(ESI)m / z:670[M+H] + . Compound 83: (5aS,6R,9S)-2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0882] [ka]

[0883]

[0728] LC / MS(ESI)m / z:662[M+H] + . Compound 84: (5aS,6R,9S)-2-(5-chloro-4-cyclopropylpyridin-3-yl)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0884] [ka]

[0885]

[0729] LC / MS(ESI)m / z:613[M+H] + . Compound 85: 5-chloro-6-((5aS,6R,9S)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methylpyridin-2-amine

[0886] [ka]

[0887]

[0730] LC / MS(ESI)m / z:602[M+H] + . Compound 86: 6-((5aS,6R,9S)-1,3-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-(difluoromethyl)-4-methylpyridin-2-amine

[0888] [ka]

[0889]

[0731] LC / MS(ESI)m / z:618[M+H] + . Compound 87: 6-((5aS,6R,9S)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0890] [ka]

[0891]

[0732] LC / MS(ESI)m / z:652[M+H] + . Compound 88: (5aS,6R,9S)-3-chloro-2-(5-(difluoromethyl)-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0892] [ka]

[0893]

[0733] LC / MS(ESI)m / z:686[M+H] + . Compound 89: (5aS,6R,9S)-3-chloro-2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0894] [ka]

[0895]

[0734] LC / MS(ESI)m / z:678[M+H] + . Compound 90: (5aS,6R,9S)-3-chloro-2-(5-chloro-4-cyclopropylpyridin-3-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0896] [ka]

[0897]

[0735] LC / MS(ESI)m / z:629[M+H] + . Compound 91: 5-chloro-6-((5aS,6R,9S)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methylpyridin-2-amine

[0898] [ka]

[0899]

[0736] LC / MS(ESI)m / z:618[M+H] + . Compound 92: 6-((5aS,6R,9S)-3-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-(difluoromethyl)-4-methylpyridin-2-amine

[0900] [ka]

[0901]

[0737] LC / MS(ESI)m / z:634[M+H] + . Compound 99: (5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1,3-difluoro-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0902] [ka]

[0903]

[0738] LC / MS(ESI)m / z:642[M+H] + . Compound 100: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0904] [ka]

[0905]

[0739] LC / MS(ESI)m / z:662[M+H] + . Compound 101: 6-((5aS,6R,9S)-1,3-difluoro-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0906] [ka]

[0907]

[0740] LC / MS(ESI)m / z:648[M+H] + . Compound 102: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0908] [ka]

[0909]

[0741] LC / MS(ESI)m / z:658[M+H] + . Compound 103: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0910] [ka]

[0911]

[0742] LC / MS(ESI)m / z:640[M+H] + . Compound 104: 5-chloro-4-((5aS,6R,9S)-1,3-difluoro-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoronaphthalen-2-ol

[0912] [ka]

[0913]

[0743] LC / MS(ESI)m / z:668[M+H] + . Compound 105: (5aS,6R,9S)-2-(8-ethynyl-7-fluoronaphthalen-1-yl)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0914] [ka]

[0915]

[0744] LC / MS(ESI)m / z:656[M+H] + . Compound 106: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0916] [ka]

[0917]

[0745] LC / MS(ESI)m / z:676[M+H] + . Compound 107: 6-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0918] [ka]

[0919]

[0746] LC / MS(ESI)m / z:662[M+H] + . Compound 108: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0920] [ka]

[0921]

[0747] LC / MS(ESI)m / z:672[M+H] + . Compound 109: 4-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethynylnaphthalen-2-ol

[0922] [ka]

[0923]

[0748] LC / MS(ESI)m / z:654[M+H] + . Compound 110: 5-chloro-4-((5aS,6R,9S)-1,3-difluoro-13-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-6-fluoronaphthalen-2-ol

[0924] [ka]

[0925]

[0749] LC / MS(ESI)m / z:682[M+H] + . Compound 111: 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0926] [ka]

[0927]

[0750] LC / MS(ESI)m / z:629.4[M+H] + .

[0928]

[0751] 1 H NMR (400 MHz, methanol-d 4) δ 8.35 (s, 2H), 7.87 - 7.82 (m, 1H), 7.35 - 7.29 (m, 2H), 7.20 (dd, J = 30.3, 2.5 Hz, 1H), 5.49 (d, J = 52.6 Hz, 1H), 5.12 (dd, J = 13.9, 2.2 Hz, 1H), 4.67 - 4.57 (m, 2H), 4.54 - 4.47 (m, 2H), 4.23 (s, 1H), 3.90 (s, 1H), 3.87 - 3.67 (m, 4H), 3.51 (d, J = 34.9 Hz, 1H), 3.34 (s, 2H), 2.63 - 2.47 (m, 2H), 2.35 (s, 1H), 2.26 (d, J = 6.7 Hz, 2H), 2.09 - 1.87 (m, 5H). Example 10 Preparation of (decanoyloxy)methyl (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (compound 45)

[0929] [ka]

[0930] To a solution of 5-ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (100 mg, 0.16 mmol) in DMF (1 mL) was added (((4-nitrophenoxy)carbonyl)oxy)methyl decanoate (46 mg, 0.13 mmol) and NaHCO 3 (28 mg, 0.26 mmol) was added at 0° C. and the mixture was stirred at room temperature for 6 h. The mixture was filtered. The filtrate was purified by preparative HPLC (C18, H with 0.1% formic acid). 2 Purification by elution with 30-90% acetonitrile in 200 afforded (decanoyloxy)methyl (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (8.1 mg, 6% yield) as a white solid.

[0931]

[0753] LC / MS(ESI)m / z:861(M+H) + .

[0932]

[0754] 1 H NMR (400 MHz, CDCl 3) 7.40 - 7.16 (m, 2H), 7.07 - 6.87 (m, 2H), 6.53 - 6.48 (m, 1H), 5.63 (s, 2H), 5.41 - 5.16 (m, 1H), 5.05 - 4.91 (m, 1H), 4.53 - 4.41 (m, 1H), 4.24 - 4.11 (m, 3H), 4.02 - 3.83 (m, 2H), 3.59 - 3.38 (m, 2H), 3.31 - 3.09 (m, 3H), 3.03 - 2.84 (m, 3H), 2.37 - 2.16 (m, 5H), 2.08 - 2.04 (m, 2H), 1.95 - 1.87 (m, 3H), 1.64 - 1.61 (m, 2H), 1.48 - 1.45 (m, 2H), 1.10 (s, 12H), 0.73 - 0.70 (m, 3H), 0.67 - 0.63 (m, 3H). The following compounds may be prepared in a similar manner to compound 45, except using other appropriate aryl boronic esters and alcohols. Compound 67: 1-(pivaloyloxy)ethyl (6R,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0933] [ka]

[0934]

[0756] LC / MS(ESI)m / z:801(M+H) + . Compound 68: 1-acetoxyethyl (6R,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0935] [ka]

[0936]

[0757] LC / MS(ESI)m / z:759(M+H) + . Compound 69: 1-(propionyloxy)ethyl (6R,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0937] [ka]

[0938]

[0758] LC / MS(ESI)m / z:773(M+H) + . Compound 70: 1-(isobutyryloxy)ethyl (6R,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0939] [ka]

[0940]

[0759] LC / MS(ESI)m / z:787(M+H) + .

[0941] Example 11 Preparation of (9S,12R)-3-(8-chloro-7-fluoronaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one (Compound 93 and Compound 94)

[0942] [ka]

[0943] Ethyl (1S,5R)-8-(4-methoxybenzyl)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0944] [ka]

[0945] To a solution of ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (4 g, 20 mmol) in DCE (100 mL) was added sodium bis(acetyloxy)boranyl acetate (6.38 g, 30 mmol), molecular sieves 4 Å (1 g, 1.0 mmol), and 4-methoxybenzaldehyde (3.2 mL, 26 mmol), AcOH (1.2 mL, 20 mmol) and the reaction was stirred at room temperature for 18 h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in chloroform (1:10) to give the title compound ethyl (1S,5R)-8-(4-methoxybenzyl)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (4 g, 62%) as a white solid.

[0946]

[0761] MS(ESI) m / z:319[M+H] + . Ethyl (1S,5R)-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0947] [ka]

[0948] To a solution of ethyl (1S,5R)-8-(4-methoxybenzyl)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (4 g, 12.5 mmol) in THF (30 mL) was added borane-methylsulfide complex (31.4 mL, 2.5 M in dimethylsulfide) and the reaction was stirred at room temperature for 18 h. LCMS showed the reaction was complete, then MeOH (5 mL) was added and refluxed at 60° C. for 18 h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in chloroform (1:10) to give the title compound ethyl (1S,5R)-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (1.3 g, 34%) as a yellow oil.

[0949]

[0763] MS(ESI) m / z:305[M+H] + . Ethyl 3-aminoisonicotinate

[0950] [ka]

[0951] To an oven-dried flask containing 3-aminoisonicotinic acid (30 g, 217 mmol) was added EtOH (300 mL), followed by H 2 SO 4 (34 mL, 651 mmol) was added. The mixture was stirred at 90° C. for 24 h. The mixture was concentrated in vacuo. The reaction was diluted with EA and saturated Na 2 CO 3 The solution was diluted to PH=8. The organic layer was separated and washed with more saturated NaCl solution. The organic layer was collected, concentrated in vacuo and dried to give the title compound ethyl 3-aminoisonicotinate (30 g, 83%).

[0952]

[0765] MS(ESI) m / z:167[M+H] + . Ethyl 2,4-dihydroxy-1,7-naphthyridine-3-carboxylate

[0953] [ka]

[0954] To a solution of ethyl 3-aminoisonicotinate (20 g, 120 mmol) in EtOH (300 mL) was added EtONa (12 g, 180 mmol) and diethyl malonate (29.9 g, 180 mmol) and the reaction was stirred at 90° C. for 24 h. The reaction was concentrated under reduced pressure, diluted with water and adjusted to pH=5 with 1N HCl. The mixture was filtered, the filter cake was washed with water and concentrated under reduced pressure to give the title compound ethyl 2,4-dihydroxy-1,7-naphthyridine-3-carboxylate (16 g, 56.7%).

[0955]

[0767] MS(ESI) m / z:235[M+H] + . 1,7-Naphthyridine-2,4-diol

[0956] [ka]

[0957]

[0768] A flask containing ethyl 2,4-dihydroxy-1,7-naphthyridine-3-carboxylate (15 g, 64 mmol) was charged with H 2 O (50 mL) was added, followed by HCl (150 mL). The mixture was stirred at 70° C. overnight. The resulting mixture was concentrated in vacuo to give the title compound 1,7-naphthyridine-2,4-diol (9.0 g, 86.6%).

[0958]

[0769] MS(ESI) m / z:163[M+H] + . 3-Nitro-1,7-naphthyridine-2,4-diol

[0959] [ka]

[0960]

[0770] A flask containing 1,7-naphthyridine-2,4-diol (10 g, 61 mmol) was heated to 0 °C with H 2 SO 4 (100 mL) was added, followed by HNO 3 (15 mL) was added. The mixture was stirred at 60° C. for 30 min. The reaction mixture was poured onto crushed ice and Na 2 CO 3 The pH was adjusted to 6 with hexanes, and the solid was filtered to give the title compound 3-nitro-1,7-naphthyridine-2,4-diol (6.0 g, 46.9%).

[0961]

[0771] MS(ESI) m / z:208[M+H] + . 4-Chloro-3-nitro-1,7-naphthyridin-2(1H)-one

[0962] [ka]

[0963] To a solution of DMF (0.48 mL, 6.27 mmol) in MeCN (15 mL) was added (COCl) 2 (0.61 mL, 7.24 mmol) was added at 0° C. After 10 min, 3-nitro-1,7-naphthyridine-2,4-diol (1.0 g, 4.82 mmol) was added and the reaction was stirred at 0° C. for 1.5 h. The reaction was quenched with water and the acetonitrile was evaporated under vacuum. The mixture was filtered and washed with water. The solid was collected and concentrated in vacuo to give the title compound 4-chloro-3-nitro-1,7-naphthyridine-2-ol (900 mg, 82.6%).

[0964]

[0773] MS(ESI) m / z:226[M+H] + . Ethyl (1R,5S)-8-(4-methoxybenzyl)-3-(3-nitro-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0965] [ka]

[0966] To a solution of 4-chloro-3-nitro-1,7-naphthyridin-2(1H)-one (718 mg, 3.19 mmol) in MeCN (25 mL) was added NaHCO 3 (803 mg, 9.56 mmol), ethyl 8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (970 mg, 3.19 mmol) were added and the reaction was stirred at 80° C. for 3 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in chloroform (1:15) to give the title compound ethyl (1R,5S)-8-(4-methoxybenzyl)-3-(3-nitro-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (375 mg, 23.8%) as a yellow solid.

[0967]

[0775] MS(ESI) m / z:494[M+H] + . Ethyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-nitro-1,7-naphthyridin-4-yl)-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0968] [ka]

[0969] To a solution of ethyl (1R,5S)-8-(4-methoxybenzyl)-3-(3-nitro-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (375 mg, 0.76 mmol) in toluene (10 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (181 mg, 1.14 mmol), and 2-(tributyl-15-phosphanylidene)acetonitrile (550 mg, 2.28 mmol) and the reaction was stirred at 110° C. for 3 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with methanol in chloroform (1:25) to give the title compound ethyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-nitro-1,7-naphthyridin-4-yl)-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (400 mg, 82.9%).

[0970]

[0777] MS(ESI) m / z:635[M+H] + . (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one

[0971] [ka]

[0972] EtOH (5 mL), H 2To a solution of ethyl (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-3-nitro-1,7-naphthyridin-4-yl)-8-(4-methoxybenzyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (200 mg, 0.31 mmol) in 2H2O (3 mL) was added Fe (105 mg, 1.89 mmol) and NH 4 Cl (100 mg, 1.89 mmol) was added and the reaction was stirred at 60° C. for 3 h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM:MeOH=10:1 to give the title compound (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1′,2′:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one (100 mg, 56.8%).

[0973]

[0779] MS(ESI) m / z:559[M+H] + . (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one

[0974] [ka]

[0975] A solution of (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one (100 mg, 0.17 mmol) in DMF (4 mL) was diluted with Cs 2 CO 3 (69 mg, 0.21 mmol) and CH 3 I (4.4 mL, 0.04 mol / L in THF) was added and the reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM:MeOH=10:1 to give the title compound (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one (15 mg, 14.6%).

[0976]

[0781] MS(ESI) m / z:573[M+H] + . (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0977] [ka]

[0978] A solution of (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-8a,9,10,11,12,13-hexahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(7H)-one (25 mg, 0.044 mmol) in AcOH (2 mL) was diluted with NaBH 4 (7 mg, 0.218 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water and the pH was adjusted to 10 with solid NaHCO 3 The pH was adjusted to about 7 with EA. The reaction mixture was extracted with EA (3×3 mL). The combined organic layer was washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the desired product as a yellow solid (25 mg, yield: 99.3%), which was used in the next step without further purification. MS(ESI) m / z: 577[M+H] + . (9S,12R)-3-(8-chloro-7-fluoronaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0979] [ka]

[0980]

[0783] A solution of (9S,12R)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one (25 mg, 0.043 mmol) in toluene (1.5 mL) was diluted with 8-chloro-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (28 mg, 0.087 mmol), RuPhos Pd G 2 (3 mg, 0.004 mmol), RuPhos (2 mg, 0.004 mmol) and Cs 2 CO 3 (42 mg, 0.13 mmol) was added and the reaction was stirred at 110° C. overnight. The reaction was concentrated in vacuo. The residue was purified by preparative TLC eluting with DCM / MeOH=10:1 to give the title compound (9S,12R)-3-(8-chloro-7-fluoronaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-15-(4-methoxybenzyl)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1′,2′:4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one (10 mg, 30.5%).

[0981] Chiral separation of this product (10.0 mg) was performed using chiral-HPLC with the following conditions: Instrument and column: SHIMADZU PREP SOLUTION SFC Column: ChiralPak IH, 250×21.2 mm ID, 5 μm; Mobile phase: CO 2 A and MEOH + 0.1% NH 3 H 2 0; B; gradient: B 40%; flow rate: 40 mL / min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm; cycle time: 8.0 min; elution time: 2.2 h) to give the two desired products as white solids.

[0982]

[0785] P1: (Retention time: 4.241 minutes). LC-MS (ESI): m / z 755 [M+H] + 。

[0983]

[0786] 1 H NMR (400 MHz, MeOD) δ 7.89 - 7.82 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.37 (ddd, J = 19.8, 12.5, 6.0 Hz, 4H), 6.89 (d, J = 7.3 Hz, 2H), 5.32 (d, J = 15.1 Hz, 1H), 5.17 (s, 1H), 4.25 - 4.13 (m, 2H), 4.07 (d, J = 10.3 Hz, 1H), 3.83 (s, 2H), 3.78 (d, J = 2.2 Hz, 3H), 3.74 - 3.68 (m, 1H), 3.61 - 3.43 (m, 6H), 3.36 (s, 2H), 3.23 - 2.94 (m, 7H), 2.28 - 2.03 (m, 7H), 1.96 (s, 3H).

[0787] P2: (Retention time: 5.621 minutes). LC-MS (ESI): m / z 755 [M+H] + 。

[0984]

[0788] 1H NMR (400 MHz, MeOD) δ 7.89 - 7.83 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.41 - 7.30 (m, 4H), 6.93 - 6.86 (m, 2H), 5.34 - 5.28 (m, 1H), 5.16 (s, 1H), 4.20 (dd, J = 14.3, 9.1 Hz, 1H), 4.05 (dd, J = 21.1, 8.0 Hz, 2H), 3.85 (t, J = 16.4 Hz, 2H), 3.78 (d, J = 2.5 Hz, 3H), 3.71 (d, J = 16.1 Hz, 1H), 3.53 (dd, J = 30.0, 8.4 Hz, 6H), 3.37 (s, 2H), 3.27 - 2.88 (m, 7H), 2.26 - 1.88 (m, 10H). (9S,12R)-3-(8-chloro-7-fluoronaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0985] [ka]

[0986]

[0789] LC-MS(ESI):m / z635[M+H] + . Compound 95: (9S,12R)-3-(8-ethynyl-7-fluoronaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0987] [ka]

[0988]

[0790] LC-MS(ESI):m / z625[M+H] + . Compound 96: (9S,12R)-3-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0989] [ka]

[0990]

[0791] LC-MS(ESI):m / z645[M+H] + . Compound 97: (9S,12R)-3-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0991] [ka]

[0992]

[0792] LC-MS(ESI):m / z651[M+H] + . Compound 98: (9S,12R)-3-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-methyl-2,3,4,7,8a,9,10,11,12,13-decahydro-9,12-epiminoazepino[1',2':4,5]pyrazino[2,3-c][1,7]naphthyridin-8(1H)-one

[0993] [ka]

[0994]

[0793] LC-MS(ESI):m / z635[M+H] + . Biological Assays

[0794] The following assays were used to measure the efficacy of compounds of the present disclosure.

[0995]

[0795] Phospho-ERK1 / 2 Assay:

[0796] Using standard tissue culture procedures, PNAC-1 / HPAC cells are grown in T75 flasks in DMEM and 10% fetal calf serum (FCS; Gibco®) until approximately 80% confluency is achieved. On day 1, 6000 cells / well are seeded into 384-well plates and incubated at 37°C, 5% CO 2 Diluted compounds are added by Echo550, final DMSO is 0.5%, and cells are incubated at 37°C, 5% CO 2Incubate at 4°C for 3 hours. Then remove medium and fix cells with 3.7% formaldehyde in PBS (PFA) by Apricot. Wash once with PBS. Permeabilize cells with cold 100% methanol and repeat wash once with PBS. Add Li-Cor blocking buffer to each well and incubate at room temperature for 1.5 hours. Remove blocking buffer and add primary antibody mixture (rabbit anti-pERK, mouse anti-GAPDH). Incubate overnight at 4°C. On the second day, wash a total of 3 times with PBST (Tween-20 in PBS) and then add secondary antibody mixture (goat anti-rabbit 800CW (1:800 dilution in combined solution) and goat anti-mouse 680RD (1:800 dilution in combined solution)) and incubate for 60 minutes at room temperature away from light. Repeat wash 3 times with PBST. After the final wash, invert the plate and centrifuge at 1000 rpm to completely remove the washing solution from the wells. Prior to scanning the plate, clean the bottom plate surface and the Odyssey® Imager scanning bed (if applicable) with a moist lint-free tissue to avoid obstructions during scanning. The plate is scanned in both the 700 and 800 nm channels of detection.

[0996] p-ERK IC of exemplary compounds of the present disclosure 50 The values ​​are shown in Table 1.

[0997] [Table 1-1]

[0998] [Table 1-2]

[0999] Other compounds of the present disclosure have an IC of 0.5-2000 nM. 50 Some compounds of the present disclosure have IC values ​​of 1-1000 nM. 50 Some compounds of the present disclosure have IC values ​​of 1-500 nM. 50 Indicates the value.

[1000]

[0799] Table 2 shows the p-ERK IC of exemplary compounds of the present disclosure and the reference compound MRTX-1133. 50 Values ​​and selectivity compared to the WT-KRAS cell line MKN-1 are given.

[1001] [Table 2]

[1002]

[0800] KRAS G12D 2D CellTiter-Glo® Proliferation Assay:

[0801] AsPC-1 (ATCC CRL-1682) and LS513 (ATCC CRL-2134) cells were purchased from ATCC, and GP2D (Cobioer CBP60010) cells were purchased from Cobioer biosciences CO., LTD. Each cell was cultured in medium supplemented with 10% fetal bovine serum (FBS) according to the protocol recommended by the manufacturer. The cells were seeded at 800 cells / well in a 384-well plate (Corning) and incubated at 37°C, 5% CO 2 Serially diluted compounds were added to the cells and the plates were incubated at 37°C, 5% CO 2 The cells were incubated at RT for 72 h. Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) according to the manufacturer's protocol.

[1003]

[0802] KRAS G12D 3D CellTiter-Glo® Proliferation Assay: HPAC (ATCC CRL-2119) and AsPC-1 (ATCC CRL-1682) cells were purchased from ATCC and cultured in medium supplemented with 10% fetal bovine serum (FBS) according to the protocol recommended by the manufacturer. Serially diluted compounds were added to 384-well ultra-low attachment surface round-bottom plates (Corning). 400 cells / well were seeded into the plates and incubated at 37°C, 5% CO. 2The cells were incubated at RT for 7 days. Cell viability was measured using the CellTiter-Glo® 3D Cell Viability Assay Kit (Promega) according to the manufacturer's protocol.

[1004]

[0804] 2D and 3D proliferation data for exemplary compounds of the present disclosure in different cell lines is shown in Table 3.

[1005] [Table 3]

[1006]

[0805] Caco-2 cell monolayer permeability: In the presence of efflux inhibitors zosuquidar, benzbromarone and KO-143, at an input concentration of 10 μM and pH 6.5 / 7.4 (apical / basolateral). Incubations were performed at 37° C. with shaking at 480 rpm on a rotary shaker for 120 min, and samples were collected at 45 and 120 min to determine recovery. All incubations were performed once. Lucifer yellow was used as a marker to confirm the integrity of the cell monolayer after 120 min of incubation. UPLC-MS / MS was used to quantify compound concentrations in the incubation media of the donor and receiver compartments. Concentration data was used to calculate the apparent permeability after 120 min of incubation. Table 4 shows the apparent permeability data for exemplary compounds of the present disclosure and the reference compound MRTX-1133.

[1007] [Table 4]

[1008]

[0807] In vivo oral bioavailability assay: Single dose following IV bolus (1 mg / kg, 0.2 mg / mL in 1% DMSO in water, 99% SBE-β-CD (10% w / v)) and oral gavage (30 mg / kg, 3 mg / mL in 1% MC in DI water) administration of test compounds in female Balb / c mice. Blood samples were collected at 2 min, 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h (and 32 h and 48 h for MRTX1133) after IV bolus and at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 8 h and 24 h (and 32 h and 48 h for MRTX1133) after PO administration. Plasma concentrations of compounds were determined by UPLC-MS / MS. Table 5 shows the bioavailability data of exemplary compounds of the present disclosure and the reference compound MRTX-1133.

[1009] [Table 5]

[1010]

[0809] The foregoing description is considered as merely illustrative of the principles of the present disclosure. Mor...

Claims

1. Formula (IIb): 【Chemical 1】 (wherein Ring A is heterocyclyl or heteroaryl, Each R １ is independently selected from the group consisting of oxo, hydroxyl, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroaryl, -C(O)R ＊ , -C(O)OR ＊ , -C(O)N(R ａ ), ２ , -N(R ａ ), ２ , -P(O)OR ＊ OR ＊＊ , and -C(O)OC(R ａ ), ２ -Z １ -Z ２ wherein alkyl, alkenyl, alkynyl and heteroaryl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, -OR ｂ , or -N(R ｂ ), ２ ​ Each R ａ and R ｂ is, independently, hydrogen, alkyl, alkenyl or alkynyl, R ＊ is selected from hydrogen, alkyl, alkylaryl or aryl, or R ＊＊ is selected from hydrogen, alkyl, alkenyl or alkynyl, or R ＊ and R ＊＊ together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl, Z １ is -OC(O)-#, -OP(=O)(OR ＊＊＊ )O-#, or -OP(=O)(OR ＊ )N(R ａ )-#, where the # end is connected to Z ２ and Z ２ is hydrogen, or alkyl optionally substituted with aryl or -C(O)OR ａ and is optionally substituted with aryl or -C(O)OR, or is alkyl R ＊＊＊ is independently selected from hydrogen, alkyl, alkenyl or alkynyl, or R ＊＊＊ and Z ２ together with the oxygen atom to which they are attached form a heterocyclyl optionally substituted with aryl or haloaryl, Ring Q is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, Each R ２ is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C(O)R ＊ wherein alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more groups consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Each R ３ is independently selected from the group consisting of hydrogen, oxo, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more groups consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, G １ is a bond, -O-, -S(O) ｐ -, -S-S-, -N(R ｃ )-, or -C(R ｄ )=C(R ｄ )-, and G ２ is a bond, -[C(R ｄ ), ２ , ｕ -C(O)- or -C(O)C(R ｄ ), ２ - and is R ｃ is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclyl, Each R ｄ is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more groups consisting of hydroxyl, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl, or Two Rs ｄ together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, where the cycloalkyl and heterocyclyl are optionally substituted with cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl and alkyl, Z is C(R ｅ ) or N, and R ｅ is absent or is hydrogen, L １ is selected from a bond, -O-, -S-, -N(R ａ ), -C(O)N(R ａ ), alkenyl, alkynyl or cycloalkyl, 【Chemical Formula 2】 is optionally substituted with hydroxyl, halogen, cyano or amino, L ２ is a bond, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl, E is selected from the group consisting of hydrogen, hydroxyl, halogen, -N(R ａ ), alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH ２ OC(O)-heterocyclyl, -CH ２ OC(O)N(R ２ ), -NH C(=NH)NH ａ ), -C(O)N(R ２ ), -OR ２ ), -O R ａ ), - (CH ２ OR ａ )(CH ２ OR ａ )(CH ２ ), -N(R ｐ )(C(O)-aryl and -(CH ａ )(C(O)-aryl and -(CH ａ )(C(O)-aryl and -(CH ２ ), -N(R ｕ )(C(O)-aryl and -(CH ａ )(C(O)-aryl and -(CH ２ ), -N(R ｕ )(C(O)-aryl and -(CH ２ ), where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R'', the aryl moiety of -N(R ), and the heterocyclyl moieties of -(CH ), -CH OC(O)-heterocyclyl are optionally substituted with one or more R''', Each R'' is independently hydroxyl, halogen, -C(O)H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or -N(R ａ ). ２ and is selected from Each R''' is independently selected from oxo, hydroxyl, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -T-phenyl, -T-phenylSO ２ F, -N(R ａ ) ２ , -SO ２ F, -C(O)(alkyl), or -C(O)(haloalkyl), where alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, and alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl, or tert-butyldimethylsilyloxy T is a bond, -O-, or -NH C(O)-, m is an integer from 0 to 6, n is an integer from 0 to 5, r is an integer from 0 to 4, p is an integer from 0 to 2, u is an integer from 0 to 4, T １ is N or C(R'), and T ２ is N or C(R') and a pharmaceutically acceptable salt thereof.

2. Ring A is heterocyclyl, and optionally, Ring A is 【Chemical Formula 3】 (wherein [Chemical Formula 4] represents a single bond or a double bond) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

3. (a) Ring Q is aryl, preferably Ring Q is phenyl or naphthalenyl; or (b) Ring Q is heteroaryl, preferably Ring Q is selected from benzothiophenyl, benzimidazolyl, quinazolinyl, benzotriazolyl, thiophenyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. G １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G is —O—.

5. G ２ is - [C(R ｄ ). ２ ) ｕ -, and preferably each R ｄ is, independently, hydrogen or alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. (a) m is 0; wherein (b) m is an integer of 1 to 3, and each R １ is independently alkyl; (c) m is 1, and R １ is -C(O)R ＊ or -C(O)OR ＊ wherein R ＊ is alkyl or alkylaryl; or (d) m is 1 and R １ is -C(O)OC(R ａ ) ２ -Z １ -Z ２ where Z １ is -OC(O)-# and Z ２ is alkyl optionally substituted with aryl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. n is an integer from 1 to 4, and each R ２ is independently selected from hydroxyl, halogen, cyano, amino, alkyl, alkenyl, alkynyl, or cycloalkyl, where alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more groups independently selected from cyano, hydroxyl, halogen, or alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. L １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is —O—.

9. L ２ is alkyl, cycloalkyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more of halogen or alkyl, and preferably L ２ is selected from hexahydro-1H-pyrrolidinyl, azetidinyl, pyrrolidinyl or pyridinyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. E is hydrogen, hydroxyl, halogen, haloalkyl, heteroalkyl, —N(R ａ ) ２ , or -CH ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from OC(O)-heterocyclyl.

11. 【Fig. 5-1】 【Chemical Formula 5-2】 【Chemical Formula 5-3】 【Chemical Formula 5-4】 【Chemical Formula 5-5】 【Chemical Formula 5-6】 [Chemical Formula 5-7] 【Chemical Formula 5-8】 [[Chemical Formula 5-9]] 【Chemical Formula 5-10】 【Chemical Formula 5-11】 【Chemical Formula 5-12】 【Chemical Formula 5-13】 【Chemical Formula 5-14】 【Chemical Formula 5-15】 【Chemical Formula 5-16】 【Chemical Formula 5-17】 【Chemical Formula 5-18】 【Chemical Formula 5-19】 【Chemical Formula 5-20】 【Chemical Formula 5-21】 【Chemical Formula 5-22】 ​ 【Chemical Formula 5-24】 ​ ​ 【Chemical Formula 5-27】 ​ 【Chemical Formula 5-29】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12 for treating KRas G12D-related cancer, preferably, the KRas G12D-related cancer is (i) Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (ii) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; (iii) Digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hyperplastic polyp, leiomyoma); (iv) Urinary and reproductive tract: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); (v) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (vi) Biliary tract: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; (vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma); (viii) Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa - theca cell tumor, Sertoli - Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), fallopian tube (carcinoma); (ix) Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non - Hodgkin's lymphoma (malignant lymphoma); (x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and (xi) Adrenal gland: neuroblastoma selected from the group consisting of; or The KRas G12D-related cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer; The pharmaceutical composition.

14. The pharmaceutical composition according to claim 12 for treating KRas G12D-related cancer, wherein the compound, the pharmaceutically acceptable salt, or the composition is administered simultaneously, separately or sequentially with one or more additional therapeutic agents, preferably, the one or more additional therapeutic agents are selected from anti-PD-1 or PD-L1 antagonists, MEK inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, SHP2 inhibitors, platinum agents or pemetrexed.

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