KRAS g12d degraders and uses thereof

Abstract

The invention relates to compounds of Formula I, II II-1, III, or III-1 and pharmaceutically acceptable salts thereof, and methods of making and using the same. The compounds of the invention are effective in inhibiting and / or degrading KRAS protein with a G12D mutation and are suitable for use in methods of treating cancers mediated, in whole or in part, by KRAS G12D mutation.

Description

[0001] KRAS G12D DEGRADERS AND USES THEREOF

[0002] CROSS-REFERENCE TO REAL TED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No.

[0004] 63 / 619,590, filed January 10, 2024, which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND

[0006] Mutations in KRAS are known to be oncogenic and are common in pancreatic, lung, colorectal, gall, thyroid and bile duct cancers. Mutation of Glycine 12 to Aspartic Acid in KRAS is a relatively common genotype in non-small cell lung cancers, pancreatic ductal adenocarcinomas and colorectal cancers. There is a need to develop KRAS G12D degraders for treating KRAS G12D-mediated cancers (i.e., cancers that are mediated, entirely or partly, by KRAS G12D mutation). The compounds and compositions of the present invention provide means for selectively degrading KRAS G12D protein and for treating cancers, particularly those that are mediated by the KRAS G12D mutation.

[0007] SUMMARY

[0008] In certain embodiments, the invention relates to a compound having

[0009] (a) the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0010] A1is an optionally substituted 6 to 12-membered saturated or partially unsaturated heterocycle; or A1is selected from: wherei denotes a point of n each attachment;

[0011] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0012] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);

[0013] X2is C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2, OC(RXa)2C(RXa)2, C(RXa)2OC(RXa)2, SC(RXa)2, SC(RXa)2C(RXa)2, or C(RXa)2SC(RXa)2;

[0014] X3is bond, O, S, S(O), S(O)2, N(H), C1-3alkyl, C2-3alkenyl, C2-3alkynyl, or (CH2)qO(CH2)qCH3;

[0015] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0016] R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4-membered carbocycle, an optionally substituted 4 to 6-membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted (e.g., F) C1-3alkoxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0017] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0018] R3is selected from: denotes the point of attachment; R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0019] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0020] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0021] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0022] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0023] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0024] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0025] R4is an optionally substituted C1-4 alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0026] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0027] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;

[0028] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment; R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0029] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0030] R7a, when present, in each instance is independently H or C1-3alkyl;

[0031] RPin each instance is independently F, Cl, OH, or CH3;

[0032] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0033] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0034] RY, when present, in each instance is independently H or C1-3alkyl;

[0035] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the X3; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q in each instance is independently 0, 1, 2, or 3; or (b) the structure of Formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0036] A1ais selected from: wherein denotes a point of each attachment;

[0037] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0038] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);

[0039] X2ais C(RXa)2, O, or S; X2bis C(RXa)2;

[0040] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0041] R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0042] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl; R3is selected from: wherein denotes the point of attachment;

[0043] R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0044] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0045] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0046] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0047] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0048] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0049] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0050] R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0051] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0052] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0053] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0054] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0055] R7a, when present, in each instance is independently H or C1-3alkyl;

[0056] RP1is H, F, Cl, OH, or CH3;

[0057] RP2is H, F, Cl, OH, or CH3; or

[0058] RP1is OH and RP2is H or F;

[0059] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0060] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0061] RY, when present, in each instance is independently H or C1-3alkyl;

[0062] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3; or

[0063] (c) the structure of F ormula II- 1 : or a pharmaceutically acceptable salt thereof, wherein:

[0064] A1ais selected from:

[0065] w denotes a point of herein each attachment;

[0066] X2bis C(RXa)2;

[0067] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl; or one instance of RXais C1alkyl (i.e., CH3) and the other is H;

[0068] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0069] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0070] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);

[0071] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: denotes the point of attachment;

[0072] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl

[0073] (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3; RP2is H, F, Cl, OH, or CH3; or

[0074] RP2is H; or

[0075] RP2is F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3; or

[0076] (d) the structure of Formula III: or a pharmaceutically acceptable salt thereof, wherein: A1ais selected from: wherein each denotes a point of attachment;

[0077] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0078] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);

[0079] X2ais C(RXa)2, O, or S,

[0080] X2bis C(RXa)2, O, or S, and

[0081] X2cis C(RXa)2, with the proviso that X2aand X2bcannot both be heteroatoms;

[0082] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0083] R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0084] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0085] R3is selected from: wherein denotes the point of attachment;

[0086] R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0087] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0088] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0089] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0090] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0091] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0092] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3); R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0093] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0094] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;

[0095] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0096] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0097] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0098] R7a, when present, in each instance is independently H or C1-3alkyl;

[0099] RP1is H, F, Cl, OH, or CH3;

[0100] RP2is H, F, Cl, OH, or CH3; or

[0101] RP1is OH and RP2is H or F;

[0102] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0103] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O); RY, when present, in each instance is independently H or C1-3alkyl;

[0104] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3; or

[0105] (e) the structure of F ormul a III- 1 : or a pharmaceutically acceptable salt thereof, wherein:

[0106] A1ais selected from: wherein each denotes a point of attachment;

[0107] X2bis C(RXa)2;

[0108] X2cis C(RXa)2;

[0109] RXain each instance is independently H, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0110] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0111] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0112] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl); R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0113] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0114] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;

[0115] RP2is H, F, Cl, OH, or CH3; or

[0116] RP2is H; or

[0117] RP2is F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

[0118] DETAILED DESCRIPTION

[0119] Definitions

[0120] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0121] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g., Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed ”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0122] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0123] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0124] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0125] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0126] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount. “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g , through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g , patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0127] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g , solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0128] The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.

[0129] The term “alkenyl,” as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls” the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0130] An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 6 carbon atoms, preferably from 1 to about 3 unless otherwise defined. Examples of straight chained and branched alkyl groups include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6straight chained or branched alkyl group is also referred to as a “lower alkyl” group.

[0131] Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen (e.g., fluoro), a hydroxyl, an oxo, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-C6alkyl, C3-C6cycloalkyl, halogen, carbonyl, cyano, and hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, and hydroxyl. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Alkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0132] The term “Cx-Cy,” when used in conjunction with a chemical moiety, such as, alkyl or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-Cyalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluorom ethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.

[0133] The term “alkylamino,” as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio,” as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0134] The term “alkynyl,” as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0135] The term “amide,” as used herein, refers to a group wherein each RAindependently represent a hydrogen, hydrocarbyl group, aryl, heteroaryl, acyl, or alkoxy, or two RAare taken together with the N atom to which they are attached complete a heterocycle having from 3 to 8 atoms in the ring structure.

[0136] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each RAindependently represents a hydrogen or a hydrocarbyl group, or two RAare taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0137] The term “aminoalkyl,” as used herein, refers to an alkyl group substituted with an amino group.

[0138] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0139] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 6- to 10- membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, aniline, and the like.

[0140] The term “carbocycle” refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and nonaromatic carbocycles. Non-aromatic carbocycles include both cycloalkyl and cycloalkenyl rings. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. l]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7- tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0141] A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3- to about 10-carbon atoms, from 3- to 8-carbon atoms, or more typically from 3- to 6-carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings (e.g., fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds). Optional substitutions of a cycloalkyl group include halogen (e.g., F and Cl), hydroxyl, amino, nitro, C(O)CH3, C(O)OH, amide, cyano, C1-3alkyl (e.g., methyl and ethyl), C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), C1-3aminoalkyl, C1-3hydroxalkyl, C1-3alkoxy (e.g., methoxy and ethoxy), C1-3cyanoalkyl, C2-3alkenyl, or C1-3alkynyl. One, two, three, or four optional susbtitutions may occur, and in each instance, the substitution is independently selected.

[0142] A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.

[0143] The term “bridged bicyclic compound” or “bridged ring” refers to a bicyclic molecule in which the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings each sharing three of their five carbon atoms. A “bridged bicyclic compound” or “bridged ring” compound can include one or more heteroatoms (such as nitrogen atoms) in the ring system, for example, diazabicyclo[3.2.1]octanes such as 3,8-diazabicyclo[3.2.1]octane.

[0144] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0145] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0146] The term “heteroalkyl”, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, for example, wherein no two heteroatoms are adjacent.

[0147] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, and combinations thereof.

[0148] The term “fused bicyclic compound” refers to a bicyclic molecule in which two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the so-called bridgehead atoms are directly connected (e.g., a-thujene and decalin). For example, in a fused cycloalkyl each of the rings shares two adjacent atoms with the other ring, and the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

[0149] The term “hydroxy alkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0150] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single or aromatic polycyclic ring structures. For example the “heteroaryl” and “hetaryl” ring structure can be 5- to 7-membered single heteroaryl rings, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms; or 8-14 membered bicyclic or polycyclic heteroaryl ring, preferably 8-10 membered bicyclic ring, more preferably 9- or 10- membered bicyclic ring, having at least one aromatic ring structure and 1-5 heteroatoms, wherein the heteroatoms are independently selected from nitrogen, oxygen, or sulfur. The terms “heteroaryl” and “hetaryl” also include aromatic polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, quinoline, quinoxaline, quinazoline, naphthyridine, indole, isoindole, indazole, isoindazole, and the like.

[0151] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0152] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, preferably 3- to 7-membered rings, more preferably 5- to 6-membered rings, in some instances, most preferably a 5 -membered ring, in other instances, most preferably a 6-membered ring, which ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. The terms “heterocyclyl” and “heterocyclic” also include spirocyclic ring systems having two or more cyclic rings in which one carbon is common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls or heterocyclyls; and include polycyclic ring systems having two or more cyclic rings in which a nitrogen atom and one or more carbons are common to two adjoining rings wherein any of the rings may have an additional heteroatom. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, pyrrolizidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, oxazolines, imidazolines, l-azaspiro[4.4]nonane and the like. Optional substitutions of a heterocycle group include halogen (e.g., F and Cl), hydroxyl, amino, nitro, C(O)CH3, C(O)OH, amide, cyano, C1-3alkyl (e.g., methyl and ethyl), C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), C1-3aminoalkyl, C1-3hydroxalkyl, C1-3alkoxy (e.g., methoxy and ethoxy), C1-3cyanoalkyl, C2-3alkenyl, or C1-3alkynyl. One, two, three, or four optional susbtitutions may occur, and in each instance, the substitution is independently selected.

[0153] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, one of the rings is a bridged ring. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0154] The term “spirocyclic compound”, “spirocycle”, and “spirocyclic” refers to a bicyclic molecule in which the two rings have only one single atom, the spiro atom, in common.

[0155] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone, or substituents replacing a hydrogen on one or more nitrogens of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substitutions can be one or more and the same or different for appropriate organic compounds.

[0156] “Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rdEd., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethyl silyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[0157] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0158] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt that is suitable for or compatible with the treatment of patients.

[0159] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds disclosed herein. Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono- , di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds disclosed herein are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of the invention for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0160] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds of the invention, or any of their intermediates. Illustrative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0161] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g, WO 01 / 062726.

[0162] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixtures and separate individual isomers.

[0163] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0164] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of the invention). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of the invention, or a pharmaceutically acceptable salt thereof. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0165] As used herein, the terms “quaternary carbon atom” or “quaternary carbon center” refer to a carbon atom having four non-hydrogen substituents. The terms “quaternary carbon atom” or “quaternary carbon center” include tetrasubstituted carbon atoms and tetrasubstituted carbon centers as they are commonly used in the art.

[0166] Example Compounds

[0167] In certain embodiments, the invention relates to a compound having the structure of Formula I : or a pharmaceutically acceptable salt thereof, wherein:

[0168] A1is selected from:

[0169] wherein each denotes a point of attachment; or

[0170] A1is an optionally substituted 6 to 12-membered saturated or partially unsaturated heterocycle;

[0171] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0172] X1is O, a bond, CH2, S, N(H), or N(C1-3alkyl);

[0173] X2is OC(RXa)2, C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2C(RXa)2, C(RXa)2OC(RXa)2, SC(RXa)2, SC(RXa)2C(RXa)2, or C(RXa)2SC(RXa)2;

[0174] X3is O, a bond, S, S(O), S(O)2, N(H), C1-3alkyl, C2-3alkenyl, C2-3alkynyl, or (CH2)qO(CH2)qCH3;

[0175] RXain each instance is independently H, C1-3alkyl, halogen (e.g., F), hydroxyl, cyano, , C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0176] R1is selected from: denotes the point of attachment; or

[0177] R1is an optionally substituted 4 to 6-membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4-membered carbocycle, or an optionally substituted 5 to 6- membered heteroaryl; R1a, when present, in each instance is independently optionally substituted C1-3alkyl, halogen, hydroxyl, optionally substituted (e.g., F) C1-3alkoxyl, , or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0178] R2is halogen (e.g., Cl), cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0179] R3is selected from: wherein denotes the point of attachment;

[0180] R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0181] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0182] R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), F, Cl, C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3; R3dis F, H, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0183] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0184] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0185] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0186] R4is an optionally substituted C1-4 alkyl (e.g. isopropyl), an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0187] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0188] R5bis optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl, e.g., CH2OH) or H; or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;

[0189] R6is selected from: denotes the point of attachment;

[0190] R6aeach independently is optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; or

[0191] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0192] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0193] R7a, when present, in each instance is independently H or C1-3alkyl;

[0194] RPin each instance is independently OH, F, Cl, or CH3; W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the X3; or

[0195] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0196] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0197] RY, when present, in each instance is independently H or C1-3alkyl;

[0198] Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or

[0199] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q in each instance is independently 0, 1, 2, or 3.

[0200] In certain embodiments, the invention relates to a compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0201] A1is an optionally substituted 6 to 12-membered saturated or partially unsaturated heterocycle; or A1is selected from: wherein ea denotes a point of ch attachment;

[0202] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0203] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);

[0204] X2is C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2, OC(RXa)2C(RXa)2, C(RXa)2OC(RXa)2, SC(RXa)2, SC(RXa)2C(RXa)2, or C(RXa)2SC(RXa)2;

[0205] X3is bond, O, S, S(O), S(O)2, N(H), C1-3alkyl, C2-3alkenyl, C2-3alkynyl, or (CH2)qO(CH2)qCH3;

[0206] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl; R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0207] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0208] R3is selected from: wherein denotes the point of attachment; R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0209] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0210] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0211] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0212] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0213] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0214] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0215] R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0216] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0217] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;

[0218] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment; R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0219] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0220] R7a, when present, in each instance is independently H or C1-3alkyl;

[0221] RPin each instance is independently F, Cl, OH, or CH3;

[0222] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0223] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0224] RY, when present, in each instance is independently H or C1-3alkyl;

[0225] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the X3; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q in each instance is independently 0, 1, 2, or 3. In certain embodiments, the invention relates to compounds having the structure of Formula I, wherein:

[0226] A1is selected from: wherein each denotes the point of attachment;

[0227] A2is optionally substituted phenyl;

[0228] X1is O;

[0229] X2is C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2, or OC(RXa)2C(RXa)2;

[0230] X3is O;

[0231] RXain each instance is H;

[0232] R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0233] R2is halogen (particularly F or Cl) or cyclopropyl; R3is

[0234] R3cC1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or

[0235] C2-3alkynyl (e.g., ethynyl and propargyl);

[0236] R3dis F or Cl;

[0237] R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl;

[0238] R6is selected from: wherein denotes the point of attachment; and

[0239] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl). In certain embodiments, the invention relates to compounds having the structure of

[0240] Formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0241] A1ais selected from: wherein each denotes a point of attachment;

[0242] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0243] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl); X2ais C(RXa)2, O, or S;

[0244] X2bis C(RXa)2;

[0245] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0246] R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0247] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl; R3is selected from: wherein denotes the point of attachment;

[0248] R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0249] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0250] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0251] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0252] R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0253] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0254] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0255] R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0256] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0257] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0258] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0259] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0260] R7a, when present, in each instance is independently H or C1-3alkyl;

[0261] RP1is H, F, Cl, OH, or CH3;

[0262] RP2is H, F, Cl, OH, or CH3; or

[0263] RP1is OH and RP2is H or F;

[0264] W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0265] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0266] RY, when present, in each instance is independently H or C1-3alkyl;

[0267] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

[0268] In certain embodiments, the invention relates to a compound having the structure of

[0269] Formula II- 1 : or a pharmaceutically acceptable salt thereof, wherein:

[0270] A1ais selected from:

[0271] wherein each denotes a point of attachment;

[0272] X2bis C(RXa)2;

[0273] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl; or one instance of RXais C1alkyl (i.e., CH3) and the other is H;

[0274] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0275] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0276] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);

[0277] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0278] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;

[0279] RP2is H, F, Cl, OH, or CH3; or

[0280] RP2is H; or

[0281] RP2is F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

[0282] In certain embodiments, the invention relates to compounds having the structure of Formula II, wherein:

[0283] A1is selected from: wherein each denotes the point of attachment;

[0284] A2is optionally substituted phenyl;

[0285] X1is O;

[0286] X2ais C(RXa)2or O;

[0287] X2bis C(RXa)2; or

[0288] X2ais O and X2bis C(RXa)2;

[0289] RXain each instance is H;

[0290] R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0291] R2is halogen (particularly F or Cl) or cyclopropyl;

[0292] R3is

[0293] R3cC1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or

[0294] C2-3alkynyl (e.g., ethynyl and propargyl);

[0295] R3dis F or Cl; R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl;

[0296] R6is selected from: wherein denotes the point of attachment; and

[0297] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl). In more specific embodiments, X2ais O and X2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3). In other specific embodiments, X2ais C(RXa)2, wherein each instance of RXais H, andX2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3). In particular embodiments, X2ais O; X2bis C(RXa)2; and RXain one instance is C1alkyl (i.e., CH3) and in the other is H.

[0298] In certain embodiments, the invention relates to a compound having the structure of

[0299] Formula III: or a pharmaceutically acceptable salt thereof, wherein:

[0300] A1ais selected from:

[0301] wherein each denotes a point of attachment;

[0302] A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;

[0303] X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);

[0304] X2ais C(RXa)2, O, or S,

[0305] X2bis C(RXa)2, O, or S, and

[0306] X2cis C(RXa)2, with the proviso that X2aand X2bcannot both be heteroatoms;

[0307] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0308] R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);

[0309] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0310] R3is selected from: wherein denotes the point of attachment;

[0311] R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);

[0312] R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0313] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0314] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl); R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;

[0315] R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);

[0316] R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);

[0317] R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;

[0318] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0319] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;

[0320] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0321] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0322] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;

[0323] R7a, when present, in each instance is independently H or C1-3alkyl;

[0324] RP1is H, F, Cl, OH, or CH3;

[0325] RP2is H, F, Cl, OH, or CH3; or

[0326] RP1is OH and RP2is H or F; W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;

[0327] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);

[0328] RY, when present, in each instance is independently H or C1-3alkyl;

[0329] Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from: denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from: denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

[0330] In certain embodiments, the invention relates to a compound having the structure of Formula III-l : or a pharmaceutically acceptable salt thereof, wherein:

[0331] A1ais selected from: wherein each denotes a point of attachment;

[0332] X2bis C(RXa)2;

[0333] X2cis C(RXa)2;

[0334] RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;

[0335] R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;

[0336] R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;

[0337] R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);

[0338] R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: wherein denotes the point of attachment;

[0339] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0340] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;

[0341] RP2is H, F, Cl, OH, or CH3; or

[0342] RP2is H; or

[0343] RP2is F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

[0344] In certain embodiments, the invention relates to compounds having the structure of Formula III, wherein:

[0345] A1is selected from: wherein each denotes the point of attachment;

[0346] A2is optionally substituted phenyl;

[0347] X1is O;

[0348] X2ais C(RXa)2or O,

[0349] X2bis C(RXa)2or O, and

[0350] X2cis C(RXa)2, with the proviso that X2aand X2bcannot both be O;

[0351] RXain each instance is H;

[0352] R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;

[0353] R2is halogen (particularly F or Cl) or cyclopropyl; R3is

[0354] R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);

[0355] R3dis F or Cl;

[0356] R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl; R6is selected from: wherein denotes the point of attachment; and

[0357] R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl). In more specific embodiments, X2ais O and X2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3). In other specific embodiments, X2ais C(RXa)2, wherein each instance of RXais H, andX2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3).

[0358] In certain embodiments, the invention relates to compounds having the structure of

[0359] Formula I, II, II- 1, III or III-l, wherein:

[0360] A1is selected from: wherein each denotes the point of attachment;

[0361] X1, when present, is O;

[0362] R1is selected from: wherein denotes the point of attachment; R1a, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3);

[0363] R2is Cl or cyclopropyl; R6is selected from: wherein denotes the point of attachment; and m is 0 or 1. In more specific embodiments, m is 0. In other specific embodiments, m is 1.

[0364] In certain embodiments, the invention relates to compounds having the structure of

[0365] Formula I, II, II- 1, III or III-l, wherein A1 In more specific embodiments, m is 0. In other embodiments, m is 1. In yet other embodiments, m is 2.

[0366] In certain embodiments, the invention relates to compounds having the structure of

[0367] Formula I, II, or III, wherein R1is selected from and wherein denotes the point of attachment; and R1a, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, or C1-3haloalkyl

[0368] (e.g., CH2F, CHF2, and CF3). In specific embodiments, R1is In other specific embodiments, R1is and n is 0. In certain embodiments, the invention relates to compounds having the structure of

[0369] Formula I, II, or III, wherein R1is and R1b, when present, in each instance is independently halogen, C1-3haloalkyl (e.g., =CF2, CH2F, CHF2, and CF3), or C2-3 haloalkenyl (e.g., CHCHF and CHCF2). In yet other specific embodiments n is 0. In yet other specific embodiments, n is 1 or 2.

[0370] In certain embodiments, the invention relates to compounds having the structure of

[0371] Formula I, II, II-l, III or III-l, wherein R6is selected from and wherein denotes the point of attachment. In specific embodiments, R6is In other specific embodiments, R6is and R is optionally substituted

[0372] C1-3alkyl. In yet other specific embodiments, R6is R6ais C1-3alkyl, and C1-3alkyl is C1alkyl (i.e., methyl).

[0373] In certain embodiments, the invention relates to compounds having the structure of

[0374] Formula I, II, or III, wherein R3is R3ais C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl); and R3bis F, Cl, Br, or CH3. In other specific embodiments, R3ais C2-3alkynyl (e.g., ethynyl and propynyl), and R3bis F, Cl, or Br. In yet other specific embodiments, R3ais ethynyl, and R3bis F.

[0375] In certain embodiments, the invention relates to compounds having the structure of Formula I, II, or III, wherein R3is R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl); and

[0376] R3dis F or Cl. In specific embodiments, R3cC1alkyl (i.e., CH3) and R3dis F. In certain embodiments, the invention relates to compounds having the structure of

[0377] Formula I, II, or III, wherein W-Y-Z is wherein denote the points of attachment and * denotes the end that attaches to the oxygen. In specific embodiments, W-Y-Z is

[0378] In certain embodiments, the invention relates to compounds having the structure of Formula I, II, or III, wherein:

[0379] W is phenyl;

[0380] Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are all a bond; and

[0381] Z is selected from: denote the points of attachment and * denotes the end that attaches to Y. In more specific embodiments, Z is . In yet other specific embodiments, Z is

[0382] In yet other specific embodiments, Z is . In yet other specific embodiments, Z is

[0383] In certain embodiments, the invention relates to compounds having the structure of Formula II, II-l, III or III- 1 , wherein R2is Cl or cyclopropyl. In other embodiments, R2is Cl. In other embodiments, R2is cyclopropyl.

[0384] In certain embodiments, the invention relates to compounds having the structure of Formula II, II-l, III or III- 1 , wherein RP2is H or F. In other embodiments, RP2is H. In other embodiments, RP2is F.

[0385] In certain embodiments, the invention relates to compounds having the structure of Formula I, II, II-l, III or III- 1 , wherein m is 0, 1, or 2, and n is 0, 1, or 2. In other specific embodiments, m is 1 and n is 1. In more specific embodiments, m is 0 and n is 0. In more specific embodiments, m is 1 and n is 0. In more specific embodiments, m is 0 and n is 1.

[0386] In certain embodiments, the invention relates to compounds having the structure of Formula I, wherein p is 1 or 2. In other embodiments, p is 1 and the one instance of RPis OH. In yet other embodiments, p is 2, wherein one instance of and RPis OH and the other is F.

[0387] In certain embodiments, the invention relates to compounds having the structure of Formula I, II, II-l, III or III- 1, wherein q in each instance is independently either 1 or 2. In other embodiments, q in each instance is 1. In other embodiments, q is 1 in one instance and is 2 in another.

[0388] In certain embodiments, the invention relates to a compound of Formula II selected from: or a pharmaceutically acceptable salt thereof.

[0389] In certain embodiments, the invention relates to a compound of Formula II having the following structural formula: , or a pharmaceutically acceptable salt thereof.

[0390] In certain embodiments, the invention relates to a compound of Formula II selected from:

[0391] , or a pharmaceutically acceptable salt thereof.

[0392] In certain embodiments, the invention relates to a compound of Formula II having the following structural formula: , or a pharmaceutically acceptable salt thereof.

[0393] In certain embodiments, the invention relates to a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein:

[0394] A1ais: wherein each denotes the point of attachment;

[0395] A2is phenyl, optionally substituted with C1-3alkoxyl;

[0396] X1is O;

[0397] X2ais O;

[0398] X2bis C(RXa)2;

[0399] RXain each instance is independently H, halogen (e.g., F), C1-3alkyl, C1-3hydroxyalkyl, or C1-3haloalkyl; R1is selected from: denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, optionally substituted (e.g., F) C1-3alkoxyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3);

[0400] R2is halogen (preferably Cl), C1-3alkyl, cyclopropyl, or cyclobutyl;

[0401] R3is wherein denotes the point of attachment;

[0402] R3cis C1-3alkyl, preferably methyl, F, Cl, C1-3haloalkyl, or C1-3alkyoxy;

[0403] R3dis F, H, Cl, or C1-3alkyl, preferably F;

[0404] R4is an optionally substituted C1-4 alkyl, preferably propyl or butyl; or an optionally substituted C3-6cycloalkyl, preferably cyclobutyl;

[0405] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);

[0406] R5bis optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; R6is: wherein denotes the point of attachment, and R6a, when present, is H or optionally substituted C1-3alkyl;

[0407] R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;

[0408] RP1is H, F, Cl, OH, or CH3, preferably OH;

[0409] RP2is H; W-Y-Z is selected from: wherein denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; preferably 0; and n is 0, 1, 2, 3, or 4; preferably 0 or 1.

[0410] In certain embodiments, A1ais

[0411] In certain embodiments, A2is

[0412] In certain embodiments, X2bis CH2or CH(CH3).

[0413] In certain embodiments, R1is selected from: In certain embodiments, R2is halogen, preferably Cl; or cyclopropyl.

[0414] In certain embodiments, R3is

[0415] In certain embodiments, R4is propyl, preferably isopropyl; butyl, preferably secbutyl; or cyclobutyl.

[0416] In certain embodiments, R6a, when present, is H, methyl or ethyl.

[0417] In certain embodiments, R6is In certain embodiments, R5ais H and R5bis CH3, CH2OH, or CH(OH)CH3.

[0418] In certain embodiments, RP1is OH.

[0419] In certain embodiments, the invention relates to a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0420] A1ais: wherein each denotes the point of attachment;

[0421] A2is phenyl;

[0422] X1is O; X2ais O;

[0423] X2bis C(RXa)2; wherein RXain each instance is independently H, or C1-3alkyl; R1is: wherein denotes the point of attachment;

[0424] R2is halogen, preferably Cl, C1-3alkyl, or cyclopropyl; R3is denotes the point of attachment;

[0425] R4is an optionally substituted C1-3alkyl, preferably isopropyl;

[0426] R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl), preferably H;

[0427] R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl), preferably CH2OH; R6is: wherein denotes the point of attachment;

[0428] RP1is OH;

[0429] RP2is H; and W-Y-Z is selected from: wherein denote the points of attachment and * denotes the end that attaches to the oxygen.

[0430] In certain embodiments, the invention relates to a compound having the structure selected from:

[0431] a pharmaceutically acceptable salt thereof.

[0432] In certain embodiments, the invention relates to a compound of Formula II selected from:

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] In certain embodiments, the invention relates to a single atropisomer of a compound of Formula I, II, II-l, III or III-l. Specific embodiments of the invention include those compounds listed in Table 1 and Tabel 1 A. The identifying number (“Cmpd”), the chemical structure (“Structure”), and the example method used to synthesize the compound (“Example”) are disclosed in Table 1 and Tabel 1 A for each compound.

[0436] Comparative compounds to those of the invention include those compounds listed in Table 2. The identifying number (“Cmpd”) and the chemical structure (“Structure”) are disclosed in Table 2 for each compound. The methods used to synthesize the compounds of Table 2 can be found in publication WO2022173032A1. Additionally, the KRAS G12D small molecule inhibitor MRTX- 1133 (4-(4-((lA,55)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2A,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) may also serve as a comparative compounds to those of the invention. In certain embodiments, the invention relates to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient.

[0437] Table 1.

[0438]

[0439] Table 1A.

[0440] Table 2.

[0441] Pharmaceutical Agents and Compositions Also provided herein are methods of synthesizing a pharmaceutical agent and / or composition, comprising preparing a compound of a formula disclosed herein (such as a compound of Formula I, II, II- 1, III, III- 1 , or a subgenus thereof), according to a method as described herein and synthesizing the pharmaceutical agent and / or composition from the compound of the formula disclosed herein (such as a compound of Formula I, II, II-l, III, Ill- 1 , or a subgenus thereof), e.g., by carrying out one or more chemical reactions on the compound of the formula disclosed herein (such as a compound of Formula I, II, II-l, III, III- 1 , or a subgenus thereof) and / or combining the pharmaceutical agent with one or more pharmaceutically acceptable carriers and / or excipients.

[0442] The pharmaceutical agent and / or composition prepared from the compound of the formula disclosed herein (such as a compound of Formula I, II, II- 1, III, III-l, or a subgenus thereof) may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0443] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0444] Example Methods of Treatment / Use

[0445] The compounds described herein are inhibitors and / or degraders of KRAS G12D and therefore may be useful for treating diseases wherein the underlying pathology is (at least in part) mediated by KRAS G12D. Such diseases include cancer and other diseases in which there is a disorder of transcription, cell proliferation, apoptosis, or differentiation.

[0446] Accordingly, in certain embodiments, the invention is directed to a method of treating a disease or disorder mediated by KRAS G12D in a subject afflicted therewith, comrpsing adminietering to the subect a compound as described herein (or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the same (i.e., and a pharmaceutically acceptable diluent or excipient). In some such embodiments, the disease mediated by KRAS G12D is a cancer selected from pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, lung adenocarcinoma (particularly, non-small cell lung carcinoma), endometrioid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, and cholangiocarcinoma. In specific embodiments, the cancer is selected from pancreatic adenocarcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, and lung adenocarcinoma (particularly, non-small cell lung adenocarcinoma).

[0447] In certain embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject any of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same (e.g., administering an effective amount of the compound or salt thereof or pharmaceutical composition comprising the same). For example, the cancer may be selected from carcinoma (e.g., a carcinoma of the ovary, uterine, endometrium, small intestine, bile duct, appendiceal, ampullary, bladder and colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma)), lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), and pancreas (e.g., pancreatic carcinoma). Other examples of cancers that may be treated with a compound of the invention include those with a KRASG12D mutation, whose frequency is low or rare.

[0448] In particular embodiments, the treated cancer is selected from pancreatic cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, bile duct cancer, and ovarian cancer.

[0449] In other particular embodiments, the treated cancer is selected from pancreatic cancer, colorectal cancer, and lung cancer (including non-small cell lung cancer). In other particular embodiments, the treated cancer is selected from pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma and ovarian carcinoma.

[0450] In some aspects, the subject is a mammal, for example, a human.

[0451] Further disclosed herein are methods of inhibiting and / or degrading KRAS G12D in a cell comprising contacting said cell with any of the compounds described herein, or a pharmaceutically acceptable salt thereof, such that KRAS G12D enzyme is inhibited and / or degraded in said cell. For example, the cell is a cancer cell. In preferred embodiments, proliferation of the cell is inhibited or cell death is induced.

[0452] Further disclosed herein is a method of treating a disease treatable by inhibition and / or degradation of KRAS G12D in a subject, comprising administering to the subject in recognized need of such treatment, an effective amount of any of the compounds described herein and / or a pharmaceutically acceptable salt thereof. Diseases treatable by inhibition and / or degradation of KRAS G12D include, for example, cancers. Further exemplary diseases include pancreatic cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, bile duct cancer, and ovarian cancer.

[0453] The methods of treatment comprise administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Individual embodiments include methods of treating any one of the above-mentioned disorders or diseases by administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0454] Certain embodiments include a method of modulating KRAS G12D activity and / or levels in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof. Additional embodiments provide a method for the treatment of a disorder or a disease mediated by KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount of the compound (such as a compound of Formula I, II, II-l, III, III-l, or a subgenus thereof), or a pharmaceutically acceptable salt thereof. Other embodiments of the invention provide a method of treating a disorder or a disease mediated by KRAS G12D, in a subject in need of treatment thereof comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the disorder or the disease is selected from carcinomas with genetic aberrations that activate KRAS activity. These include, but are not limited to, cancers. The present method also provides the use of a compound of invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by KRAS G12D.

[0455] In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is used for the treatment of a disorder or a disease mediated by KRAS G12D.

[0456] Yet other embodiments of the present method provide a compound of the invention (such as a compound of Formula I, II, II- 1, III, III-l, or a subgenus thereof), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0457] Still other embodiments of the present method encompass the use of a compound of the invention (such as a compound of Formula I, II, II- 1, III, III-l, or a subgenus thereof), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by KRAS G12D.

[0458] INCORPORATION BY REFERENCE

[0459] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0460] EQUIVALENTS

[0461] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0462] EXEMPLIFICATION

[0463] Synthetic Protocols

[0464] Compounds as disclosed herein can be synthesized via a number of specific methods. The examples, which outline specific synthetic routes, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.

[0465] Example 1 : Synthesis of Oxazepino-quinazoline Compounds

[0466] Preparation of Intermediate 1-3 ([(1S,3S,4S)-5-Trityl-2,5-diazabicyclo[2.2.1]heptan-3- yl] methanol) tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (9.01 g, 45.4 mmol) was dissolved in anhydrous DCM (90 mL) and treated with trityl chloride (13.3 g, 47.7 mmol) and Et3N (8.4 mL, 60.5 mmol) at rt and stirred for 40 min. The mixture was diluted with Et2O (200 mL) and filtered through Celite and the filtrate was directly adsorbed onto silica gel (~80 g) and purified by flash column chromatography on silica gel (120 g) eluted with 10-20% EtOAc in hexanes to give Intermediate 1-1 (19.9g, 99.5%) as a white solid.

[0467] Intermediate 1-1 (2.31 g, 5.24 mmol) and TMEDA (1.57 mL, 10.5 mmol) were dissolved in anhydrous THF (21 mL) and cooled to -78 °C then sec-butyllithium, 1.3 M (7.5 mL, 10.5 mmol) was added dropwise. The mixture was stirred for 60min then ethyl formate (2.96 mL, 36.7 mmol) was added and the mixture was warmed to -40°C and stirred for 15min. The mixture was amended with NaBH4(396 mg, 10.5 mmol) and MeOH (6.9 mL) and warmed to rt and stirred for 30min. Saturated NaHCO3was added extracted with EtOAc (x2). The combined extract was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was dissolved in DCM / hexanes and purified by flash column chromatography on silica gel (40g) eluted with 10-70% EtOAc in hexanes to give Intermediate 1-2 (tert-Butyl (1S,3S,4S)-3- (hydroxymethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 1.15g, 47%) as a white foam.

[0468] Intermediate 1-2 (265 mg, 0.563 mmol) was dissolved in anhydrous DCM (2.8 mL) and treated with 2,6-lutidine (228 uL, 1.97 mmol) and TMS-OTf (255 uL, 1.41 mmol) at 0°C then allowed to warm to rt and stirred for 60min. Methanol (1 mL) and NH4F (80 mg, 2.16 mmol) were added and the mixture was stirred for 5min then poured into 5% K2CO3and extracted with MTBE (x2). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated then further dried in vacuo. The residue was dissolved in DCM, filtered through Celite, and again concentrated and further dried in vacuo to give Intermediate 1-3 ([(1S,3S,4S)-5-Trityl-2,5- diazabicyclo[2.2.1]heptan-3-yl]methanol; 216.9mg, quant.) as a white foam.1H NMR (400 MHz, CDCI3) δ 7.47 (d, J = 7.6 Hz, 6H), 7.15 (t, J = 7.9 Hz, 6H), 7.05 (t, J = 7.3 Hz, 3H), 3.56 (dd, J = 9.4, 5.3 Hz, 1H), 3.26 (dd, J = 10.6, 5.1 Hz, 1H), 3.13 - 3.03 (m, 2H), 2.92 (d, J = 9.9 Hz, 1H), 2.64 (dd, J = 9.9, 2.4 Hz, 1H), 2.42 (s, 2H), 1.94 - 1.65 (m, 1H), 0.84 (d, J = 9.3 Hz, 1H), -0.46 - -0.53 (m, 1H).

[0469] Preparation of Intermediate 2-2 ((4-((triisopropylsilyl)ethynyl)phenyl)methanol)

[0470] A mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and pyridine (40.9 mL) was cooled to 0°C and triflic anhydride (7.6 mL, 45.0 mmol) was added dropwise then the mixture was allowed to warm to rt and stirred for 3.5hrs. The mixture was concentrated and the residue was diluted with hexanes and sequentially filtered through a thin pad of silica gel then a thin pad of acidic alumina rinsing with 95:5 hexanes :EtO Ac both times and the filtrate was concentrated to give Intermediate 2-1 ((4-Formylphenyl) trifluoromethanesulfonate; 7.32g, 70%) as a pale yellow foam.

[0471] Intermediate 2-1 (7.32 g, 28.8 mmol) and ethynyl(triisopropyl)silane (8.40 mL, 37.4 mmol) were dissolved in anhydrous toluene (29 mL) and treated with diisopropylamine (5.28 mL, 37.4 mmol) and the mixture was sparged with N2for 5min then CuI (549 mg, 2.88 mmol) and Pd(PPh3)2Cl2(202 mg, 0.288 mmol) were added simultaneously and sparging was continued for 5min then the mixture was warmed to 50°C. After 30min, additional Pd(PPh3)2Cl2(700 mg, 0.9973 mmol) was added and stirring continued for 24hrs. The mixture was diluted with 7:3 hexanes:EtOAc and filtered through a thin pad of silica gel and concentrated. The residue was dissolved in THF (115 mL) and Methanol (29 mL) and treated with NaBH4(2.18 g, 57.6 mmol) at rt for 50min. The mixture was diluted with EtOAc and washed with sat NH4CI, brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (80g) eluted with 0-30% acetone in hexanes to give Intermediate 2-2 ([4-(2- Triisopropylsilylethynyl)phenyl]methanol; 7.83g, 94%) of an amber colored syrup.1H NMR (400 MHz, CDCI3) δ 7.33 (d, J= 8.3 Hz, 2H), 7.10 (d, J= 8.1 Hz, 2H), 4.41 (s, 2H), 3.21 (s, 1H), 1.17 - 0.81 (m, 21H).

[0472] Preparation of Intermediate 3-3 (tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-l-carboxylate) tert- Butyl A-[(1H)-1-(4-bromophenyl)-2-hydroxy-ethyl]carbamate (1.095 g, 3.46 mmol), 4-methylthiazole (687 mg, 6.93 mmol), KOAc (1360 mg, 13.9 mmol), and Pd(OAc)2(78 mg, 0.35 mmol) were suspended in DMF (6.9 mL) and the mixture was sparged with N2for 5min then sealed and heated to 100°C for 5 hr. Additional Pd(OAc)2(78 mg, 0.35 mmol) was added and heating continued for 2 hrs. The mixture was diluted with EtOAc and H2O and filtered through Celite. The organic phase was collected and washed with water (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The material was purified by flash column chromatography on silica gel (40g) eluted with 10-70% Me2CO in hexanes to give Intermediate 3-1 (tert-Butyl A-[(1R)- 2-hydroxy-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate; 810mg, 70%) as a yellow oil, which solidified upon standing. LC / MS-ESI, [M+H]+ = 335.2 m / z.

[0473] Intermediate 3-1 (810 mg, 2.42 mmol) was treated with TFA (3 mL) at rt for 30min then concentrated and further dried in vacuo. The residue was suspended in MeCN (8.1 mL) and treated with iPr2EtN (1.69 mL, 9.69 mmol), (2S,4R)- l-tert-butoxycarbonyl-4- hydroxy-pyrrolidine-2-carboxylic acid (588 mg, 2.54 mmol), HOBt-H2O (818 mg, 4.84 mmol), and EDC-HCl (532 mg, 3.15 mmol) at rt for 3 hrs. The mixture was poured into sat NaHCO3and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated, and purified by flash column chromatography on silica gel (40g) eluted with 0-15% MeOH in EtOAc to give Intermediate 3-2 (tert-Butyl (2S,4R)-4-hydroxy-2-[[(1R)-2-hydroxy-1-[4-(4-methylthiazol- 5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate; 695mg, 64%) as a yellow foam. LC / MS-ESI, [M+H]+ = 448.3 m / z.

[0474] Intermediate 3-2 (695 mg, 1.55 mmol) was treated with TFA (3 mL) at rt for 30min then concentrated, co-evaporated from toluene once, then further dried in vacuo. This material was dissolved in MeCN (5.2 mL) and treated with iPr2EtN (1.62301 mL, 9.3174 mmol), HOBt-H2O (525 mg, 3.11 mmol), (2S)-2-azido-3 -methyl-butanoic acid (289mg, 2.02 mmol), and EDC-HCl (532 mg, 2.02 mmol) at rt. After 60 min, DMF (ImL) was added, followed by a second charge of EDC-HCl (531.80546 mg, 2.0188 mmol). After an additional 2hrs, IM NaOH (5mL) and MeOH (10mL) were added and the mixture was stirred for 10min then poured into water (10OmL) and extracted with EtOAc (x2) and the combined extract was washed with sat NaHCO3(x2), brine, dried over Na2SO4, and purified by flash column chromatography on silica gel (24g) eluted with EtOAc to give Intermediate 3-3 (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-4-hydroxy-N-[(1R)-2- hydroxy-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 252.2mg, 34%) as a pale yellow foam. LC / MS-ESI, [M+H]+= 473.4 m / z. Synthesis of Compound 1-1 and Compound 1-2

[0475] (2S, 4R)-1-[(2S)-2-{4-[4-( {[(3S, 6S, 7S)-11-chloro-12-( 6-jluoro-5-methyl-1H-indazol-4-yl)-

[0476] 16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17 -tetraazapentacyclo [8. 7.1.13,6.02, 7.014,18]nonadeca-

[0477] 1(17), 10, 12, 14(18), 15-pentaen-13-yl ]oxy]methyl)phenyl ]-1H-1, 2, 3-triazol-1-yl}-3- methylbutanoyl] -4-hydroxy-N- [( lR)-2-hydroxy- 1- [4-(4-methyl- 1 ,3-thiazol-5- yl)phenyl ] ethyl ]pyrrolidine-2-carboxamide

[0478]

[0479] Intermediate 1-3 (206.4 mg, 0.557 mmol) was dissolved in anhydrous THF (1 mL) and treated with NaH, 60% dispersion (63.7 mg, 1.59 mmol) and stirred at rt for Ihr. The mixture was cooled to 0°C and 7-bromo-2,6-dichloro-5,8-difluoro-3H-quinazolin-4- one (175 mg, 0.530 mmol) was added as a solution in THF (2 mL) then the mixture was warmed to 60°C for 1 hr. The mixture was cooled, poured into 5% K2CO3and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give Intermediate 4-1 (7-Bromo-2,6-dichloro-8-fluoro-5- (((1S,3S,4S)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-3-yl)methoxy)quinazolin-4-ol; 523.8mg, >100%) as a tan colored glassy residue, which was used without purification. LC / MS-ESI, [M+H]+= 681.3 m / z.

[0480] Intermediate 4-1 (crude, 0.530mmol) was dissolved in anhydrous DCM (5 mL) and amended with iPr2EtN (277μL, 1.59 mmol) and this mixture was added dropwise via syringe pump over 30 min to a stirred solution of BOP-CI (675 mg, 2.65 mmol) in DCM (4 mL) at 40°C and the mixture was stirred overnight. The mixture was poured into saturated NaHCO3and extracted with EtOAc (x2). The combined extract was washed with sat NaHCO3, brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (12g) eluted with 5-30% Me2CO in hexanes to give Intermediate 4-2 ((lS,4S,13aS)-10-Bromo-7,11- dichloro-9-fluoro-2-trityl- 1,2,3,4,13,13 a-hexahy dro- 1,4- methanopyrazino[2',1':3,4][l,4]oxazepino[5,6,7-de]quinazoline; 78 mg, 22%) as a pale yellow solid. LC / MS-ESI, [M+H]+ = 661.3

[0481] Intermediate 4-2 (72.5 mg, 0.139 mmol) and tetrahydropyran-4-ol (33.2 μL, 0.348 mmol) were dissolved in anhydrous THF (1.4 mL) and treated with KOtBu, IM in THF (307 μL, 0.307 mmol) at 0°C for 10min. The mixture was poured into saturated NaHCO3and extracted with EtOAc (x3). The combined extract was dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 4-3 ((1S,4S,13aS)-

[0482] 10-Bromo- 11 -chloro-9-fluoro-7-((tetrahydro-2H-pyran-4-yl)oxy)-2 -trityl- 1 ,2,3,4,13,13a- hexahydro-l,4-methanopyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline; 78.9mg, 78%) as a pale yellow foam. LC / MS-ESI, [M+H]+= 729.4 m / z

[0483] Intermediate 4-3 (78.9 mg, 0.108 mmol) and Intermediate 2-2 (68.8 mg, 0.238 mmol) were dissolved in anhydrous THF (1.1 mL) and cooled to 0°C then KOtBu, IM in THF (217 μL, 0.217 mmol) was added dropwise. After 45min, the reaction was quenched cold with saturated NaHCO3then poured into saturate NaHCO3and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (4g) eluted with 5-15% EtOAc in hexanes to give Intermediate 4-4 ((1S,4S,13aS)-10-bromo-

[0484] 11-chloro-7-((tetrahydro-2H-pyran-4-yl)oxy)-9-((4-((triisopropylsilyl)ethynyl)benzyl)oxy)- 2-trityl-l,2,3,4,13,13a-hexahydro-l,4-methanopyrazino[2',1':3,4][l,4]oxazepino[5,6,7- de]quinazoline; 33.3mg, 31%) as a faintly yellow film.

[0485] Intermediate 4-4 (33.3 mg, 0.033 mmol), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-trityl-indazole (24.3 mg, 0.047 mmol), K3PO4(14.2 mg, 0.067 mmol), and Pd(PPh3)4 (5.8 mg, 0.005 mmol) were suspended in 1,4-Dioxane (0.5 mL) and Water (0.1 mL) and the mixture was sparged with N2for 5min then sealed and heated to 100°C overnight. The mixture was poured into saturated NaHCO3and extracted with EtOAc and the organic phase was collected and washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (4g) eluted with 5-25% Me2CO in hexanes to give Intermediate 4-5 ((lS,4S,13aS)-11-chloro- 10-(6-fluoro-5-methyl-2-trityl-2H-indazol -4- yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-9-((4-((triisopropylsilyl)ethynyl)benzyl)oxy)-2- trityl-l,2,3,4,13,13a-hexahydro-l,4-methanopyrazino[2',l':3,4][l,4]oxazepino[5,6,7- de]quinazoline; 34.3mg, 78%) of a pale yellow foam.

[0486] Intermediate 4-5 (32.1 mg, 0.0245 mmol) was dissolved in THF (165 uL) and treated with TBAF, IM in THF (49 uL, 0.049 mmol) at rt. After 10min, the material was diluted with EtOAc, filtered through a thin pad of silica gel, and concentrated to give Intermediate 4-6 ((lS,4S,13aS)-11-chloro-9-((4-ethynylbenzyl)oxy)-10-(6-fluoro-5- methyl-2-trityl-2H-indazol-4-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-2-trityl-l,2,3,4,13,13a- hexahydro-l,4-methanopyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline; 29.7mg, >100%) as a light brown colored foam. LC / MS-ESI, [M+H]+= 1151.8 m / z

[0487] Intermediate 4-6 (29.7mg, 0.0245 mmol) was dissolved in THF (300 uL), MeOH (150 uL), DMF (250 uL), and H2O (50 uL) and treated with Intermediate 3-3 (13.9 mg, 0.0294 mmol), THPTA, 200mM in H2O (12.3 uL, 0.0025 mmol), CUSO4, 500mM in water (4.9 uL, 0.0025 mmol), and sodium ascorbate (9.7 mg, 0.049 mmol) and stirred at 40°C overnight. The mixture was diluted with EtOAc and washed with water, brine (x2), dried over Na2SO4, filtered through a thin pad of Celite, and concentrated. This residue was dissolved in DCM (400 uL) and treated with Et3SiH (20 uL, 0.13 mmol) and TFA (20 uL, 0.26 mmol) at rt for 5min then concentrated and triturated with Et2O. The solids were collected by centrifugation and air dried then dissolved in ACN / H2O, filtered, and purified by preparative HPLC to give Compound 1-1 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11- chloro-12-(6-fluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 12.1mg, 43%) as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1139.7 m / z, [M+2H]++= 571.0 m / z.1H NMR (400 MHz, MeOD) δ 8.92 (s, 1H), 8.69 (d, J= 7.9 Hz, 1H), 8.44 (s, 1H), 7.57 (d, J= 8.1 Hz, 2H), 7.52 - 7.43 (m, 4H), 7.34 - 7.27 (m, 1H), 6.78 (d, J= 8.3 Hz, 1H), 5.71 (s, 1H), 5.52 - 5.42 (m, 1H), 5.38 (d, J= 10.3 Hz, 1H), 4.96 - 4.90 (m, 1H), 4.69 - 4.56 (m, 2H), 4.52 - 4.43 (m, 1H), 4.35 - 4.29 (m, 1H), 4.03 - 3.89 (m, 3H), 3.85 (d, J= 6.1 Hz, 1H), 3.70 - 3.56 (m, 3H), 2.70 - 2.58 (m, 1H), 2.56 - 2.44 (m, 2H), 2.27 - 1.98 (m, 5H), 1.96 - 1.81 (m, J= 6.6 Hz, 3H), 1.80 - 1.48 (m, 7H), 1.38 - 1.33 (m, 1H), 1.22 - 1.04 (m, 8H), 0.84 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, MeOD) δ -77.20, -117.04.

[0488] Atropisomer Compound 1-2 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12- (6-fluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 7mg, 21%) was concurrently isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1139.7 m / z, [M+2H]++= 571.0 m / z.1H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 8.52 (s, 1H), 7.59 - 7.55 (m, 1H), 7.50 - 7.41 (m, 4H), 7.36 - 7.25 (m, 4H), 7.22 (d, J= 9.8 Hz, 1H), 5.71 - 5.68 (m, 1H), 5.54 (d, J= 9.9 Hz, 1H), 5.49 - 5.40 (m, 1H), 5.07 - 4.90 (m, 4H), 4.73 - 4.69 (m, 1H), 4.66 - 4.60 (m, 1H), 4.53 - 4.34 (m, 2H), 4.29 - 4.21 (m, 1H), 4.00 - 3.89 (m, 4H), 3.81 (d, J = 6.1 Hz, 1H), 3.70 - 3.48 (m, 5H), 2.66 - 2.56 (m, 1H), 2.54 - 2.44 (m, 4H), 2.25 - 2.06 (m, 7H), 1.93 - 1.76 (m, 2H), 1.32 - 1.27 (m, 1H), 1.17 (dd, J= 6.6, 2.9 Hz, 3H), 0.81 (d, J= 3.4 Hz, 3H).

[0489] Synthesis of Compound 2-1 and 2-2 (2S,4R)-l-[(2S)-2-{4-[4-({[(7S)-l 1 -chloro- 12-(6- jluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazatetracyclo[8. 7.1.02, 7014,18]octadeca-l( 17), 10, 12, 14( 18), 15-pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( 1R)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 5-1 (tert-butyl (S)-3-(((7-bromo-2,6-dichloro-8-fluoro-4- hydroxyquinazolin-5-yl)oxy)methyl)piperazine-1-carboxylate; 1.87g, >100%) was obtained as an off-white solid following the methods for preparation of Intermediate 4-1, except that tert-butyl (5)-3-(hydroxymethyl)piperazine-1-carboxylate was used in place of Intermediate 1-3. LC / MS-ESI, [M+H]+= 526.8 m / z.

[0490] Intermediate 5-2, (tert-butyl (S)-10-bromo-7,1 1-dichloro-9-fluoro-3,4,13,13a- tetrahydropyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline-2(lH)-carboxylate; 564mg, 37%) was prepared in the same manner as Intermediate 4-2 and was obtained as a pale yellow solid. LC / MS-ESI, [M+H]+= 509.2 m / z.

[0491] Intermediate 5-3 (tert-butyl (S)-10-bromo-11-chloro-9-fluoro-7-((tetrahydro-2H- pyran-4-yl)oxy)-3,4,13,13a-tetrahydropyrazino[2',l':3,4][l,4]oxazepino[5,6,7- de]quinazoline-2(lH)-carboxylate; 528mg, 83%) was prepared in the same manner as Intermediate 4-3 and was obtained as an off-white foam. LC / MS-ESI, [M+H]+= 572.9 / 574.9 m / z (3:4).

[0492] Intermediate 5-4 (tert-butyl (S)-10-bromo-11-chloro-7-((tetrahydro-2H-pyran-4- yl)oxy)-9-((4-((triisopropylsilyl)ethynyl)benzyl)oxy)-3,4,13,13a- tetrahydropyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline-2(lH)-carboxylate; 258mg, 33%) was prepared in the same manner as Intermediate 4-4 and was obtained as a pale yellow foam.

[0493] Intermediate 5-5 (tert-butyl (S)- 11 -chloro- 10-(6-fluoro-5-methyl-2 -trityl-2H- indazol-4-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-9-((4- ((triisopropylsilyl)ethynyl)benzyl)oxy)-3,4,13,13a- tetrahydropyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline-2(lH)-carboxylate; 12.8mg, 70%) was prepared in the same manner as Intermediate 4-5 and was obtained as a faintly yellow residue.

[0494] Intermediate 5-6 (tert-butyl (S)-11-chloro-9-((4-ethynylbenzyl)oxy)-10-(6-fluoro- 5-methyl-2-trityl-2H-indazol-4-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-3,4,13,13a- tetrahydropyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline-2(lH)-carboxylate;

[0495] 11.8mg, >100%) was prepared in the same manner as Intermediate 4-6 and was obtained as a pale yellow film. LC / MS-ESI, [M+H]+= 997.0 m / z.

[0496] Compound 2-1 and Compound 2-2 ((2S,4R)-1-[(2S)-2-{4-[4-({[(7S)-11-chloro- 12-(6-fluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazatetracyclo[8.7.1.02’7.014,18]octadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide) were prepared in the same manner as Compound 1-1 except that the final deprotection was carried out using TFA:Et3SiH:H2O (92.5:5:2.5, 300 μL) at rt for 30min in place of DCM / TFA / Et3SiH. The material was obtained as a mixture of two diastereoisomers which was resolved by preparative HPLC (C18, 10-75% ACN in H2O+0.25% TFA) to give Compound 2-1 (3.8mg, 30%, Rt = 20.7min), as its TFA salt as a white solid, LC / MS- ESI, [M+H]+= 1127.0 m / z,1H NMR (400 MHz, MeOD) δ 8.93 (s, 1H), 8.71 (d, J= 7.8 Hz, 1H), 8.45 (s, 1H), 7.64 - 7.56 (m, 3H), 7.49 (s, 3H), 7.33 (d, J= 10.1 Hz, 1H), 6.83 (d, J= 8.1 Hz, 2H), 5.43 - 5.36 (m, 2H), 5.29 (d, J= 13.1 Hz, 1H), 5.12 - 4.98 (m, 2H), 4.79 - 4.71 (m, 2H), 4.61 (t, J= 8.4 Hz, 1H), 4.52 (s, 1H), 4.39 - 4.32 (m, 1H), 4.03 - 3.92 (m, 3H), 3.90 - 3.84 (m, 2H), 3.75 - 3.67 (m, 1H), 3.64 - 3.49 (m, 6H), 2.69 - 2.60 (m, 1H), 2.50 (s, 3H), 2.31 - 1.98 (m, 9H), 1.91 - 1.80 (m, 3H), 1.19 (d, J= 6.5 Hz, 3H), 0.85 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, MeOD) δ -77.36, -117.27. And Compound 2-2 (3.2mg, 26%, Rt = 21.3min) as its TFA salt as a white solid, LC / MS-ESI, [M+H]+= 1127.0 m / z,1H NMR (400 MHz, MeOD) δ 8.93 (d, J= 7.1 Hz, 1H), 8.71 (d, J= 7.8 Hz, 1H), 8.46 (s, 1H), 7.61 (d, J= 8.4 Hz, 2H), 7.51 - 7.44 (m, 5H), 7.34 (d, J= 9.8 Hz, 1H), 6.84 (d, J= 8.1 Hz, 2H), 5.43 - 5.36 (m, 2H), 5.27 (d, J= 14.5 Hz, 1H), 5.12 - 5.04 (m, 1H), 5.01 (d, J= 11.5 Hz, 1H), 4.79 (d, J= 11.5 Hz, 1H), 4.74 - 4.69 (m, 1H), 4.66 - 4.57 (m, 1H), 4.52 (s, 1H), 4.38 - 4.31 (m, 1H), 4.00 - 3.92 (m, 3H), 3.87 (d, J= 6.1 Hz, 2H), 3.73 - 3.66 (m, 1H), 3.65 - 3.50 (m, 6H), 2.71 - 2.61 (m, 1H), 2.50 (s, 3H), 2.31 - 2.21 (m, 1H), 2.18 - 1.98 (m, 7H), 1.93 - 1.81 (m, 2H), 1.47 (s, 1H), 1.19 (d, J= 6.6 Hz, 3H), 0.86 (d, J= 6.8 Hz, 3H).19F NMR (376 MHz, MeOD) δ -77.36, -117.19.

[0497] Synthesis of Intermediate 6-3 7-bromo-2,4-dichloro-5,8-dijluoro-6-iodoquinazoline

[0498] Ethyl 2-amino-4-bromo-3,6-difluorobenzoate (41.46 g, 148.0 mmol) was dissolved in DMF (400 mL) and treated with A-iodosuccinimide (36.637 g, 162.8 mmol) and pTsOH (8.448 g, 44.41 mmol) and the mixture was warmed to 70 °C for 60 min. The mixture was poured into water (IL) and extracted with MTBE (400mL then 2 x 200mL) and the combined extract was washed with 10% Na2S2O3(10OmL), 5% K2CO3(3 x 10OmL), brine (100mL), dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 6-1 (ethyl 2-amino-4-bromo-3,6-difluoro-5-iodobenzoate, 58.73 g, 97.7%) as a light brown colored solid. TLC, Rf = 0.35 (9: 1 hexanes:EtOAc). LC / MS- ESI, [M+H]+= 405.7 / 407.7 m / z (1 :1).

[0499] Intermediate 6-1 (27.19 g, 66.98 mmol) was dissolved in anhydrous THF (171 mL) and treated with trichloroacetyl isocyanate (9.58 mL, 80.4 mmol) at 0 °C then warmed to rt and stirred for 25 min. The mixture was concentrated by rotary evaporation to give an amber colored vitreous oil which solidified upon standing. This material was suspended in anhydrous MeOH (256 mL) and treated with ammonia, 7M in MeOH (11.5 mL, 80.4 mmol) at rt. After 15 min, the mixture was re-cooled to 0 °C and diluted with 5% NaHCO3(2 vol) and stirred for 10 min. The solids were collected by filtration and rinsed with water, 5: 1 hexanes:iPrOH (2 x 75 mL), hexanes (250 mL), dried under suction, and further dried in vacuo at 60 °C to give Intermediate 6-2 (7-bromo-5,8-difluoro-6-iodoquinazoline-2,4- diol; 25.335 g, 93.9%) as an off-white powdery solid. LC / MS-ESI, [M+H]+= 402.7 / 404.7 m / z (1 : 1).1H NMR (400 MHz, DMSO) δ 11.51 (s, 2H).19F NMR (376 MHz, DMSO) δ - 88.29 (d, J= 15.7 Hz), -116.72 (d, J= 15.7 Hz).13C NMR (101 MHz, DMSO) δ 158.55, 156.63 (d, J = 255.4 Hz), 149.61, 142.77 (d, J = 246.0 Hz), 131.48 (d, J= 17.1 Hz), 122.13 (d, J= 19.3 Hz), 105.05 (d, J= 13.4 Hz), 83.18 (d, J= 30.5 Hz).

[0500] Intermediate 6-2 (2.115 g, 5.249 mmol) was suspended in anhydrous toluene (12.7 mL) and treated with POCI3(2.45 mL, 26.2 mmol) at 25 °C. After 30min, iPr2EtN (2.1 mL, 12 mmol) was added dropwise then the mixture was warmed to 35 °C and stirred for 15 min. H2O (24 μL, 1.3 mmol) was added and the mixture was heated to 70 °C for 3 hrs. The mixture was cooled to rt and immersed in a rt water bath and quenched by dropwise addition of H2O (16.9 mL), stirred for 15 min, and filtered through Celite rinsing with toluene. The filtrate was washed with half-saturated brine (x2), dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 6-3 (7-bromo-2,4- dichloro-5,8-difluoro-6-iodoquinazoline; 1.827g, 79%) as a pale yellow solid. TLC Rf = 0.80 (toluene). LC / MS-ESI, [M+H]+= 440.6 m / z.

[0501] Synthesis of Intermediate 7-3 7-bromo-2,4,6-trichloro-5,8-dijluoroquinazoline

[0502] Ethyl 2-amino-4-bromo-3,6-difluoro-benzoate (12.76 g, 45.56 mmol) was dissolved in DMF (113 mL) and treated with N-chlorosuccinimide (6.996 g, 52.39 mmol) and the mixture was warmed to 70 °C for 2 hrs. The mixture was cooled to rt and partitioned between Et2O and H2O and the organic phase was washed with 10% Na2S2O3, 5% K2CO3, brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 7-1 (ethyl 2-amino-4-bromo-5-chloro-3,6-difluorobenzoate; 13.16 g, 91.8%) as a pale orange colored crystalline solid. LC / MS-ESI, [M+H]+= 310.8 / 312.8 m / z (1 :1). Intermediate 7-2 (7-bromo-6-chl oro-5, 8-difluoroquinazoline-2,4-diol; 4.14g, 75.3%) was prepared in the same manner as Intermediate 6-2 and was obtained as an off- white solid. LC / MS-ESI, [M+H]+= 310.8 / 312.8 m / z (4:5).

[0503] Intermediate 7-3 (7-bromo-2,4,6-trichloro-5,8-difluoroquinazoline; 1.958g, 87.5%) was prepared in the same manner as Intermediate 6-3 and was obtained as a pale yellow solid. LC / MS-ESI, [M+H]+= 348.7 m / z.

[0504] Synthesis of Intermediate 8-2, ( 1 S,4S,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-trityl-

[0505] 2, 5-diazabicyclo[ 2.2.1 ] heptane

[0506] Intermediate 1-2 (8.32 g, 17.68 mmol) was dissolved in DCM (60 mL) and treated with imidazole (1.81 g, 26.53 mmol), Et3N (3.7 mL, 26.53 mmol), and TBSC1 (2.80 g, 18.56 mmol) at rt for 6hrs. TLC analysis of an aliquot worked up from EtOAc / H2O showed complete conversion to a major spot. The mixture was filtered through a thin pad of silica gel rinsing with DCM and concentrated then the residue was triturated with 9: 1 hexanes :EtO Ac and again filtered through a thin pad of silica gel rinsing with the same. The filtrate was concentrated to give Intermediate 8-1 (tert-butyl (lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 9.69g, 93.7%) as a white foam. TLC Rf = 0.62 (85: 15 hexanes:Me2CO).

[0507] Intermediate 8-1 (9.69 g, 16.57 mmol) was dissolved in anhydrous DCM (110 mL) and cooled to 0 °C and treated with 2,6-lutidine (4.3 mL, 37.28 mmol) followed by dropwise addition of TMSOTf (4.5 mL, 24.85 mmol) then the mixture was allowed to warm to rt and stirred for 30 min. The reaction was quenched by dropwise addition of sat NaHCO3(0.15 vol) and the mixture was stirred for 10 min. The organic phase was collected, dried over Na2SO4, filtered, and concentrated. The resulting solids were triturated with hexanes and collected by filtration to give Intermediate 8-2 ((lS,4S,6S)-6-(((tert- butyldimethylsilyl)oxy)methyl)-2-trityl-2,5-diazabicyclo[2.2.1]heptane; 9.18 g, >100%) as a white solid. LC / MS-ESI, [M+H]+= 485.1 m / z.1H NMR (400 MHz, CDCl3) δ 7.47 (d, J= 7.4 Hz, 6H), 7.28 - 7.19 (m, 6H), 7.19 - 7.10 (m, 3H), 4.09 - 4.01 (m, 1H), 3.80 (s, 1H), 3.61 - 3.52 (m, 2H), 3.45 (dd, J= 10.9, 7.9 Hz, 1H), 3.38 (d, J = 11.5 Hz, 1H), 2.72 (dd, J = 11.5, 2.6 Hz, 1H), 1.23 (d, J= 11.4 Hz, 1H), 0.79 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H), -0.20 (d, J= 11.4 Hz, 1H).

[0508] Synthesis of Intermediate 9-4, (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-

[0509] 2-hydroxy-l-( 4-(l -methyl- lH-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide tert-Butyl (R)-(l-(4-bromophenyl)-2-hydroxyethyl)carbamate (1.58 g, 5.00 mmol) was treated with TFA (8 mL) for 30 min at rt then concentrated and further dried in vacuo. The residue was reconstituted in DMF (10 mL) and treated with iPr2EtN (5.2 mL, 30 mmol), Boc-trans-4-hydroxy-L-proline (1.16 g, 5.00 mmol), and HCTU (2.27 g, 5.5 mmol) at 0 °C then allowed to warm to rt and stirred for 60 min. IM NaOH (50mL) was added and stirring continued for 20min then the mixture was diluted with water and extracted with EtOAc (x2) and the combined extract was washed with saturated NH4CI (x2), saturated NaHCO3(x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 5% MeOH in EtOAc, and concentrated to give Intermediate 9-1 (tert-butyl (2S,4R)- 2-(((R)-1-(4-bromophenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1- carboxylate; 2.83 g, >100%) as a white foam. LC / MS-ESI, [M+Na]+= 450.9 / 452.9 m / z (1 : 1).

[0510] Intermediate 9-1 (295mg, 75% purity, 0.515mmol), (l-methyl-lH-pyrazol-5- yl)boronic acid (91 mg, 0.722 mmol), Pd(dppf)Cl2(45 mg, 0.062 mmol), and Na2CO3(164 mg, 1.55 mmol) were suspended in 1,4-dioxane (2.2 mL) and H2O (0.4 mL) and sparged with N2for 5min then sealed and heated to 100 °C for 80 min. The mixture was cooled and diluted with EtOAc and washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 9: 1 EtOAc:MeOH, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 5-20% MeOH in EtOAc to give Intermediate 9-2 (tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4-(l-methyl- lH-pyrazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate; 131 mg, 59%) as a red-brown foamy solid. LC / MS-ESI, [M+H]+= 431.2 m / z

[0511] Intermediate 9-2 (131 mg, 0.304 mmol) was dissolved in DCM / MeOH (5:1, 1 mL) and treated with 4N HCl in dioxane (609 uL) at rt for 30min then concentrated and further dried in vacuo. The residue was dissolved in DMF (ImL) and treated with iPr2EtN (265 uL, 1.52 mmol), Boc-L-valine (66 mg, 0.304 mmol) and HCTU (139 mg, 0.335 mmol) at rt. The mixture was diluted with EtOAc and washed with sat NaHCO3(x2), brine (x2), dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 85: 15 EtOAc:MeOH and concentrated to give Intermediate 9-3 (tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy- 1 -(4-( 1 -methyl- lH-pyrazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -y l)-3 - methyl- l-oxobutan-2-yl)carbamate; 190.2mg, >100%) as a pale red-brown foamy solid.

[0512] Intermediate 9-3 (190.2 mg, 0.359 mmol) was dissolved in DCM / MeOH (5: 1, 1 mL) and treated with 4N HCl in dioxane (718 uL) at rt for 60min then concentrated and further dried in vacuo. The residue was dissolved in DCM / ACN (3.6 mL) and basified with Et3N (251uL, 1.8 mmol) then cooled to 0 °C and treated with 2-azido-l,3-dimethyl-4,5- dihydroimidazol-1-ium hexafluorophosphate (102 mg, 0.359 mmol) for 60 min. The mixture was poured into brine and extracted with EtOAc (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (12g) eluted with 5-20% MeOH in DCM to give Intermediate 9-4 ((2S,4R)-1- ((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(l-methyl-lH-pyrazol- 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 64.4 mg, 39%) as a white solid. LC / MS-ESI, [M+H]+= 456.2 m / z

[0513] Synthesis of Intermediate 10, ((4-(bromomethyl)phenyl)ethynyl)triisopropylsilane

[0514] Intermediate 2-2 (1.00 g, 3.466 mmol) was dissolved in anhydrous DCM (14 mL) and treated with PPhs (1.09 g, 4.159 mmol) and A-bromosuccinimide (771 mg, 4.33 mmol) at 0°C then allowed to warm to rt and stirred for 60 min. The mixture was diluted with MTBE and washed with dilute Na2S2O3(x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was reconstituted in hexanes plus a minimal amount of DCM to achieve an even suspension and again filtered through a thin pad of silica gel rinsing with hexanes. Recovered Intermediate 10 (((4- (bromomethyl)phenyl)ethynyl)triisopropylsilane; 1.12 g, 92%) as a pale yellow oil.1H NMR (400 MHz, CDCl3) δ 7.51 - 7.43 (m, 2H), 7.38 - 7.30 (m, 2H), 4.49 (s, 2H), 1.19 - 1.10 (m, 21H).

[0515] Synthesis of Intermediate 11-3, ((4-(bromomethyl)-3- jluorophenyl)ethynyl)triisopropylsilane

[0516] A mixture of 2-fluoro-4-hydroxy -benzaldehyde (1.05 g, 7.494 mmol) and Pyridine (7.49 mL) was cooled to 0 °C and triflic anhydride (1.4 mL, 8.32 mmol) was added dropwise then the mixture was allowed to warm to rt and stirred for 2 hrs. The mixture was concentrated and the residue was diluted with hexanes and filtered through a thin pad of silica gel, and again concentrated. The material was further purified by flash column chromatography on silica gel (40g) eluted with 0-10% EtOAc in hexanes to give Intermediate 11-1 (3-fluoro-4-formylphenyl trifluoromethanesulfonate; 899.5 mg, 44.1%) as an oil.

[0517] Intermediate 11-1 (899.5 mg, 3.31 mmol) and ethynyl(triisopropyl)silane (964 uL, 4.30 mmol) were dissolved in anhydrous THF (6.6 mL) and treated with diisopropylamine (606 uL, 4.30 mmol) and the mixture was sparged with N2for 5min then CuI (63 mg, 0.331 mmol) and Pd(PPh3)2Cl2(46.4 mg, 0.0661 mmol) were added simultaneously and sparging was continued for 5min then the mixture was warmed to 60 °C for 60 min. The mixture was cooled to rt, diluted with 8:2 hexanes :EtO Ac, filtered through a thin pad of silica gel, and concentrated. The residue was dissolved in THF (10 mL) and methanol (3 mL) and treated with NaBH4(125 mg, 3.31 mmol) at rt. After 5min, the mixture was poured into sat NH4Cl and extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (24g) eluted with 0-20% EtOAc in hexanes to give Intermediate 11-2 ((2-fluoro-4- ((triisopropylsilyl)ethynyl)phenyl)methanol; 925.5 mg, 91.4%) as a faintly yellow viscous oil. TLC Rf = 0.60 (7:3 hexanes:Me2CO).1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 10.6 Hz, 1H), 4.75 (s, 2H), 1.69 (s, 1H), 1.13 (s, 21H).

[0518] Intermediate 11-3 (((4-(bromomethyl)-3-fluorophenyl)ethynyl)triisopropylsilane; 203.3 mg, 98%) was prepared from Intermediate 11-2 (172 mg, 0.561 mmol) following the procedure described for Intermediate 10 and was recovered as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.31 (t, J= 7.8 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.16 (dd, J= 10.3, 1.6 Hz, 1H), 4.51 - 4.47 (m, 2H), 1.12 (s, 21H).19F NMR (376 MHz, CDCI3) δ -117.01.

[0519] Synthesis of Intermediate 12-5, (1S,4S,6S)-6-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-2- trityl-2,5-diazabicyclo[2.2.1]heptane & Intermediate 12-7, (lS,4S,6S)-6-((R)-l-((tert- butyldimethylsilyl)oxy)ethyl)-2-trityl-2, 5-diazabicyclo[2.2.1 ] heptane Intermediate 1-2 (692 mg, 1.47 mmol) was dissolve in anhydrous DCM (7.5 mL) and treated NaHCO3(494 mg, 5.88 mmol) followed by DMP (686 mg, 1.62 mmol) at 0°C and stirred for 5 min then allowed to warm to rt and stirred for 60 min. The mixture was filtered through a pre-wetted pad of silica gel rinsing with 7:3 hexanes:EtOAc and concentrated to give Intermediate 12-1 (tert-butyl (lS,3S,4S)-3-formyl-5-trityl-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate; 673.9 mg, 98%) as a white foam. TLC Rf = 0.57 (7:3 hexanes :EtO Ac).

[0520] Intermediate 12-1 (673.9 mg, 1.44 mmol) was dissolved in anhydrous THF (15 mL) and treated with MeMgBr, 3M in Et2O (588 uL) at 0 °C and stirred for 20min. The mixture was poured into sat NH4CI and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 10-40% EtOAc in hexane to give Intermediate 12-2 (tert-butyl (lS,3S,4S)-3- ((S)-1-hydroxyethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 423 mg, 59%) as a white foamy solid and Intermediate 12-3 (tert-butyl (lS,3S,4S)-3-((R)-1- hydroxyethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 190 mg, 39%) as a white foamy solid. Intermediate 12-2: TLC Rf = 0.59 (7:3 hexanes: EtOAc).1H NMR (400 MHz, CDCI3) δ 7.81 (d, J= 7.6 Hz, 6H), 7.54 (t, J= 7.8 Hz, 6H), 7.45 (t, J= 13 Hz, 3H), 5.42 (d, J= 3.0 Hz, 1H), 4.26 (d, J= 9.3 Hz, 1H), 4.21 (s, 1H), 3.74 - 3.63 (m, 2H), 3.49 (d, J= 9.8 Hz, 1H), 2.91 (dd, J= 9.9, 2.1 Hz, 1H), 1.76 (s, 9H), 1.43 (d, J= 9.9 Hz, 1H), 1.38 (d, J= 6.3 Hz, 3H), -0.01 (d, J= 10.1 Hz, 1H). Intermediate 12-3: TLC Rf = 0.44 (7:3 hexanes :EtO Ac).1H NMR (400 MHz, CDCI3) δ 7.47 (d, J= 7.8 Hz, 6H), 7.18 (t, J= 7.7 Hz, 6H), 7.09 (t, J= 13 Hz, 3H), 3.89 - 3.79 (m, 2H), 3.52 (s, 1H), 3.12 (d, J= 10.3 Hz, 1H), 2.81 - 2.71 (m, 1H), 2.57 (d, J= 9.3 Hz, 1H), 1.54 - 1.36 (m, 10H), 1.27 (dt, J= 10.1, 1.2 Hz, 1H), 1.07 (d, J= 13 Hz, 3H), -0.44 (d, J= 8.8 Hz, 1H).

[0521] Intermediate 12-2 (423 mg, 0.873 mmol) was dissolved in anhydrous DMF (1.5 mL) and treated with imidazole (189 mg, 2.6 mmol), Et3N (366 uL, 2.6 mmol), and TBSC1 (276 mg, 1.82 mmol) at rt for 24 hrs. The mixture was diluted with EtOAc and washed with H2O (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (24g) eluted with 0-10% EtOAc in hexanes to give Intermediate 12-4 (tert-butyl (lS,3S,4S)-3- ((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate; 436.3 mg, 100%) as a white foamy solid. TLC Rf = 0.57 (9: 1 hexanes: EtOAc). Intermediate 12-5 ((1 S,4S,6S)-6-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2- trityl-2,5-diazabicyclo[2.2.1]heptane; 416.9 mg, >100%) was prepared in the same manner as Intermediate 8-2 and was isolated as a white foamy solid. LC / MS-ESI, [M+H]+= 499.1 m / z. Intermediate 12-6 (tert-butyl (lS,3S,4S)-3-((R)-1-((tert- butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate; 211 mg, 90%) was prepared in the same manner as Intermediate 12-4 and was isolated as a white foamy solid.

[0522] Intermediate 12-7 ((1 S,4S,6S)-6-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2- trityl-2,5-diazabicyclo[2.2. l]heptane; 169 mg, 90%) was prepared in the same manner as Intermediate 8-2 and was isolated as a white foamy solid. LC / MS-ESI, [M+H]+= 499.1 m / z.

[0523] Synthesis of Compound 3, (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-cyclopropyl- 12-(6- jluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0524]

[0525] Intermediate 6-3 (3.658 g, 7.527 mmol) was dissolved in anhydrous DMF (22 mL) and cooled to 0 °C then Intermediate 8-2 (3.649 g, 7.527 mmol) and iPr2EtN (2.0 mL, 11.5 mmol) were added dropwise as a solution in DMF (14.6 mL). After 30 min, the mixture was poured into water (100 mL) and extracted with EtOAc (2 x 75 mL) and the combined extract was washed with saturated NaHCO3(x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (80g) eluted with 0-10% EtOAc in hexanes to give Intermediate 13-1 (7-bromo-4-(( l S,3S,4S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5- trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-chloro-5,8-difluoro-6-iodoquinazoline; 5.35g, 80.0%) as an off-white glassy foam.

[0526] Intermediate 13-1 (3.84 g, 4.32 mmol) was dissolved in anhydrous THF (20mL) and cooled to -78°C then a mixture of KOtBu, IM in THF (4.3 mL) and tetrahydropyran-4- ol in THF (23mL) was added dropwise via cannula and the mixture was allowed to warm to 0 °C over a period of 2 hrs. The mixture was quenched cold with aqueous NaHCO3then poured into saturated NaHCO3and extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (80g) eluted with 10-40% EtOAc in hexanes to give Intermediate 13-2 (7-bromo-4-((lS,3S,4S)- 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2. l ]heptan-2-yl)-5,8- difluoro-6-iodo-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 3.72 g, 90.2%) as a white foamy solid.

[0527] 4-Methoxybenzyl alcohol (1.45 mL, 11.70 mmol) was dissolved in anhydrous toluene (10mL) and treated with KOtAm, 1.7M in toluene (3.44mL) and the resulting mixture was stirred for 5 min then added to a stirred solution of the Intermediate 13-2 (3.72 g, 3.90 mmol) in toluene (10mL) at 40 °C. After 15min, the mixture was diluted with EtOAc and washed with saturated NaHCO3, brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (80g) eluted with 10-50% EtOAc in hexanes to give Intermediate 13-3 (7-bromo-4-((lS,3S,4S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5- trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-6-iodo-8-((4-methoxybenzyl)oxy)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 3.536 g, 84.6%) as a white foamy solid.

[0528] CsF (2.51 g, 16.5 mmol) was added to a solution of Intermediate 13-3 (3.536 g, 3.299 mmol) in anhydrous ACN (66 mL) and DME (10 mL) followed by Bu4NHSO4(336 mg, 0.990 mmol) and the mixture was heated to 80 °C for 18 hrs. The mixture was cooled then poured into saturated NaHCO3and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (80g) eluted with 10-50% EtOAc in hexanes to give Intermediate 13-4 ((3S,6S,7S)-12-bromo-11-iodo-13-[(4-methoxyphenyl)methoxy]-16- (oxan-4-yloxy)-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10(18), 11, 13, 15 -pentaene; 2.84 g, 91.8%) as a white foam.

[0529] Intermediate 13-4 (330 mg, 0.352 mmol), cyclopropylboronic acid (91 mg, 1.06 mmol), Pd(dppf)Cl2(26mg, 0.0352 mmol), and K3PO4(224mg, 1.06mmol) were suspended in dioxane (1.9 mL) and H2O (380 uL) and the mixture was gently sparged with N2for 5min then sealed and heated to 90 °C for 3 hrs. A second charge of cyclopropyl boronic acid (91 mg, 1.06 mmol) was added and the reaction was continued for an additional 2 hr then cooled to rt, diluted with EtOAc, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 5-30% Me2CO in hexanes to give Intermediate 13-5 (3S,6S,7S)-12-bromo-l 1- cyclopropyl- 13-[(4-methoxyphenyl)m ethoxy]- 16-(oxan-4-yloxy)-5-(triphenylmethyl)-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene; 321.0 mg, >100%) as a white foam. Analysis of an aliquot treated DCM / Et3SiH / TFA (92.5:2.5:5) for 3 min at rt showed LC / MS-ESI, [M+H]+= 489.1 / 491.1 m / z (1 : 1) consistent with the des-trityl, des-PMB material.

[0530] Intermediate 13-5 (321.0 mg, 93.5% purity, 0.3519 mmol) and anisole (153 uL, 1.41 mmol) were dissolved in DCM (3.5 mL) and treated with Et3SiH (169 uL, 1.06 mmol) followed by TFA (390 uL) at rt for 20 min. The mixture was concentrated and the oily residue was triturated with MTBE (x2) and further dried in vacuo. The residue was reconstituted in THF (3.5mL) and basified with Et3N (343uL, 2.46 mmol) then treated with Boc2O (100 mg, 0.457 mmol). Tstop = 17:30 HPLC analysis showed complete conversion to a less polar peak showing The mixture was diluted with EtOAc and washed with sat NaHCO3, brine, filtered through a thin pad of silica gel, and concentrated. TLC analysis (1 :1 hexanes :EtO Ac) showed a major spot Rf = 0.35. The material was purified by flash column chromatography on silica gel (12g) eluted with 20-70% EtOAc in hexanes to give Intermediate 13-6 (tert-butyl (3S,6S,7S)-12-bromo-11-cyclopropyl-13-hydroxy-16-(oxan- 4-yloxy)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- 1(17), 10, 12, 14(18), 15-pentaene-5-carboxylate; 121. Img, 58%) as an off-white foam. LC / MS-ESI [M+H]+= 589.2 / 591.2 m / z (1 : 1). Intermediate 13-6 (121. Img, 0.2054 mmol) and Intermediate 10 (108 mg, 0.308 mmol) were dissolved in THF (2 mL) and treated with K2CO3(56mg, 0.41 mmol) and KI (68mg, 0.41 mmol) and heated to 60°C for 3 hrs. The mixture was diluted with EtOAc and washed with saturated NaHCCE, brine, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 0-40% EtOAc in hexanes to give Intermediate 13-7 (tert-butyl (3S,6S,7S)-12- bromo- 11 -cyclopropyl- 16-(oxan-4-yloxy)- 13 -[(4- {2-[tris(propan-2- yl)silyl]ethynyl }phenyl)methoxy]-9-oxa-2,5, 15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene-5- carboxylate; 137.3mg, 77.7%) as a white solid residue. TLC Rf = 0.64 (1 : 1 hexanes :EtO Ac).1H NMR (400 MHz, CDCI3) δ 7.50 - 7.40 (m, 4H), 5.26 - 5.10 (m, 3H), 5.07 (d, J= 11.0 Hz, 1H), 4.52 - 4.21 (m, 2H), 4.07 - 3.96 (m, 1H), 3.96 - 3.83 (m, 2H), 3.73 - 3.24 (m, 5H), 2.10 - 1.61 (m, 8H), 1.33 (s, 9H), 1.14 - 0.96 (m, 22H), 0.82 - 0.63 (m, 1H), 0.63 - 0.50 (m, 1H).

[0531] Intermediate 13-7 (113.2 mg, 0.1316 mmol),6-fluoro-5-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-trityl-indazole (102mg, 0.197 mmol), CPhos Pd G3 (21 mg, 0.023 mmol), CPhos (5.7 mg, 0.013 mmol), and K3PO4(70 mg, 0.329 mmol) were suspended in Toluene:dioxane:H2O (2.5:2.5: 1, 877 uL) and heated to 80 °C for 60 min. The mixture was cooled, diluted with EtOAc, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 30-80% EtOAc in hexanes to give Intermediate 13-8 (tert-butyl (3S,6S,7S)- 11 -cyclopropyl- 12-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-(oxan-4- yloxy)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene-5- carboxylate; 130.1 mg, 84.4%) as an off-white foamy solid.

[0532] Intermediated 13-9 (tert-butyl (3S,6S,7S)-11-cyclopropyl-13-[(4- ethynylphenyl)methoxy]-12-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16- (oxan-4-yloxy)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- 1(17), 10, 12, 14(18), 15-pentaene-5-carboxylate; 97. Img, 71.3%) was prepared from Intermediate 13-8 (157.2 mg, 0.134 mmol) following the procedure described for Intermediate 4-6 and was isolated as a faintly yellow colored foamy solid.1H NMR (400 MHz, CDCI3) δ 7.42 - 7.01 (m, 14H), 6.92 (d, J= 7.9 Hz, 5H), 6.72 - 6.43 (m, 2H), 5.18 - 4.83 (m, 3H), 4.59 - 4.23 (m, 3H), 4.02 - 3.79 (m, 3H), 3.70 - 3.20 (m, 5H), 2.11 - 1.66 (m, 10H), 1.39 - 1.23 (m, 1OH), 0.86 - 0.67 (m, 1H), 0.49 - -0.05 (m, 3H).19F NMR (376 MHz, CDCl3) δ -115.42.

[0533] Compound 3 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-cyclopropyl- 12-(6-fluoro- 5 -methyl- 1 H-indazol -4-yl)- 16-(oxan-4-yloxy)-9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 67.2 mg, 53%) was prepared from Intermediate 13-8 (97.1mg, 0.0924 mmol) following the procedure described for Compound 2-1 and was recovered as its TFA salt as a white solid. LC / MS-ESI [M+H]+= 1145.0 m / z.1H NMR (400 MHz, DMSO) δ 12.93 (br s, 1H), 9.23 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 8.32 (d, J= 8.0 Hz, 1H), 8.14 (s, 1H), 7.52 (d, J= 8.1 Hz, 2H), 7.34 - 7.19 (m, 6H), 6.56 (d, J= 8.4 Hz, 2H), 5.17 (d, J= 10.3 Hz, 1H), 5.13 - 5.03 (m, 2H), 4.88 (d, J= 11.9 Hz, 1H), 4.69 (q, J= 5.8 Hz, 1H), 4.45 (d, J= 10.8 Hz, 2H), 4.35 (s, 1H), 4.29 (t, J = 8.0 Hz, 1H), 4.23 (t, J= 10.9 Hz, 1H), 4.17 (s, 1H), 3.99 (dd, J= 11.4, 3.9 Hz, 1H), 3.71 (d, J= 11.6 Hz, 2H), 3.66 - 3.39 (m, 3H), 3.11 - 3.40 (m, 6H), 2.33 - 2.26 (m, 4H), 2.01 - 1.76 (m, 8H), 1.65 (d, J= 13.0 Hz, 1H), 1.54 (d, J= 12.6 Hz, 2H), 1.38 - 1.26 (m, 1H), 0.92 (d, J= 6.8 Hz, 3H), 0.56 (d, J= 6.8 Hz, 3H), 0.43 - 0.32 (m, 1H), 0.29 - 0.19 (m, 1H), 0.18 - 0.08 (m, 1H), 0.08 - -0.06 (m, 1H).19F NMR (376 MHz, DMSO) δ -116.62.

[0534] Synthesis of Compound 4 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7 S)- 11 -cyclopropyl- 12-(6- fluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13-

[0535] yl ]oxy}methyl)- 3 -fluorophenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-

[0536] [ (lR)-2-hydroxy-l-[ 4-(4-methyl-l, 3-thiazol-5-yl)phenyl ] ethyl ]pyrrolidine-2-carboxamide

[0537] Intermediate 14-1 (tert-butyl (3S,6S,7S)-12-bromo-11-cyclopropyl-13-[(2-fluoro- 4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene-5- carboxylate; 24.1mg, 39%) was prepared in the same manner as Intermediate 13-7 except that Intermediate 11-3 was used in place of Intermediate 10. TLC Rf = 0.42 (8:2 hexanes :EtO Ac).

[0538] Intermediate 14-2 (tert-butyl (3S,6S,7S)-1 l-cyclopropyl-13-[(2-fluoro-4-{2- [tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene-5- carboxylate; 22.3 mg, 70%) was prepared in the same manner as Intermediate 13-8. TLC Rf = 0.24 (8:2 hexanes:EtOAc)

[0539] Intermediate 14-3 (tert-butyl (3S,6S,7S)-11-cyclopropyl-13-[(4-ethynyl-2- fluorophenyl)methoxy]-12-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16- (oxan-4-yloxy)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- 1(17), 10, 12, 14(18), 15-pentaene-5-carboxylate; 17.1mg, 87%). TLC Rf = 0.17 (8:2 hexanes :EtO Ac).

[0540] Compound 4 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-cyclopropyl- 12-(6-fluoro- 5 -methyl- 1 H-indazol -4-yl)- 16-(oxan-4-yloxy)-9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)-3-fluorophenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N- [(lR)-2-hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 1.1 mg, 9.5%) was prepared from Intermediate 14-3 (8.6mg, 0.083 mmol) following the procedure described for Compound 3 and was recovered as its TFA salt as a white solid. LC / MS-ESI [M+H]+= 1163.0 m / z.1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 9.31 - 9.14 (m, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 8.34 (d, J= 8.0 Hz, 1H), 8.20 - 8.04 (m, 1H), 7.43 (dd, 7= 11.1, 1.8 Hz, 1H), 7.35 - 7.20 (m, 7H), 6.30 (t, J= 7.9 Hz, 1H), 5.22 (d, J= 10.3 Hz, 1H), 5.16 - 5.02 (m, 3H), 4.71 (q, 7= 6.2 Hz, 1H), 4.58 (d, 7= 11.3 Hz, 1H), 4.43 (dd, 7 = 10.8, 4.1 Hz, 1H), 4.39 - 4.13 (m, 5H), 4.00 (dd, 7 = 11.0, 4.3 Hz, 1H), 3.79 - 3.70 (m, 2H), 3.68 - 3.13 (m, 8H), 2.32 (s, 4H), 2.00 - 1.78 (m, 8H), 1.70 - 1.60 (m, 1H), 1.60 - 1.46 (m, 2H), 1.38 - 1.27 (m, 1H), 0.94 (d, 7 = 6.6 Hz, 3H), 0.58 (d, 7 = 6.6 Hz, 3H), 0.46 - 0.35 (m, 1H), 0.29 - 0.20 (m, 1H), 0.18 - 0.07 (m, 1H), 0.05 - -0.06 (m, 1H).19F NMR (376 MHz, DMSO) δ -116.73, -119.07.

[0541] Synthesis of Compound 5 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ (lS)-l-[4- (4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0542] (S)-1-(4-(4-Methylthiazol-5-yl)phenyl)ethan-1-amine hydrochloride (1.009 g, 3.96 mmol) was dissolved in DMF (8 mL) and treated with iPr2EtN (2.07 mL, 11.9 mmol), Boc- trans-4-hydroxy-L-proline (916mg, 3.96 mmol), and HCTU (1.80 g, 4.36 mmol) at 0 °C then allowed to warm to rt and stirred for Ihr. IM NaOH (50mL) was added and stirring for 20min then the mixture was diluted with water and extracted with EtOAc (x2) and the combined extract was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 5% MeOH in EtOAc, and concentrated to give Intermediate 15-1 (tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate; 1.46 g, 85.4%) as a white foam. LC / MS-ESI [M+H]+= 432.0 m / z.

[0543] Intermediate 15-1 (1.46 g, 3.26 mmol) was dissolved in MeOH:DCM (3:2, 10 mL) and treated with 4N HCl in dioxane (3.3 ml) at rt for 60 min then concentrated and further dried in vacuo. A portion of the residue (250 mg, 73% purity, 0.496 mmol) was reconstituted in DMF (1.5 mL) and treated with iPr2EtN (259 uL, 1.49 mmol), Boc-L- valine (113 mg, 0.521 mmol), and HCTU (226mg, 0.546 mmol) at rt for 60 min. The reaction was quenched with IM NaOH (5 mL) and stirred for 5 min then poured into sat NaHCO3and extracted with EtOAc (x2). The organic phase was washed with brine (x2), dried over Na2SO4, filtered through a thin pad of silica gel rinsing with 95:5 EtOAc:MeOH, and concentrated to give Intermediate 15-2 (tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -y l)-3 -methyl- 1 -oxobutan- 2-yl)carbamate; 192.7 mg, 73%) as a white solid. TLC Rf = 0.48 (95:5 EtOAc:MeOH). LC / MS-ESI [M+H]+= 531.0 m / z.

[0544] Intermediate 15-2 (192.7 mg, 0.363 mmol) was dissolved in MeOH:DCM (3:2, 1.5 mL) and treated with 4N HCl in dioxane (726 uL) at rt for 60 min, then the mixture was concentrated and further dried in vacuo. The residue was dissolved in DCM / ACN (1 :1, 3 mL) and treated with Et3N (253 uL, 1.82 mmol) then cooled to 0°C and treated with 2- azido-l,3-dimethyl-4,5-dihydroimidazol-1-ium hexafluorophosphate (104 mg, 0.363 mmol) and stirred for 60 min. The mixture was poured into brine and extracted with EtOAc (x3) and the combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (12g) eluted with 2-15% MeOH in DCM to give Intermediate 15-3 ((2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 138.0 mg, 83%) as a pale yellow solid. LC / MS-ESI [M+H]+= 457.0 m / z.

[0545] Compound 5 (2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lS)-1-[4- (4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 32.9 mg, 63%) was prepared from Intermediate 4-6 (44.3 mg, 0.0385 mmol) following the procedure described for Compound 1-1 except that Intermediate 15-3 was used in place of Intermediate 3-3. LC / MS-ESI [M+H]+= 1123.4 m / z.1H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 8.99 (s, 1H), 8.67 (s, 1H), 8.52 (d, J= 7.5 Hz, 1H), 8.32 (s, 1H), 7.68 (d, J= 8.3 Hz, 2H), 7.58 (s, 1H), 7.50 - 7.34 (m, 5H), 6.77 (d, J= 8.4 Hz, 2H), 5.33 (d, J= 10.1 Hz, 1H), 5.24 - 5.12 (m, 4H), 5.02 - 4.88 (m, 1H), 4.65 (dd, J= 10.7, 2.4 Hz, 2H), 4.40 (t, J= 8.2 Hz, 1H), 4.36 - 4.23 (m, 2H), 3.91 - 3.66 (m, 5H), 3.43 - 3.28 (m, 2H), 3.02 - 2.87 (m, 2H), 2.49 - 2.44 (m, 4H), 2.19 - 1.93 (m, 8H), 1.85 - 1.75 (m, 1H), 1.75 - 1.63 (m, 3H),

[0546] 1.39 (d, J= 7.0 Hz, 3H), 1.08 (d, J= 6.6 Hz, 3H), 0.72 (d, J= 6.5 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.94.

[0547] Synthesis of Compound 6 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S,8R)-11-chloro- 12-(6- jluoro-5-methyl-lH-indazol-4-yl)-8-methyl-16-(oxan-4-yloxy)-9-oxa-2, 5,15,17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0548]

[0549]

[0550] Intermediate 7-3 (937 mg, 2.69 mmol) was dissolved in 1 : 1 THF:DMF (7 mL) and cooled to -40 °C then iPr2EtN (1.2 mL, 6.7 mmol) and the Intermediate 12-7 (1.652 g, 2.69 mmol) were added. After 30min, the mixture was poured into sat NaHCO3and extracted with EtOAc. The organic phase was washed with sat NaHCCE (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The material was purified by flash column chromatography on silica gel (40g) eluted with 0-20% EtOAc in bexanes to give Intermediate 16-1 (7-bromo-4-(( 1 S,3S,4S)-3-((S)- 1 -((tert- butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,6-dichloro-5,8- difluoroquinazoline; 2.135g, 97.9%) as a pale yellow foam. TLC Rf = 0.72 (8:2 hexanes :EtO Ac)

[0551] Intermediate 16-1 (2.135 g, 2.634 mmol) and tetrahyropyran-4-ol (753 uL, 7.901 mmol) were dissolved in anhydrous THF (17.5 mL) and cooled to -30 °C then KOtBu, IM in THF (2.8mL) was added. After 30min, the mixture was poured into sat NaHCO3and extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (40g) eluted with 0-20% EtOAc in hexanes to give Intermediate 16-2 (7-bromo-4-((lS,3S,4S)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-5- trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8-difluoro-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazoline; 1.791 g, 77.6%) as a white foamy solid. 4-Iodobenzyl alcohol (848 mg, 3.625 mmol) was dissolved in anhydrous toluene (3 mL) and treated with KOtAm, 1.7 M in toluene (1.07mL) and the resulting mixture was added rapidly via cannula to a stirred solution of the Intermediate 16-2 (1.059 g, 1.208 mmol) in toluene (3 mL) at 45°C. After 10 min, the mixture was poured into sat NaHCO3and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (24g) eluted with 0-20% EtOAc in hexanes to give Intermediate 16-3 (7-bromo-4-((lS,3S,4S)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-5- trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5-fluoro-8-((4-iodobenzyl)oxy)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 1.129g, 85.7%) as a colorless residue. TLC Rf = 0.39 (toluene: hexane :ACN, 46:46:8, x2)

[0552] Intermediate 16-3 (1.129 g, 1.035 mmol) was dissolved in anhydrous ACN / DME (5: 1, 21 mL) and treated with anhydrous CsF (786 mg, 5.18 mmol) and Bu4NHSO4(105 mg, 0.311 mmol) and heated to 90 °C in a sealed vial for 48 hrs. The mixture was poured into saturated NaHCO3and extracted with EtOAc. The organic phase was filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (40g) eluted with 10-50% EtOAc in hexanes to give Intermediate 16-4 (3S,6S,7S,8R)- 12-bromo- 11 -chloro- 13 -[(4-iodophenyl)methoxy]-8-m ethyl- 16-(oxan-4-yloxy)-5- (triphenylmethyl)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- 1(17), 10, 12, 14(18), 15-pentaene; 857.2 mg, 86.6%) as a white foam.1H NMR (400 MHz, CDCI3) δ 7.74 - 7.64 (m, 2H), 7.50 - 7.37 (m, 6H), 7.36 - 7.26 (m, 2H), 7.18 (t, J= 7.8 Hz, 6H), 7.08 (t, J= 7.3 Hz, 3H), 5.25 - 5.10 (m, 3H), 4.87 (d, J= 7.1 Hz, 1H), 4.67 (tt, J= 6.5, 3.4 Hz, 1H), 3.98 - 3.83 (m, 3H), 3.59 (s, 1H), 3.34 (dddd, J= 12.8, 11.5, 9.9, 2.8 Hz, 2H), 3.25 (dd, J= 10.6, 4.4 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.05 (ddt, J= 14.8, 4.4, 2.1 Hz, 1H), 1.96 (s, 1H), 1.79 (ddtd, J= 30.6, 13.4, 9.8, 4.3 Hz, 2H), 1.39 - 1.28 (m, 1H), 1.17 (dd, J= 6.9, 4.3 Hz, 3H), 0.01 (d, J= 9.8 Hz, 1H). Analysis of an aliquot deprotected with DCM / Et3SiH / TFA (92.5:2.5:5) for 3 min at rt showed LC / MS-ESI, [M+H]+= 712.9 / 715.0 m / z (3:4).

[0553] Intermediate 16-4 (857.2 mg, 0.897 mmol), iPr2NH (316 uL, 2.24 mmol), and TIPS acetylene (302uL, 1.345 mmol) were dissolved in DMF:ACN (1: 1, 4.5 mL) and sparged with N2for 5 min then Pd(PPh3)2Cl2(47.2 mg, 0.0672 mmol) and Cui (34 mg, 0.179 mmol) were added and sparging continued for another 5 min then the vessel was sealed and stirring continued at rt for an additional 5 min. The mixture was diluted with MTBE and washed with dilute NaHCCE, brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (24g) eluted with 0-30% EtOAc in hexanes to give Intermediate 16-5 ((3S,6S,7S,8R)-12-bromo-11-chloro-8-methyl-16-(oxan-4-yloxy)-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 795.6 mg, 87.8%) as a tan colored foam.

[0554] Intermediate 16-5 (416.7 mg, 0.4123 mmol), K3PO4(219 mg, 1.031 mmol), CPhos (18 mg, 0.0412 mmol), and CPhos Pd G3 (66.5 mg, 0.0823 mmol) were suspended in degassed toluene (1.1 mL) and H2O (450 uL) and treated with 6-fluoro-5-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-trityl-indazole (321 mg, 0.619 mmol) as a solution in 1,4-dioxane (1.1 mL) and the mixture was heated to 65 °C for 60 min. The mixture was cooled, diluted with EtOAc and washed with H2O, brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (24g) eluted with 5-25% EtOAc in hexanes to give Intermediate 16-6 ((8R,8aS,9S,12S)-6-chloro-5-(6-fluoro-5-methyl-2-trityl-2H-indazol-4- yl)-8-methyl-2-((tetrahydro-2H-pyran-4-yl)oxy)-4-((4- ((triisopropylsilyl)ethynyl)benzyl)oxy)-10-trityl-8,8a,9,10,11,12-hexahydro-9,12- methanopyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline; 284.8 mg, 52.2%) as a tan colored foam.

[0555] Intermediate 16-7 ((3S,6S,7S,8R)-1 l-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-8-methyl-16-(oxan-4-yloxy)-5-(triphenylmethyl)-13- [(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 264.9 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a pale brown foam. TLC Rf = 0.18 (8:2 hexanes:EtOAc).

[0556] Compound 6 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S,8R)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-methyl-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 63.0 mg, 41.4%) was prepared from Intermediate 16-7 (136.6 mg, 95% purity, 0.1113 mmol) by the protocol described for Compound 1-1 and was recovered as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.4 m / z.1H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 9.49 - 9.34 (m, 1H), 8.99 (s, 1H), 8.66 (s, 1H), 8.48 (d, J= 7.9 Hz, 1H), 8.13 - 8.03 (m, 1H), 7.70 (d, J= 8.3 Hz, 2H), 7.50 - 7.34 (m, 6H), 6.78 (d, J= 8.5 Hz, 2H), 5.33 (d, J= 10.3 Hz, 1H), 5.29 - 5.14 (m, 3H), 4.96 - 4.80 (m, 2H), 4.73 (d, J= 11.3 Hz, 1H), 4.56 (s, 1H), 4.45 (t, J = 8.0 Hz, 1H), 4.32 (s, 1H), 4.22 (d, J= 4.3 Hz, 1H), 3.91 - 3.82 (m, 2H), 3.81 - 3.67 (m,

[0557] 2H), 3.67 - 3.46 (m, 2H), 3.43 - 3.31 (m, 2H), 2.56 - 2.48 (m, 1H), 2.46 (s, 3H), 2.40 - 2.33 (m, 1H), 2.19 - 1.89 (m, 7H), 1.86 - 1.63 (m, 4H), 1.41 (d, J= 6.5 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 0.72 (d, J= 6.6 Hz, 5H). Synthesis of Compound 7 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S, 6S, 7S,8S)-11 -chloro- 12-(6-fluoro-

[0558] 5-methyl-lH-indazol-4-yl)-8-methyl-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0559]

[0560] Intermediate 17-1 (7-bromo-4-((lS,3S,4S)-3-((S)-1-((tert- butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,6-dichloro-5,8- difluoroquinazoline; 535.0 mg, 81%) was prepared in the same manner as Intermediate 16-1 except that Intermediate 12-5 was used in place of Intermediate 12-7. TLC Rf =

[0561] 0.26 (8:2 hexanes:EtOAc).

[0562] Intermediate 17-2 (7-bromo-4-((lS,3S,4S)-3-((S)-1-((tert- butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 347.3 mg, 60%) was prepared in the same manner as Intermediate 16-2. TLC Rf = 0.24 (8:2 hexanes:EtOAc). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS- ESI [M+H]+= 634.9 m / z.

[0563] Intermediate 17-3 (7-bromo-4-((lS,3S,4S)-3-((S)-1-((tert- butyldimethylsilyl)oxy)ethyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 352.8 mg, 82%) was prepared in the same manner as Intermediate 16-3 and was isolated as a white colored foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI [M+H]+ = 846.8 / 848.7 m / z (4:5).

[0564] Intermediate 17-4 ((3S,6S,7S,8S)-12-bromo-11-chloro-13-[(4- iodophenyl)methoxy]-8-methyl-16-(oxan-4-yloxy)-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 312.1 mg, 100%) was prepared in the same manner as Intermediate 16-4 and was isolated as a white foam.1H NMR (400 MHz, CDCl3) δ 7.74 (d, J= 8.3 Hz, 2H), 7.48 (d, J= 7.8 Hz, 6H), 7.39 (d, J= 8.3 Hz, 2H), 7.30 - 7.20 (m, 6H), 7.15 (t, J= 7.3 Hz, 3H), 5.34 (d, J= 11.0 Hz, 1H), 5.28 - 5.15 (m, 2H), 4.71 (s, 1H), 4.43 - 4.31 (m, 1H), 4.03 - 3.89 (m, 2H), 3.76 (d, J= 10.6 Hz, 1H), 3.57 - 3.47 (m, 2H), 3.47 - 3.32 (m, 2H), 2.86 (dd, J= 10.4, 2.6 Hz, 1H), 2.17 - 2.08 (m, 1H), 2.06 - 1.98 (m, 1H), 1.96 - 1.75 (m, 2H), 1.49 (d, J= 6.3 Hz, 3H), 1.37 (d, J= 9.6 Hz, 1H), -0.01 (d, J= 9.5 Hz, 1H). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 712.7 / 714.7 m / z (4:5).

[0565] Intermediate 17-5 ((3S,6S,7S,8S)-12-bromo-11-chloro-8-methyl-16-(oxan-4- yloxy)-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene; 286.1 mg, 87%) was prepared in the same manner as Intermediate 16-5 and was isolated as an amber colored foamy solid. TLC Rf = 0.34 (8:2 hexanes :EtO Ac, x2).

[0566] Intermediate 17-6 ((3S,6S,7S,8S)-11 -chloro- 12- [6-fluoro-5 -methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-8-methyl-16-(oxan-4-yloxy)-5-(triphenylmethyl)-13- [(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 95.5 mg, 26%) was prepared in the same manner as Intermediate 16-6 and was isolated as a pale brown film.

[0567] Intermediate 17-7 ((3S,6S,7S,8S)-1 l-chloro-13-[(4-ethynylphenyl)methoxy]-12- [6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-methyl-16-(oxan-4-yloxy)-5- (triphenylmethyl)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- l(17),10,12,14(18),15-pentaene; 49.4 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a pale brown foam. TLC Rf = 0.25 (7:3 hexanes :EtO Ac).

[0568] Compound 7 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S,8S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-methyl-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 23 mg, 46%) was prepared from Intermediate 17-7 (47.8 mg, 0.111 mmol) by the protocol described for Compound 1-1 and was recovered as its TFA salt as a white solid. LC / MS- ESI, [M+H]+= 1153.0 m / z.1H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 9.57 - 9.26 (m, 1H), 8.99 (s, 1H), 8.66 (s, 1H), 8.47 (d, J= 7.9 Hz, 1H), 8.05 - 7.91 (m, 1H), 7.69 (d, J= 8.3 Hz, 2H), 7.50 - 7.41 (m, 4H), 7.38 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 5.33 (d, J= 10.1 Hz, 1H), 5.30 - 5.18 (m, 2H), 5.05 (s, 1H), 4.84 (dq, J= 12.4, 6.4 Hz, 2H), 4.68 (d, J= 11.4 Hz, 1H), 4.50 - 4.41 (m, 2H), 4.32 (s, 1H), 3.91 - 3.74 (m, 4H), 3.74 - 3.29 (m, 8H), 2.48 - 2.44 (m, 4H), 2.18 - 1.95 (m, 8H), 1.84 - 1.64 (m, 3H), 1.46 (d, J= 6.3 Hz, 3H), 1.08 (d, J= 6.6 Hz, 3H), 0.72 (d, J= 6.6 Hz, 3H).

[0569] Synthesis of Compound 8 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13-

[0570] yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(l-methyl-lH-pyrazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0571] Compound 8 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy- 1 -[4-( 1 -methyl- lH-pyrazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 3.5 mg, 60%) was prepared according to the protocol described for Compound 1-1, except that Intermediate 9-4 was used in place of Intermediate 3-3, and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1122.3 m / z.1H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 9.56 - 9.41 (m, 1H), 8.67 (s, 1H), 8.55 - 8.46 (m, 2H), 7.70 (d, J= 8.3 Hz, 2H), 7.52 - 7.44 (m, 5H), 7.40 (d, J= 8.4 Hz, 2H), 6.77 (d, J= 8.4 Hz, 2H), 6.38 (d, J= 1.9 Hz, 1H), 5.39 - 5.31 (m, 2H), 5.29 - 5.14 (m, 2H), 4.88 (q, J= 5.9 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.58 (s, 1H), 4.52 - 4.42 (m, 2H), 4.35 - 4.31 (m, 1H), 4.19 (dd, J= 10.2, 3.2 Hz, 1H), 3.92 - 3.83 (m, 7H), 3.83 - 3.69 (m, 2H), 3.68 - 3.55 (m, 2H), 3.51 - 3.31 (m, 3H), 2.61 - 2.45 (m, 1H), 2.40 (d, J= 10.6 Hz, 1H), 2.20 - 1.92 (m, 8H), 1.86 - 1.66 (m, 3H), 1.09 (d, J = 6.6 Hz, 3H), 0.73 (d, J= 6.6 Hz, 3H). Synthesis of Compound 9 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(3-methyl-lH-pyrazol-4-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0572] Intermediate 18-1 (tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4-(3- methyl-lH-pyrazol-4-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate; 102.3 mg, 70%) was prepared in the same manner as Intermediate 9-2 except that 3-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole was used in place of (1-methyl- lH-pyrazol-5-yl)boronic acid. LC / MS-ESI, [M+H]+= 431.3 m / z.

[0573] Intermediate 18-2 (tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4- (3-methyl-lH-pyrazol-4-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan- 2-yl)carbamate; 125.3mg, 100%) was prepared in the same manner as Intermediate 9-3. LC / MS-ESI, [M+H]+= 530.3 m / z.

[0574] Intermediate 18-3 ((2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)- 2-hydroxy-1-(4-(3-methyl-lH-pyrazol-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 16.8mg, 16%) was prepared in the same manner as Intermediate 9-4. LC / MS-ESI, [M+H]+= 456.2 m / z.

[0575] Compound 9 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(3-methyl-lH-pyrazol-4-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 2.1 mg, 28%) was prepared according to the protocol described for Compound 1-1, except that Intermediate 18-3 was used in place of Intermediate 3-3, and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1122.4 m / z.1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.42 (s, 1H), 8.66 (s, 1H), 8.51 - 8.39 (m, 2H), 7.74 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.49 (s, 1H), 7.46 (d, J= 9.9 Hz, 1H), 7.38 (d, J= 8.4 Hz, 2H), 7.28 (d, J= 8.4 Hz, 2H), 6.76 (d, J= 8.4 Hz, 2H), 5.39 - 5.30 (m, 2H), 5.28 - 5.13 (m, 2H), 4.81 (q, J = 6.6 Hz, 1H), 4.72 - 4.64 (m, 2H), 4.57 (s, 1H), 4.51 - 4.40 (m, 3H), 4.32 (s, 1H), 4.17 (dd, J= 10.1, 3.0 Hz, 2H), 3.91 - 3.49 (m, 8H), 3.50 - 3.31 (m, 2H), 2.56 - 2.44 (m, 1H), 2.43 - 2.29 (m, 4H), 2.17 - 1.89 (m, 7H), 1.85 - 1.64 (m, 3H), 1.08 (d, J= 6.6 Hz, 3H), 0.72 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.74.

[0576] Synthesis of Compound 10 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-fluoro- 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-N-[ ( lR)-l-[ 4-( 1 -ethyl- 1H- pyrazol-5-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide

[0577] Intermediate 19-1 (tert-butyl (2S,4R)-2-(((R)-1-(4-(l-ethyl-lH-pyrazol-5- yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate; 127 mg, 91%) was prepared in the same manner as Intermediate 9-2 except that l-ethylpyrazole-5- boronic acid pinacol ester was used in place of (1 -methyl- lH-pyrazol-5-yl)boronic acid. LC / MS-ESI, [M+H]+= 445.3 m / z.

[0578] Intermediate 19-2 (tert-butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(l-ethyl-lH-pyrazol-5- yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2- yl)carbamate; 146mg, 94%) was prepared in the same manner as Intermediate 9-3. LC / MS-ESI, [M+H]+= 544.3 m / z.

[0579] Intermediate 19-3 (2S,4R)- 1 -((S)-2-azido-3 -methylbutanoyl)-N-((R)- 1 -(4-(l -ethyl- lH-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide; 71.5mg, 57%) was prepared in the same manner as Intermediate 9-4. LC / MS-ESI, [M+H]+= 470.3 m / z.

[0580] Compound 10 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-N-[(lR)-1-[4-(l-ethyl- lH-pyrazol-5-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide; 1.4 mg, 22%) was prepared according to the protocol described for Compound 1-1, except that Intermediate 19-3 was used in place of Intermediate 3-3, and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1136.4 m / z.1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.42 (s, 1H), 8.66 (s, 1H), 8.55 - 8.40 (m, 2H), 7.72 - 7.65 (m, 2H), 7.54 - 7.38 (m, 8H), 6.77 (d, J= 8.4 Hz, 2H), 6.31 (d, J= 1.9 Hz, 1H), 5.38 - 5.30 (m, 2H), 5.29 - 5.08 (m, 3H), 4.87 (q, J= 6.2 Hz, 1H), 4.68 (dd, J= 11.3, 3.4 Hz, 2H), 4.57 (s, 1H), 4.51 - 4.41 (m, 2H), 4.32 (s, 1H), 4.21 - 4.06 (m, 3H), 3.91 - 3.76 (m, 3H), 3.74 - 3.55 (m, 4H), 3.45 (s, 2H), 2.58 - 2.45 (m, 1H), 2.39 (d, J= 10.0 Hz, 1H), 2.17 - 1.92 (m, 7H), 1.85 - 1.62 (m, 3H), 1.31 (t, J= 7.3 Hz, 3H), 1.08 (d, J= 6.8 Hz, 3H), 0.76 - 0.69 (m, 3H).

[0581] Synthesis of Compound 11 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-fluoro- 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)- 3 -fluorophenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N- [ (lR)-2-hydroxy-l-[ 4-(4-methyl-l, 3-thiazol-5-yl)phenyl (ethyl ]pyrrolidine-2-carboxamide

[0582]

[0583] Intermediate 20-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,6-dichloro- 5,8-difluoroquinazoline; 3.21 g, 72%) was prepared in the same manner as Compound 16- 1, except that Intermediate 8-2 was used in place of Intermediate 12-7, and was isolated as an off-white solid.

[0584] Intermediate 20-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 1.896 g, 86%) was prepared in the same manner as Compound 16-2 and was isolated as a white foamy solid.1H NMR (400 MHz, CDCl3) δ 7.53 - 7.39 (m, 6H), 7.25 - 7.17 (m, 6H), 7.16 - 7.09 (m, 3H), 5.43 - 5.34 (m, 1H), 5.08 (dd, J= 8.8, 4.1 Hz, 1H), 4.37 (s, 1H), 4.14 - 4.00 (m, 2H), 3.82 - 3.74 (m, 2H), 3.72 - 3.59 (m, 2H), 3.31 (t, J= 9.6 Hz, 1H), 2.78 (d, J= 10.5 Hz, 1H), 2.63 (dd, J= 10.6, 2.5 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.20 - 2.10 (m, 1H), 2.07 - 1.90 (m, 2H), 1.49 (d, J = 9.4 Hz, 1H), 0.91 - 0.71 (m, 9H), 0.00 (s, 3H), -0.04 (s, 3H), -0.19 (d, J= 8.6 Hz, 1H).

[0585] Intermediate 20-3 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((2-fluoro-4-iodobenzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline; 204.6 mg, 65%) was prepared in the same manner as Intermediate 16-3, except that (2- fluoro-4-iodophenyl)methanol was used in place of 4-iodobenzyl alcohol, and was isolated as a white foamy solid. TLC Rf = 0.39 (toluene: hexane :ACN, 46:46:8). Intermediate 20-4 ((3S,6S,7S)-12-bromo-11-chloro-13-[(2-fluoro-4- iodophenyl)methoxy]-16-(oxan-4-yloxy)-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 201.0 mg 78%) was prepared in the same manner as Intermediate 16-4 and was isolated as a pale yellow colored foamy solid. TLC Rf = 0.34 (8:2 hexane s:EtO Ac). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 717.0 / 719.0 m / z (3:4).

[0586] Intermediate 20-5 ((3S,6S,7S)-12-bromo-11-chloro-13-[(2-fluoro-4-{2- [tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-16-(oxan-4-yloxy)-5-(triphenylmethyl)-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene; 191.0 mg, 90%) was prepared in the same manner as Intermediate 16-5 and was isolated as a light brown colored foamy solid. TLC Rf = 0.43 (8:2 hexanes :EtO Ac).

[0587] Intermediate 20-6 ((3S,6S,7S)-1 l-chloro-13-[(2-fluoro-4-{2-[tris(propan-2- yl)silyl]ethynyl}phenyl)methoxy]-12-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol- 4-yl]-16-(oxan-4-yloxy)-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 101.4mg, 41%) was prepared in the same manner as Intermediate 16-6 and was isolated as a yellow colored foamy solid.

[0588] Intermediate 20-7 ((3S,6S,7S)-1 l-chloro-13-[(4-ethynyl-2-fluorophenyl)methoxy]- 12-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-(oxan-4-yloxy)-5- (triphenylmethyl)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- l(17),10,12,14(18),15-pentaene; 98.6mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as an amber colored foamy solid. TLC Rf = 0.76 (1 : 1 hexanes :EtO Ac).

[0589] Compound 11 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)-3-fluorophenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N- [(lR)-2-hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 40.4 mg, 38%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1157.4 m / z.1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.45 - 9.32 (m, 1H), 8.99 (s, 1H), 8.77 (s, 1H), 8.48 (d, J= 7.9 Hz, 1H), 8.45 - 8.37 (m, 1H), 7.64 - 7.54 (m, 1H), 7.51 - 7.42 (m, 5H), 7.38 (d, J= 8.4 Hz, 2H), 6.50 (t, J= 7.9 Hz, 1H), 5.43 - 5.21 (m, 4H), 4.85 (q, J= 6.1 Hz, 1H), 4.76 (d, J= 11.4 Hz, 1H), 4.69 (dd, J= 11.3, 3.0 Hz, 1H), 4.57 (s, 1H), 4.47 (d, J= 10.4 Hz, 1H), 4.44 (d, J= 6.4 Hz, 1H), 4.35 - 4.30 (m, 1H), 4.17 (dd, J= 10.4, 3.3 Hz, 1H), 3.94 - 3.68 (m, 5H), 3.67 - 3.55 (m, 2H), 3.53 - 3.35 (m, 4H), 2.53 - 2.45 (m, 4H), 2.39 (d, J= 11.1 Hz, 1H), 2.14 - 1.90 (m, 7H), 1.84 - 1.61 (m, 3H), 1.08 (d, J= 6.6 Hz, 3H), 0.73 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.82, -119.00.

[0590] Synthesis of Compound 12 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-{[(2R)-l-methoxypropan-2-yl]oxy}-9-oxa-2,5,15,17- tetraazapentacyclo [8. 7.1.13,6.02,' 014,18]nonadeca- 1( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0591] Intermediate 21-1 (7-bromo-4-((1S,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-(((R)-1-methoxypropan-2-yl)oxy)quinazoline; 332.9mg, 75%) was prepared in the same manner as Intermediate 16-1, except that (R)-1-methoxypropan-2-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0592] Intermediate 21-2 (7-brorno-4-(( 1 S,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-(((R)-1-methoxypropan-2-yl)oxy)quinazoline; 353.5 mg, 85%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid. TLC Rf = 0.64 (85: 15 hexanes:EtOAc, x2).1H NMR (400 MHz, CDCl3) δ 7.73 (d, J= 8.3 Hz, 2H), 7.58 (d, J= 7.8 Hz, 6H), 7.38 (d, J= 8.4 Hz, 2H), 7.29 (t, J= 7.8 Hz, 6H), 7.19 (t, J= 7.3 Hz, 3H), 5.58 - 5.49 (m, 1H), 5.42 (d, J= 11.0 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 5.18 (dd, J= 8.5, 4.3 Hz, 1H), 4.38 (s, 1H), 3.93 - 3.78 (m, 3H), 3.65 (dd, J = 10.1, 4.4 Hz, 1H), 3.50 (s, 3H), 3.41 (t, J= 9.1 Hz, 1H), 2.87 (d, J= 10.5 Hz, 1H), 2.69 (dd, J= 10.6, 2.6 Hz, 1H), 1.57 (d, J= 10.9 Hz, 1H), 1.46 (d, J= 6.4 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H), -0.17 (d, J= 9.8 Hz, 1H).19F NMR (376 MHz, CDCl3) δ -105.39.

[0593] Intermediate 21-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-{[(2R)-1-methoxypropan-2-yl]oxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 276.9 mg, 90%) was prepared in the same manner as Intermediate 16-3 and was isolated as a pale brown foamy solid. TLC Rf = 0.18 (8:2 hexanes :EtO Ac). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 686.9 / 689.0 m / z (3:4).

[0594] Intermediate 21-4 ((3S,6S,7S)-12-bromo-11-chloro-16-{[(2R)-1-methoxypropan- 2-yl]oxy}-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]- 9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene; 221.8 mg, 76%) was prepared in the same manner as Intermediate 16-4 and was isolated as a tan colored foamy solid. TLC Rf = 0.24 (8:2 hexanes:EtOAc).

[0595] Intermediate 21-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-{[(2R)-1-methoxypropan-2-yl]oxy}-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 216.8 mg, 74%) was prepared in the same manner as Intermediate 16-5 and was isolated as a tan colored foamy solid. TLC Rf = 0.39 (7:3 hexane s:EtO Ac).

[0596] Intermediate 21-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-{[(2R)-1-methoxypropan-2- yl]oxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 173.8 mg, 91%) was prepared in the same manner as Intermediate 4-6 and was isolated as an off-white colored foamy solid. TLC Rf = 0.21 (7:3 hexanes:EtOAc). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 655.2 m / z.

[0597] Compound 12 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)- 16-{[(2R)-1 -methoxypropan-2-yl]oxy}-9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 25.0 mg, 52%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1127.4 m / z.1H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 9.44 - 9.32 (m, 1H), 8.99 (s, 1H), 8.66 (s, 1H), 8.49 (d, J= 7.9 Hz, 1H), 8.45 - 8.32 (m, 1H), 7.66 (d, J= 8.3 Hz, 2H), 7.52 - 7.42 (m, 4H), 7.38 (d, J= 8.4 Hz, 2H), 6.74 (d, J= 8.4 Hz, 2H), 5.42 - 5.30 (m, 3H), 5.21 (d, J= 11.4 Hz, 1H), 4.85 (q, J= 6.2 Hz, 1H), 4.68 (d, J= 11.4 Hz, 2H), 4.57 (s, 1H), 4.52 - 4.41 (m, 2H), 4.34 - 4.30 (m, 1H), 4.17 (dd, J= 10.2, 3.1 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.70 (d, J= 11.0 Hz, 1H), 3.67 - 3.53 (m, 3H), 3.52 - 3.40 (m, 3H), 3.30 - 3.25 (m, 3H), 2.46 (s, 5H), 2.41 (d, J= 11.7 Hz, 1H), 2.13 - 2.03 (m, 1H), 1.99 (d, J= 2.4 Hz, 3H), 1.96 (d, J= 11.8 Hz, 1H), 1.79 (ddd, J= 13.0, 8.6, 4.7 Hz, 1H), 1.34 (d, J= 6.4 Hz, 3H), 1.08 (d, J= 6.6 Hz, 3H), 0.72 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.76.

[0598] Synthesis of Compound 13 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-f!uoro- 5-methyl-lH-indazol-4-yl)-16-{[(2S)-l-methoxypropan-2-yl]oxy}-9-oxa-2,5,15,17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 22-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-(((S)-1-methoxypropan-2-yl)oxy)quinazoline; 221.3 mg, 82%) was prepared in the same manner as Intermediate 16-1, except that (S)-1-methoxypropan-2-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white crystalline solid.

[0599] Intermediate 22-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-(((S)-1-methoxypropan-2-yl)oxy)quinazoline; 166.5 mg, 60%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid. TLC Rf = 0.77 (7:3 hexanes :EtO Ac).

[0600] Intermediate 22-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16- { [(2 S)- 1 -methoxypropan-2-yl]oxy } -5 -(triphenylmethyl)-9-oxa-2, 5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 149.3 mg, 99%) was prepared in the same manner as Intermediate 16-3 and was isolated as a tan colored foamy solid. TLC Rf = 0.54 (7:3 hexanes:EtOAc).

[0601] Intermediate 22-4 ((3S,6S,7S)-12-bromo-11-chloro-16-{[(2S)-1-methoxypropan-2- yl]oxy}-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene; 102.5 mg, 65%) was prepared in the same manner as Intermediate 16-4 and was isolated as a faintly yellow solid.

[0602] Intermediate 22-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-{[(2S)-1-methoxypropan-2-yl]oxy}-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 72.5 mg, 54%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid. TLC Rf = 0.48 (7:3 hexane s:EtO Ac).

[0603] Intermediate 22-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-{[(2S)-1-methoxypropan-2- yl]oxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 74.3 mg, >100% ) was prepared in the same manner as Intermediate 4-6 and was isolated as a yellow colored foamy solid. TLC Rf = 0.26 (7:3 hexanes :EtO Ac). Compound 13 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl- 1 H-indazol-4-yl)- 16- { [(2 S)- 1 -methoxypropan-2-yl] oxy } -9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 12.9 mg, 41%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1127.4 m / z.1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 9.39 - 9.24 (m, 1H), 8.96 (s, 1H), 8.62 (s, 1H), 8.45 (d, J= 7.8 Hz, 1H), 8.41 - 8.30 (m, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.48 - 7.38 (m, 4H), 7.34 (d, J= 8.3 Hz, 2H), 6.70 (d, J= 8.4 Hz, 2H), 5.41 - 5.26 (m, 3H), 5.15 (d, J = 11.4 Hz, 1H), 4.86 - 4.76 (m, 1H), 4.68 (d, J= 11.6 Hz, 1H), 4.64 (dd, J= 11.6, 3.6 Hz, 1H), 4.53 (s, 1H), 4.47 - 4.36 (m, 2H), 4.30 - 4.26 (m, 1H), 4.13 (dd, J= 9.8, 2.7 Hz, 1H), 3.77 - 3.71 (m, 1H), 3.69 - 3.64 (m, 1H), 3.62 - 3.37 (m, 7H), 3.25 (s, 3H), 2.49 - 2.39 (m, 4H), 2.35 (d, J= 11.6 Hz, 1H), 2.10 - 1.99 (m, 1H), 1.95 (d, J = 2.4 Hz, 3H), 1.91 (d, J= 11.0 Hz, 1H), 1.80 - 1.70 (m, 1H), 1.26 (d, J= 6.5 Hz, 3H), 1.04 (d, J= 6.6 Hz, 3H), 0.68 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.75.

[0604] Synthesis of Compound 14 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-[(3R)-oxolan-3-yloxy]-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 23-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)quinazoline; 192.6 mg, 58%) was prepared in the same manner as Intermediate 16-1, except that (R)-tetrahydrofuran-3-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid. TLC Rf = 0.49 (95:5 toluene :MeCN).

[0605] Intermediate 23-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-(((R)-tetrahydrofuran-3-yl)oxy)quinazoline; 127.9 mg, 53%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid. TLC Rf = 0.62 (95:5 toluene :MeCN). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 819.0 / 821.0 m / z (3:4).

[0606] Intermediate 23-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-[(3R)-oxolan-3-yloxy]-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 115.6 mg, >100%) was prepared in the same manner as Intermediate 16-3 and was isolated as a tan colored foamy solid. TLC Rf = 0.28 (7:3 hexanes:EtOAc). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 685.0 / 686.9 m / z (3:4).

[0607] Intermediate 23-4 ((3S,6S,7S)-12-bromo-11-chloro-16-[(3R)-oxolan-3-yloxy]-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 75.3 mg, 62%) was prepared in the same manner as Intermediate 16-4 and was isolated as a faintly yellow foamy solid. TLC Rf = 0.39 (7:3 hexanes:EtOAc).

[0608] Intermediate 23-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-[(3R)-oxolan-3-yloxy]-5-(triphenylmethyl)-13-[(4- {2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 73.7 mg, 74%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid. TLC Rf = 0.43 (7:3 hexanes:EtOAc).

[0609] Intermediate 23-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-[(3R)-oxolan-3-yloxy]-5- (triphenylmethyl)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- l(17),10,12,14(18),15-pentaene; 83.1 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a yellow colored foamy solid. TLC Rf = 0.22 (7:3 hexanes :EtO Ac). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 653.2 m / z.

[0610] Compound 14 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-[(3R)-oxolan-3-yloxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 34.3 mg, 45%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1125.4 m / z.1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.52 - 9.29 (m, 1H), 9.00 (s, 1H), 8.65 (s, 1H), 8.49 (d, J= 7.7 Hz, 1H), 8.46 - 8.39 (m, 1H), 7.69 - 7.63 (m, 2H), 7.51 - 7.41 (m, 4H), 7.40 - 7.35 (m, 2H), 6.74 (d, J= 8.4 Hz, 2H), 5.58 (d, J= 2.1 Hz, 1H), 5.38 - 5.30 (m, 2H), 5.23 (d, J= 11.6 Hz, 1H), 4.85 (q, J= 6.2 Hz, 1H), 4.75 - 4.64 (m, 2H), 4.57 (s, 1H), 4.51 - 4.40 (m, 2H), 4.32 (s, 1H), 4.17 (dd, J= 10.5, 3.4 Hz, 1H), 3.94 - 3.82 (m, 3H), 3.82 - 3.67 (m, 3H), 3.61 (qd, J= 10.9, 6.4 Hz, 2H), 3.54 - 3.39 (m, 2H), 2.56 - 2.44 (m, 5H), 2.40 (d, J= 12.5 Hz, 1H), 2.26 (dt, J= 13.4, 7.3 Hz, 1H), 2.16 - 2.03 (m, 2H), 2.02 - 1.91 (m, 4H), 1.79 (ddd, J= 12.7, 8.4, 4.5 Hz, 1H), 1.08 (d, J= 6.6 Hz, 3H), 0.72 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.76.

[0611] Synthesis of Compound 15 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-f!uoro- 5-methyl-lH-indazol-4-yl)-16-[ ( 3S) -oxolan-3-yloxy ]-9-oxa-2, 5,15,17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 24-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline; 203.3 mg, 66%) was prepared in the same manner as Intermediate 16-1, except that (S)-tetrahydrofuran-3-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0612] Intermediate 24-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline; 176.7 mg, 69%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid.

[0613] Intermediate 24-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-[(3S)-oxolan-3-yloxy]-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 162.2 mg, >100%) was prepared in the same manner as Intermediate 16-3 and was isolated as a tan colored foamy solid. TLC Rf = 0.29 (7:3 hexanes:EtOAc). Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 685.0 / 687.0 m / z (3:4).

[0614] Intermediate 24-4 ((3S,6S,7S)-12-bromo-11-chloro-16-[(3S)-oxolan-3-yloxy]-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 82.7 mg, 48%) was prepared in the same manner as Intermediate 16-4 and was isolated as a faintly yellow foamy solid. TLC Rf = 0.52 (7:3 hexanes:EtOAc).

[0615] Intermediate 24-5 ((8aS,9S,12S)-6-chloro-5-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-2-(((S)-tetrahydrofuran-3-yl)oxy)-4-((4- ((triisopropylsilyl)ethynyl)benzyl)oxy)-10-trityl-8,8a,9,10,11,12-hexahydro-9,12- methanopyrazino[2',l':3,4][l,4]oxazepino[5,6,7-de]quinazoline; 72.7 mg, 67%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid. TLC Rf = 0.44 (7:3 hexanes :EtO Ac).

[0616] Intermediate 24-6 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-[(3S)-oxolan-3-yloxy]-5-(triphenylmethyl)-13-[(4- {2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 75.9 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a red- brown colored foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 653.2 m / z.

[0617] Compound 15 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-[(3 S)-oxolan-3-yloxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 29.6 mg, 39%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1125.4 m / z.1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.55 - 9.30 (m, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.52 - 8.46 (m, 1H), 8.43 (s, 1H), 7.65 (d, J= 8.3 Hz, 2H), 7.50 - 7.41 (m, 4H), 7.38 (d, J= 8.4 Hz, 2H), 6.73 (d, J= 8.6 Hz, 2H), 5.63 - 5.51 (m, 1H), 5.37 - 5.30 (m, 2H), 5.20 (d, J= 11.6 Hz, 2H), 4.85 (q, J= 6.1 Hz, 1H), 4.74 - 4.64 (m, 2H), 4.57 (s, 1H), 4.52 - 4.40 (m, 2H), 4.35 - 4.29 (m, 1H), 4.22 - 4.14 (m, 1H), 3.96 - 3.83 (m, 3H), 3.83 - 3.67 (m, 3H), 3.61 (qd, J= 10.9, 6.2 Hz, 2H), 3.53 - 3.39 (m, 2H), 2.56 - 2.44 (m, 4H), 2.40 (d, J= 10.5 Hz, 1H), 2.29 - 2.18 (m, 1H), 2.13 - 2.03 (m, 2H), 2.01 - 1.92 (m, 4H), 1.84 - 1.73 (m, 1H), 1.08 (d, J= 6.6 Hz, 3H), 0.71 (d, 7 = 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.76.

[0618] Synthesis of Compound 16 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-[ (Is, 3 s) -3 -methoxy cyclobutoxy ]-9-oxa-2, 5,15,17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 25-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-((ls,3R)-3 -methoxy cy cl obutoxy)quinazoline; 353.4 mg, 100%) was prepared in the same manner as Intermediate 16-1, except that cis-3 -methoxy cyclobutanol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0619] Intermediate 25-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-((ls,3R)-3-methoxycyclobutoxy)quinazoline; 226.5 mg, 61%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 835.0 m / z.

[0620] Intermediate 25-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-[(ls,3s)-3-methoxycyclobutoxy]-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 202 mg, >100%) was prepared in the same manner as Intermediate 16-3 and was isolated as a tan colored foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 699.0 / 701.0 m / z (3:4).

[0621] Intermediate 25-4 ((3S,6S,7S)-12-bromo-11-chloro-16-[(ls,3s)-3- methoxycyclobutoxy]-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2- yl)silyl]ethynyl }phenyl)methoxy]-9-oxa-2,5, 15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 110.1 mg, 53%) was prepared in the same manner as Intermediate 16-4 and was isolated as a pale brown foamy solid.

[0622] Intermediate 25-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-[(ls,3s)-3-methoxycyclobutoxy]-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 100.9 mg, 70%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid.

[0623] Intermediate 25-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-[(ls, 3 s)-3-m ethoxy cyclobutoxy]- 5-(triphenylmethyl)-9-oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 100.8 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a yellow colored foamy solid.

[0624] Compound 16 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-[(ls,3s)-3-methoxycyclobutoxy]-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 58.4 mg, 49%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1139.4 m / z.1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.51 - 9.32 (m, 1H), 9.00 (s, 1H), 8.67 (s, 1H), 8.49 (d, J= 7.8 Hz, 1H), 8.40 (s, 1H), 7.73 - 7.66 (m, 2H), 7.52 - 7.42 (m, 4H), 7.41 - 7.35 (m, 2H), 6.80 (d, J= 8.6 Hz, 2H), 5.37 - 5.30 (m, 2H), 5.20 (d, J= 11.5 Hz, 1H), 4.89 - 4.81 (m, 2H), 4.73 - 4.63 (m, 2H), 4.56 (s, 1H), 4.51 - 4.40 (m, 2H), 4.35 - 4.28 (m, 1H), 4.16 (dd, J = 10.1, 3.2 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.70 (d, J= 10.8 Hz, 1H), 3.67 - 3.39 (m, 5H), 3.10 (d, J= 1.1 Hz, 3H), 2.79 - 2.70 (m, 2H), 2.54 - 2.44 (m, 4H), 2.45 - 2.36 (m, 2H), 2.13 - 2.03 (m, 1H), 2.02 - 1.89 (m, 6H), 1.79 (ddd, J = 13.0, 8.4, 4.5 Hz, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.72 (dd, J= 6.6, 3.2 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.75.

[0625] Synthesis of Compound 17 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11 -chloro- 12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-{2-oxaspiro[3.3 ]heptan-6-yloxy}-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 26-1 (2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-7-bromo-4-((lS,3S,4S)-3- (((tert-butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6- chloro-5,8-difluoroquinazoline;) was prepared in the same manner as Intermediate 16-1, except that 2-oxaspiro[3.3]heptan-6-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0626] Intermediate 26-2 (2-((2-oxaspiro[3.3]heptan-6-yl)oxy)-7-bromo-4-((lS,3S,4S)-3- (((tert-butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6- chloro-5-fluoro-8-((4-iodobenzyl)oxy)quinazoline;) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid.

[0627] Intermediate 26-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-{2-oxaspiro[3.3]heptan-6-yloxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene;) was prepared in the same manner as Intermediate 16-3 and was isolated as a tan colored foamy solid.

[0628] Intermediate 26-4 ((3S,6S,7S)-12-bromo-11-chloro-16-{2-oxaspiro[3.3]heptan-6- yloxy}-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene;) was prepared in the same manner as Intermediate 16-4 and was isolated as a faintly yellow foamy solid.

[0629] Intermediate 26-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-{2-oxaspiro[3.3]heptan-6-yloxy}-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene;) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid.

[0630] Intermediate 26-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-{2-oxaspiro[3.3]heptan-6- yloxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene;) was prepared in the same manner as Intermediate 4-6 and was isolated as a red-brown colored foamy solid. Compound 17 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl- 1 H-indazol-4-yl)- 16- { 2-oxaspiro[3.3 ]heptan-6-yloxy } -9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1151.4 m / z.1H NMR (400 MHz, DMSO) 5 13.12 (s, 1H), 8.95 (s, 1H), 8.63 (s, 1H), 8.46 (d, J= 7.8 Hz, 1H), 8.28 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.42 - 7.38 (m, 3H), 7.34 (d, J= 8.4 Hz, 2H), 6.76 (d, J= 8.4 Hz, 2H), 5.29 (d, J= 10.3 Hz, 1H), 5.19 (d, J = 11.5 Hz, 1H), 5.13 (d, J = 3.9 Hz, 1H), 5.07 - 4.96 (m, 2H), 4.86 - 4.77 (m, 2H), 4.66 - 4.55 (m, 2H), 4.50 - 4.37 (m, 5H), 4.34 - 4.18 (m, 2H), 3.80 - 3.71 (m, 2H), 3.65 (d, J= 11.5 Hz, 2H), 3.62 - 3.49 (m, 2H), 2.97 - 2.83 (m, 2H), 2.71 - 2.59 (m, 2H), 2.42 (s, 3H), 2.30 - 2.21 (m, 2H), 2.03 (t, J= 10.8 Hz, 1H), 1.98 - 1.89 (m, 5H), 1.75 (ddd, J= 12.8, 8.3, 4.5 Hz, 1H), 1.66 (d, J= 9.7 Hz, 1H), 1.04 (d, J= 6.6 Hz, 3H), 0.71 - 0.64 (m, 3H).19F NMR (376 MHz, DMSO) δ -116.94.

[0631] Synthesis of Compound 18 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-{[ 1 -(methoxymethyl)cyclopropyl]methoxy}-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 27-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-((l-(methoxymethyl)cyclopropyl)methoxy)quinazoline; 322.8 mg, 73%) was prepared in the same manner as Intermediate 16-1, except that (1- (methoxymethyl)cyclopropyl)methanol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0632] Intermediate 27-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-((l-(methoxymethyl)cyclopropyl)methoxy)quinazoline; 233.7 mg, 58%) was prepared in the same manner as Intermediate 16-2 and was isolated as a white foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 847.0 / 849.0 m / z (3:4).

[0633] Intermediate 27-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-{[l-(methoxymethyl)cyclopropyl]methoxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 138.9 mg, 68%) was prepared in the same manner as Intermediate 16-3 and was isolated as a white colored foamy solid. Analysis of an aliquot deprotected with DCM / TFA / Et3SiH (92.5:5:2.5) at rt for 5 min showed LC / MS-ESI, [M+H]+= 713.0 / 714.9 m / z (4:5).

[0634] Intermediate 27-4 ((3S,6S,7S)-12-bromo-11-chloro-16-{[l- (methoxymethyl)cyclopropyl]methoxy}-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2- yl)silyl]ethynyl }phenyl)methoxy]-9-oxa-2,5, 15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 113.1 mg, 77%) was prepared in the same manner as Intermediate 16-4 and was isolated as a pale yellow foamy solid.

[0635] Intermediate 27-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-{[l-(methoxymethyl)cyclopropyl]methoxy}-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 109.0 mg, 74%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid.

[0636] Intermediate 27-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6-fluoro-5- methyl-2-(triphenylmethyl)-2H-indazol-4-yl]- 16- { [ 1 - (methoxymethyl)cyclopropyl]methoxy}-5-(triphenylmethyl)-9-oxa-2, 5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 93.2 mg, 97%) was prepared in the same manner as Intermediate 4-6 and was isolated as a red- brown colored foamy solid.

[0637] Compound 18 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl- 1 H-indazol-4-yl)- 16- { [ 1 -(methoxymethyl)cy clopropyl]methoxy } -9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 56.0 mg, 51%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.4 m / z.1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.48 - 9.36 (m, 1H), 9.00 (s, 1H), 8.65 (s, 1H), 8.52 - 8.42 (m, 2H), 7.69 - 7.60 (m, 2H), 7.51 - 7.41 (m, 4H), 7.41 - 7.34 (m, 2H), 6.76 (d, J= 8.6 Hz, 2H), 5.39 (s, 1H), 5.33 (d, J= 10.1 Hz, 1H), 5.20 (d, J= 11.4 Hz, 1H), 4.85 (q, J= 6.3 Hz, 1H), 4.68 (dd, J= 11.3, 3.2 Hz, 2H), 4.58 (s, 1H), 4.51 - 4.41 (m, 2H), 4.34 - 4.27 (m, 3H), 4.17 (dd, J= 10.1, 3.3 Hz, 1H), 3.78 (dd, J= 10.5, 4.2 Hz, 1H), 3.70 (d, J= 11.0 Hz, 1H), 3.61 (qd, J= 10.9, 6.3 Hz, 2H), 3.47 (s, 2H), 3.32 (s, 2H), 3.23 (s, 3H), 2.46 (s, 5H), 2.40 (d, J= 12.3 Hz, 1H), 2.13 - 2.03 (m, 1H), 2.01 - 1.92 (m, 4H), 1.79 (ddd, J= 12.7, 8.4, 4.5 Hz, 1H), 1.08 (d, J= 6.7 Hz, 3H), 0.72 (d, J= 6.6 Hz, 3H), 0.63 - 0.56 (m, 2H), 0.57 - 0.49 (m, 2H).19F NMR (376 MHz, DMSO) δ -116.77.

[0638] Synthesis of Compound 19 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11 -chloro- 12-(6-jluoro-

[0639] 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-l-yl}-3-methylbutanoyl]-4-hydroxy-N-[(2S)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]propyl]pyrrolidine-2-carboxamide

[0640]

[0641] (S)-Methyl lactate (2.44 g, 23.4 mmol) and imidazole (3.19 g, 46.9 mmol) were dissolve in anhydrous DCM (23 mL) and treated with TBSC1 (4.59 g, 30.5 mmol) at 0 °C then allowed to warm to rt and stirred for 2 hrs. The mixture was washed with H2O, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The material was purified by flash column chromatography on silica gel (80g) eluted with 0-10% EtOAc in hexanes to give Intermediate 28-1 (methyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate; 4.471 g, 87%) as a colorless oil. TLC Rf = 0.54 (9: 1 hexanes :EtO Ac).1H NMR (400 MHz, CDCl3) δ 4.33 (q, J= 6.8 Hz, 1H), 3.72 (s, 3H), 1.40 (d, J= 6.8 Hz, 3H), 0.90 (s, 9H), 0.08 (d, J= 10.6 Hz, 6H).

[0642] Intermediate 28-1 (4.47 g, 20.5 mmol) was dissolved in anhydrous DCM and cooled to -78°C and DIBAL, IM in toluene (22.5 mL) was added dropwise and stirring continued at the same temperature for 40 min. The reaction was quenched with saturated Rochelle’s salt (20 mL) and allowed to warm to rt. The mixture was diluted with additional H2O (20 mL) and extracted with DCM (3 x 30 mL). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give Intermediate 28-2 ((S)-2- ((tert-butyldimethylsilyl)oxy)propanal; 4.42g, >100%) as a colorless syrup. TLC Rf = 0.46 (9:1 hexanes :EtO Ac).

[0643] Intermediate 28-2 (4.42 g, 87% purity, 20.5 mmol) and S-tert-butanesulfinamide (2.58 g, 20.5 mmol) were suspended in anhydrous THF (41 mL) and treated with Ti(OEt)4 (8.6 mL, 41 mmol) at rt for 6 hrs. The mixture was poured into brine (20mL) and stirred for 10min then filtered through Celite rinsing with EtOAc. The organic phase was collected, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (80g) eluted with 0-15% EtOAc in hexanes to give Intermediate 28-3 ((S)-A-((S,E)-2-((tert- butyldimethylsilyl)oxy)propylidene)-2-methylpropane-2-sulfinamide; 2.631 g, 44%) as a white solid.

[0644] 4-Bromoiodobenzene (5.62 g, 19.9 mmol) was dissolved in anhydrous Et2O (20 mL) and treating with isopropylmagnesium bromide lithium chloride complex, 1.3M in THF (15.3 mL) at -40 °C and stirred for 30 min. Intermediate 28-3 (2.631g, 9.03 mmol) was dissolved in DCM (27 mL) and cooled to -78 °C then the above Grignard solution was added dropwise and the cooling bath was allowed to slowly warm to rt. The mixture was then poured into saturated NH4CI and extracted with EtOAc (x2). The combined extract was dried over MgSO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (80g) eluted with 5-30% EtOAc in hexanes to give Intermediate 28-4 ((S)-A-((2S)-1-(4-bromophenyl)-2-((tert- butyldimethylsilyl)oxy)propyl)-2-methylpropane-2-sulfinamide; 3.39 g, 7: 1 dr, 84%) as a colorless oil. LC / MS-ESI, [M+H]+= 448.1 / 450.1 m / z (1 :1).

[0645] Intermediate 28-4 (3.39 g, 7.56 mmol) was dissolved in MeOH (3.5 mL) and treated with 4N HCl in dioxane (3.8 mL) at rt for 90 min. The mixture was concentrated and the remainder was triturated with MTBE and the solids were collected by filtration and dried in vacuo to give Intermediate 28-5 ((2S)-1-amino-1-(4-bromophenyl)propan-2-ol hydrochloride; 1.957 g, 97%) as a white solid. LC / MS-ESI, [M+H]+= 230.0 / 232.0 m / z (1 : 1).

[0646] Intermediate 28-6 (tert-butyl (2S,4R)-2-(((2S)-1-(4-bromophenyl)-2- hydroxypropyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate; 2.81 g, 86%) was prepared from Intermediate 28-5 (1.957 g, 7.34 mmol) in the same manner as Intermediate 9-1 and was isolated as an off-white foam. LC / MS-ESI, [M+Na]+= 465.1 / 467.1 m / z (1 : 1).

[0647] Intermediate 28-7 (tert-butyl (2S,4R)-4-hydroxy-2-(((2S)-2-hydroxy-1-(4-(4- methylthiazol-5-yl)phenyl)propyl)carbamoyl)pyrrolidine-1-carboxylate; 1.694 g, 7:1 dr, 58%) was prepared in the same manner as Intermediate 3-1. LC / MS-ESI, [M+H]+= 462.2 m / z.

[0648] Intermediate 28-8 (tert-butyl ((2S)-1-((2S,4R)-4-hydroxy-2-(((2S)-2-hydroxy-1-(4- (4-methylthiazol-5-yl)phenyl)propyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)carbamate; 2.0 g, 97%) was prepared in the same manner as Intermediate 9-3. LC / MS- ESI, [M+H]+= 561.3 m / z.

[0649] Intermediate 28-9 ((2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((2S)- 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide; 207.5 mg, 12%) was prepared in the same manner as Intermediate 9-4 and was recovered as an off- white foamy solid. LC / MS-ESI, [M+H]+= 487.2 m / z.

[0650] Compound 19 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- m ethyl- 1 H-indazol-4-yl)- 16- { [ 1 -(methoxymethyl)cy clopropyl]methoxy } -9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 5.0 mg, >20: 1 dr, 51%) was prepared from Intermediate 4-6 (8.2 mg, 0.0071 mmol) and Intermediate 28-9 (4.2 mg, 0.0085 mmol) according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.4 m / z.1H NMR (400 MHz, MeOD) δ 8.92 (s, 1H), 8.44 (s, 1H), 7.90 (s, OH), 7.60 - 7.53 (m, 2H), 7.51 - 7.43 (m, 5H), 7.30 (d, J= 9.7 Hz, 1H), 6.78 (d, J= 8.4 Hz, 2H), 5.69 (s, 1H), 5.51 - 5.42 (m, 1H), 5.37 (d, J= 10.3 Hz, 1H), 5.00 - 4.77 (m, 2H), 4.72 (s, 1H), 4.69 - 4.55 (m, 2H), 4.52 - 4.43 (m, 2H), 4.35 - 4.28 (m, 1H), 4.16 - 4.05 (m, 1H), 4.02 - 3.85 (m, 4H), 3.71 - 3.52 (m, 5H), 2.70 - 2.58 (m, 1H), 2.50 (s, 3H), 2.23 - 2.08 (m, 8H), 2.03 - 1.78 (m, 3H), 1.25 (d, J= 6.4 Hz, 3H), 1.17 (d, J= 6.7 Hz, 3H), 0.84 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, MeOD) δ -117.02.

[0651] Synthesis of Compound 20 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11 -chloro- 12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-2-cyclobutylacetyl ]-4-hydroxy-N-[ lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Intermediate 29-1 (tert-butyl ((S)-1-cyclobutyl-2-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-2- oxoethyl)carbamate; 173.3mg, 69%) was prepared from Intermediate 3-2 (200 mg, 0.447 mmol) following the procedure described for Intermediate 9-3, except that (S)-2-((tert- butoxycarbonyl)amino)-2-cyclobutylacetic acid was used in place of Boc-L-valine, and was isolated as a white solid. LC / MS-ESI, [M+H]+= 559.3 m / z. Intermediate 29-2 ((2S,4R)-1-((S)-2-azido-2-cyclobutylacetyl)-4-hydroxy-N-((R)- 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamides; 108.3 mg, 72%) was prepared in the same manner as Intermediate 9-4 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 485.2 m / z.

[0652] Compound 20 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-2-cyclobutylacetyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 3.4 mg, 28%) was prepared from Intermediate 4-6 (10.1 mg, 0.00877 mmol) and Intermediate 29-2 (4.7 mg, 0.00965 mmol) according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1151.4 m / z.1H NMR (400 MHz, MeOD) δ 8.91 (s, 1H), 8.38 (s, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.49 - 7.40 (m, 5H), 7.30 (d, J= 9.8 Hz, 1H), 6.78 (d, J= 8.4 Hz, 2H), 5.73 (d, J= 10.1 Hz, 1H), 5.65 (s, 1H), 5.47 - 5.39 (m, 1H), 5.08 - 5.01 (m, 1H), 4.88 (s, 3H), 4.74 - 4.66 (m, 2H), 4.61 (t, J = 8.3 Hz, 1H), 4.52 - 4.42 (m, 2H), 4.26 (d, J= 8.8 Hz, 1H), 4.01 - 3.89 (m, 3H), 3.84 (d, J = 6.1 Hz, 2H), 3.69 - 3.55 (m, 4H), 2.49 (s, 4H), 2.30 - 1.80 (m, 17H).19F NMR (376 MHz, MeOD) δ -117.07.

[0653] Synthesis of Compound 21 (2S,4R)-l-[(2S,3R)-2-{4-[4-({[(3S, 6S, 7S)-11-chloro-12-(6- jluoro-5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylpentanoyl ]-4-hydroxy-N-[ fR) -2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0654]

[0655] Intermediate 30-1 (tert-butyl ((S)-1-cyclobutyl-2-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-2- oxoethyl)carbamate; 141.9 mg, 57%) was prepared from Intermediate 3-2 (200 mg, 0.447 mmol) following the procedure described for Intermediate 9-3, except that Boc-L- alloisoleucine was used in place of Boc-L-valine, and was isolated as a white solid. LC / MS- ESI, [M+H]+= 561.3 m / z.

[0656] Intermediate 29-2 ((2S,4R)-1-((2S,3R)-2-azido-3-methylpentanoyl)-4-hydroxy-N- ((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 72.7 mg, 59%) was prepared in the same manner as Intermediate 9-4 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 487.2 m / z.

[0657] Compound 21 ((2S,4R)-1-[(2S,3R)-2-{4-[4-({[(3S,6S,7S)-11-chloro- 12-(6-fluoro-

[0658] 5 -methyl- 1 H-indazol -4-yl)- 16-(oxan-4-yloxy)-9-oxa-2, 5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylpentanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 7.9 mg, 70%) was prepared from Intermediate 4-6 (9.4 mg, 0. 0.00816 mmol) and Intermediate 30-2 (4.4 mg, 0.00898 mmol) according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.5 m / z.1H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 9.47 - 9.33 (m, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.49 - 8.37 (m, 2H), 7.70 (d, J= 8.3 Hz, 2H), 7.51 - 7.43 (m, 4H), 7.38 (d, J= 8.3 Hz, 2H), 6.76 (d, J= 8.4 Hz, 2H), 5.42 (d, J= 9.5 Hz, 1H), 5.36 (s, 1H), 5.28 - 5.20 (m, 1H), 5.17 (d, J = 11.4 Hz, 1H), 4.85 (q, J= 6.3 Hz, 1H), 4.72 - 4.63 (m, 2H), 4.57 (s, 1H), 4.51 - 4.41 (m, 2H), 4.34 - 4.29 (m, 1H), 4.17 (dd, J= 10.3, 3.2 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.82 - 3.73 (m, 1H), 3.71 - 3.65 (m, 1H), 3.64 - 3.55 (m, 2H), 3.52 - 3.43 (m, 2H), 3.43 - 3.31 (m, 2H), 2.46 (s, 3H), 2.39 (d, J= 10.8 Hz, 1H), 2.35 - 2.25 (m, 1H), 2.18 - 1.91 (m, 8H), 1.79

[0659] (ddd, J= 13.0, 8.5, 4.7 Hz, 1H), 1.75 - 1.61 (m, 3H), 1.22 - 1.10 (m, 1H), 0.89 (t, J= 7.3 Hz, 3H), 0.70 (d, J= 6.7 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.73.

[0660] Synthesis of Compound 22 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11 -chloro- 12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15 -pentaen- 13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ (lS)-l-[2- methoxy-4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0661]

[0662] 4-Bromo-2-methoxybenzaldehyde (1.075g, 5.00 mmol), 4-methylthiazole (1.77 mL, 20 mmol), Pd(0Ac)2(56 mg, 0.25 mmol), and KO Ac (1.96 g, 20 mmol) were suspended in NMP (10 mL) and the mixture was vigorously sparged with N2for 5 min then heated to 120 °C for 8 hrs. The mixture was filtered through Celite rinsing with EtOAc and the filtrate was washed with brine (x3), dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (24g) eluted with 0-40% EtOAc in hexanes to give Intermediate 31-1 (2-methoxy-4-(4- methylthiazol-5-yl)benzaldehyde; 770.2 mg, 66%) as a bright yellow solid. TLC Rf = 0.27 (7:3 hexanes :EtO Ac). LC / MS-ESI, [M+H]+= 234.1 m / z.

[0663] Intermediate 31-1 (770 mg, 3.30 mmol) and A-tert-butanesulfmamide (440 mg, 3.63 mmol) were suspended in anhydrous THF (6.6 mL) and treated with Ti(OiPr)4 (1.95 mL, 6.6 mmol) at rt for 20 hrs. The mixture was poured in to brine (2 mL) and stirred for 10 min then filtered through Celite rinsing with EtOAc. The filtrate was dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 31-2 ((R,E)- N-(2-methoxy-4-(4-methylthiazol-5-yl)benzylidene)-2-methylpropane-2-sulfinamide; 1.085g, 98%). LC / MS-ESI, [M+H]+= 337.1 m / z.

[0664] Intermediate 31-2 (1.085 g, 3.22 mmol) was dissolved in anhydrous DCM (11 mL) and cooled to -78 °C then MeMgBr, 3M in Et2O (2.1 mL) was added dropwise and the cooling bath was allowed to gradually warm to rt and stirred for 3 hrs. The mixture was poured into saturated NH4CI and extracted with EtOAc (x3). The combined extract was dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give Intermediate 31-3 ((R)-N-((S)-1 -(2 -methoxy -4-(4-methylthiazol-5-yl)phenyl)ethyl)-2- methylpropane-2-sulfmamide; 828mg, 7: 1 dr, 73%). TLC Rf = 0.27 (1 :1 hexanes:EtOAc, x2). LC / MS-ESI, [M+H]+= 353.2 m / z.

[0665] Intermediate 31-3 (821 mg, 2.33 mmol) was dissolved in MeOH (1.2 mL) and treated with 4N HCl in dioxane (1.75 mL) at rt for 60 min. The mixture was concentrated and the remainder was triturated with MTBE and the solids were collected by filtration and dried in vacuo to give Intermediate 31-4 ((S)-1-(2-methoxy-4-(4-methylthiazol-5- yl)phenyl)ethan-1-amine hydrochloride; 850.7 mg, >100%) as a white solid.

[0666] Intermediate 31-5 (tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(2-methoxy-4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate; 1.825g, >100%) was prepared from Intermediate 31-4 (850.7 mg, 2.33 mmol) following the procedure described for Intermediate 9-2 and was isolated as a faintly yellow oily residue. LC / MS- ESI, [M+H]+= 462.2 m / z.

[0667] Intermediate 31-6 (tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(2-methoxy-4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -y l)-3 -methyl- 1 -oxobutan-2- yl)carbamate; 1.56 g, >100%) was prepared in the same manner as Intermediate 9-3 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 561.3 m / z.

[0668] Intermediate 31-7 ((2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1- (2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 187.7 mg, 49%) was prepared in the same manner as Intermediate 9-4 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 487.2 m / z.

[0669] Compound 22 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lS)-1-[2- methoxy-4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 9.1 mg, 72%) was prepared from Intermediate 4-6 (10.5 mg, 0.00912 mmol) and Intermediate 31-7 (4.9 mg, 0.0100 mmol) according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.4 m / z.1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 9.48 - 9.30 (m, 1H), 8.96 (s, 1H), 8.64 (s, 1H), 8.42 (d, J= 7.8 Hz, 2H), 7.65 (d, J= 8.3 Hz, 2H), 7.51 - 7.38 (m, 2H), 7.23 (d, J= 8.3 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.72 (d, J= 8.4 Hz, 2H), 5.36 - 5.25 (m, 2H), 5.23 - 5.04 (m, 3H), 4.69 - 4.60 (m, 2H), 4.53 (s, 1H), 4.44 (d, J= 10.3 Hz, 1H), 4.41 (d, J= 7.6 Hz, 1H), 4.36 (d, J= 8.2 Hz, 1H), 4.29 (s, 1H), 4.18 - 4.10 (m, 1H), 3.83 (s, 3H), 3.77 - 3.63 (m, 2H), 3.49 - 3.27 (m, 5H), 2.44 (s, 3H), 2.36 (d, J= 11.0 Hz, 1H), 2.13 - 1.86 (m, 8H), 1.79 - 1.58 (m, 3H), 1.26 (d, J= 7.0 Hz, 3H), 1.04 (d, J= 6.6 Hz, 3H), 0.68 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.73.

[0670] Synthesis of Compound 23 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-jluoro- 5-methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7.014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-N-[ ( 1 S)-l-[4-(4-ethyl-l, 3- thiazol-5-yl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide

[0671]

[0672] 4-Bromobenzaldehyde (999 mg, 5.40 mmol), 4-ethylthiazole (916.8 mg, 8.10 mmol), Pd(0Ac)2(60 mg, 0.27 mmol), and KO Ac (2.12 g, 21.6 mmol) were suspended in NMP (10 mL) and the mixture was sparged with N2for 5min then sealed and heated to 130°C for 2 hrs. The mixture was cooled, filtered through Celite rinsing with EtOAc, and the filtrate was washed with brine (x3), dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (12g) eluted with 5-40% EtOAc in hexanes to give Intermediate 32-1 (4-(4- ethylthiazol-5-yl)benzaldehyde; 703 mg, 60%). LC / MS-ESI, [M+H]+= 218.1 m / z.

[0673] Intermediate 32-2 ((R,E)-A-(4-(4-ethylthiazol-5-yl)benzylidene)-2-methylpropane- 2-sulfinamide; 810mg, 75%) was prepared in the same manner as Intermediate 31-2. LC / MS-ESI, [M+H]+= 321.1 m / z.

[0674] Intermediate 32-3 ((R)-A-((S)-1-(4-(4-ethylthiazol-5-yl)phenyl)ethyl)-2- methylpropane-2-sulfmamide; 726 mg, 88%) was prepared in the same manner as Intermediate 31-3. LC / MS-ESI, [M+H]+= 337.1 m / z.

[0675] Intermediate 32-4 ((S)- 1 -(4-(4-ethylthiazol-5-yl)phenyl)ethan- 1 -amine hydrochloride; 722 mg, >100%) was prepared in the same manner as Intermediate 31-4. LC / MS-ESI, [M+H]+= 233.1 m / z.

[0676] Intermediate 32-5 (tert-butyl (2S,4R)-2-(((S)-1-(4-(4-ethylthiazol-5- yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate; 806 mg, 84%) was prepared from Intermediate 32-4 (crude, 2.16 mmol) following the procedure described for Intermediate 9-2 and was isolated as a faintly yellow oil. LC / MS-ESI, [M+H]+= 446.1 m / z.

[0677] Intermediate 32-6 (tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(4-(4-ethylthiazol-5- yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3 -methyl- 1 -oxobutan-2- yl)carbamate; 872 mg, 89%) was prepared in the same manner as Intermediate 9-3 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 545.3 m / z.

[0678] Intermediate 32-7 ((2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((S)-1-(4-(4- ethylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide, 444 mg, 59%) was prepared in the same manner as Intermediate 9-4 and was isolated as a white solid. LC / MS-ESI, [M+H]+= 471.1 m / z.

[0679] Compound 23 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-(oxan-4-yloxy)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-N-[(lS)-1-[4-(4-ethyl- l,3-thiazol-5-yl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide; 13.9 mg, 47%) was prepared from Intermediate 4-6 (25 mg, 0.0217 mmol) and Intermediate 32-7 (13.2 mg, 0.0282 mmol) according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1137.4 m / z.1H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 9.36 (s, 1H), 8.97 (d, J= 1.7 Hz, 1H), 8.64 (s, 1H), 8.48 (d, J= 7.6 Hz, 1H), 8.39 (s, 1H), 7.65 (dd, J= 8.2, 3.9 Hz, 2H), 7.45 (d, J= 1.1 Hz, 1H), 7.43 (d, J= 9.8 Hz, 1H), 7.35 (q, J= 8.5 Hz, 4H), 6.72 (d, J= 8.4 Hz, 2H), 5.33 (s, 1H), 5.29 (d, J= 10.3 Hz, 1H), 5.24 - 5.07 (m, 2H), 4.90 (q, J= 7.3 Hz, 1H), 4.64 (dd, J= 9.4, 2.4 Hz, 2H), 4.53 (s, 1H), 4.42 (t, J= 10.7 Hz, 1H), 4.35 (t, J= 8.1 Hz, 1H), 4.29 (s, 1H), 4.14 (dd, J= 10.0, 3.3 Hz, 1H), 3.88 - 3.77 (m, 2H), 3.78 - 3.70 (m, 1H), 3.67 (d, J= 11.1 Hz, 1H), 3.48 - 3.26 (m, 5H), 2.71 (q, J= 7.5 Hz, 2H), 2.36 (d, J= 10.9 Hz, 1H), 2.12 - 1.88 (m, 7H), 1.80 - 1.59 (m, 3H), 1.34 (d, J= 7.1 Hz, 3H), 1.19 (td, J= 7.5, 2.5 Hz, 3H), 1.04 (d, J= 6.6 Hz, 3H), 0.68 (d, J= 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) δ -116.73.

[0680] Synthesis of Compound 24 (2S,4R)-l-[(2S)-2-{4-[4-({[(3S,6S, 7S)-11-chloro-12-(6-f!uoro- 5-methyl-lH-indazol-4-yl)-16-{[(2R, 4R)-2-methyloxan-4-yl]oxy}-9-oxa-2, 5, 15, 17- tetraazapentacyclo[8. 7.1.13,6.02, 7014,18]nonadeca-l( 17), 10, 12, 14(18), 15-pentaen-13- yl ]oxy}methyl)phenyl ]-1H-1, 2, 3-triazol-l-yl}-3-methylbutanoyl ]-4-hydroxy-N-[ ( lR)-2- hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0681]

[0682] Intermediate 33-1 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5,8- difluoro-2-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)oxy)quinazoline; 290.8 mg, 92%) was prepared in the same manner as Intermediate 16-1, except that (2R,4R)-2- methyltetrahydro-2H-pyran-4-ol was used in place of tetrahydropyran-4-ol, and was isolated as a white foamy solid.

[0683] Intermediate 33-2 (7-bromo-4-((lS,3S,4S)-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-trityl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-5- fluoro-8-((4-iodobenzyl)oxy)-2-(((2R,4R)-2-methyltetrahydro-2H-pyran-4- yl)oxy)quinazoline; 298.9 mg, 83%) was prepared in the same manner as Intermediate 16- 2 and was isolated as a white foamy solid.

[0684] Intermediate 33-3 ((3S,6S,7S)-12-bromo-11-chloro-13-[(4-iodophenyl)methoxy]- 16-{[(2R,4R)-2-methyloxan-4-yl]oxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene ; 296.8 mg, >100%) was prepared in the same manner as Intermediate 16-3 and was isolated as an amber colored foamy solid.

[0685] Intermediate 33-4 ((3S,6S,7S)-12-bromo-11-chloro-16-{[(2R,4R)-2-methyloxan-4- yl]oxy}-5-(triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9- oxa-2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15- pentaene \ 218.8mg, 79%) was prepared in the same manner as Intermediate 16-4 and was isolated as a faintly orange solid.

[0686] Intermediate 33-5 ((3S,6S,7S)-11-chloro-12-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-16-{[(2R,4R)-2-methyloxan-4-yl]oxy}-5- (triphenylmethyl)-13-[(4-{2-[tris(propan-2-yl)silyl]ethynyl}phenyl)methoxy]-9-oxa- 2,5,15,17-tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaene; 141 mg, 49%) was prepared in the same manner as Intermediate 16-5 and was isolated as a yellow colored foamy solid.

[0687] Intermediate 33-6 ((3S,6S,7S)-11-chloro-13-[(4-ethynylphenyl)methoxy]-12-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-16-{[(2R,4R)-2-methyloxan-4- yl]oxy}-5-(triphenylmethyl)-9-oxa-2,5,15,17- tetraazapentacy clo[8.7.1.13,6.02,7.014, 18]nonadeca- 1(17), 10, 12, 14(18), 15 -pentaene; 141 mg, >100%) was prepared in the same manner as Intermediate 4-6 and was isolated as a yellow colored foamy solid.

[0688] Compound 24 ((2S,4R)-1-[(2S)-2-{4-[4-({[(3S,6S,7S)-11-chloro-12-(6-fluoro-5- methyl-lH-indazol-4-yl)-16-{[(2R,4R)-2-methyloxan-4-yl]oxy}-9-oxa-2,5,15,17- tetraazapentacyclo[8.7.1.13’6.02’7.014,18]nonadeca-l(17),10,12,14(18),15-pentaen-13- yl]oxy}methyl)phenyl]-lH-l,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-[(lR)-2- hydroxy-1-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide; 12.5mg, 39%) was prepared according to the protocol described for Compound 1-1 and was isolated as its TFA salt as a white solid. LC / MS-ESI, [M+H]+= 1153.4 m / z.1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.33 - 9.23 (m, 1H), 8.96 (s, 1H), 8.63 (s, 1H), 8.45 (d, J= 8.1 Hz, 1H), 8.36 - 8.25 (m, 1H), 7.65 (d, J= 8.3 Hz, 2H), 7.48 - 7.38 (m, 4H), 7.34 (d, J= 8.3 Hz, 2H), 6.72 (d, J= 8.4 Hz, 2H), 5.33 - 5.26 (m, 2H), 5.20 - 5.08 (m, 2H), 4.86 - 4.76 (m, 1H), 4.69 - 4.60 (m, 2H), 4.53 (s, 1H), 4.47 - 4.37 (m, 2H), 4.30 - 4.26 (m, 1H), 4.13 (dd, J= 9.9, 2.8 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.74 (dd, J= 11.0, 3.0 Hz, 1H), 3.66 (d, J=

[0689] 11.2 Hz, 1H), 3.61 - 3.50 (m, 2H), 3.45 - 3.20 (m, 5H), 2.47 - 2.40 (m, 4H), 2.36 (d, J=

[0690] 14.3 Hz, 1H), 2.15 - 1.99 (m, 3H), 1.96 (d, J= 2.6 Hz, 3H), 1.93 - 1.87 (m, 1H), 1.80 - 1.70 (m, 1H), 1.59 - 1.45 (m, 1H), 1.33 - 1.21 (m, 1H), 1.09 - 1.01 (m, 6H), 0.68 (d, J= 6.7 Hz, 3H). Biological Experiments

[0691] KRAS G12D (GDP -bound) Competitive Binding Assay

[0692] Test compounds were assessed for their ability to out-compete a FITC-labelled tracer in binding to biotinylated GDP-bound KRasG12Dprotein. The working assay mixture comprised 3 nM C-terminally labeled KRasG12D-biotin (amino acids 1-166, Amid Biosciences) and 1.5 nM Tb3+-Streptavidin (Thermo Fisher Scientific #PV3966) in a buffer containing 20 mM HEPES (pH 7.4), 120 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.02% Tween-20, and 10 uM GDP -Na. 30 μL of this working assay mixture were aliquoted per well in a black-well, non-binding 384-well plate (Coming #3575). Test compounds were dispensed from a Multidrop Pico8 digital dispenser (Thermo Fisher Scientific) in duplicate starting at 10 uM in a 1 :3 dilution series to generate a 10-point dose response curve (3-fold serial dilution; final tested concentrations were 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.0412 μM, 0.0137 μM, 0.00457 μM, 0.00152 μM and 0.000508 μM). This reaction mixture was incubated at room temperature (RT) in the dark with shaking at 525 RPM for 2 hours. Homogeneous time-resolved fluorescence (HTRF) using a Biotek Synergy Neo2 (Agilent, USA; excitation: 340 nm; emission 1 : 520 nm, emission 2: 620 nm) was used to measure the resonance energy transfer from Tb3+-Streptavidin-KRas-biotin (FRET donor) to the FITC-labelled tracer (FRET acceptor). The data were normalized using DMSO as a control for 100% binding of FITC-labelled tracer to KRasG12D-biotin. The average signal and standard deviation were calculated for all samples. The dose response curves were plotted on a semi-log axis using the calculation (sample signal / average vehicle signal) to normalize the high (vehicle) signal to 1. IC50values were calculated by fitting the data of each test compound to a 3-parameter dose response curve in GraphPad Prism software. See Table DI. “A” represents an IC50of 10 nM or less, “B” represents an IC50of greater than 10 nM and less than 100 nM, and “C” represents an IC50of 100 nM or greater.

[0693] Caco-2 Assay (PappA to B)

[0694] The degree of bi-directional human intestinal permeability for compounds is estimated using a Caco-2 cell permeability assay. Caco-2 cells are seeded onto polyethylene membranes in 96-well plates. The growth medium is refreshed every 4 to 5 days until cells form a confluent cell monolayer. HBSS with 10 mM HEPES at pH 7.4 is used as the transport buffer. Compounds are tested at 2 μM bi-directionally in duplicate. Digoxin, nadolol and metoprolol are included as standards. Digoxin is tested at 10 μM bi- directionally in duplicate, while nadolol and metoprolol are tested at 2 μM in the A to B direction in duplicate. The final DMSO concentration is adjusted to less than 1% for all experiments. The plate is incubated for 2 hours in a CO2incubator at 37°C, with 5% CO2at saturated humidity. After incubation, all wells are mixed with acetonitrile containing an internal standard, and the plate is centrifuged at 4,000 rpm for 10 minutes. 100 μL supernatant is collected from each well and diluted with 100 μL distilled water for LC / MS / MS analysis. Concentrations of test and control compounds in starting solution, donor solution, and receiver solution are quantified by LC / MS / MS, using peak area ratio of analyte to internal standard.

[0695] The apparent permeability coefficient Papp(cm / s) is calculated using the equation: Papp= (dCr / dt) X Vr / (A X C0), where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (μM / s); Vris the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, which is 0.0804 cm2for the area of the monolayer; and C0is the initial concentration in the donor chamber (μM).

[0696] The efflux ratio is calculated using the equation:

[0697] Efflux Ratio = Papp(BA) / Papp(AB) Percent recovery is calculated using the equation:

[0698] % Recovery = 100 x [(Vrx Cr) + (Vdx Cd)] / (Vdx C0), where Vd is the volume in the donor chambers, which are 0.075 mL on the apical side and 0.25 mL on the basolateral side; and Cdand Crare the final concentrations of transport compound in donor and receiver chambers, respectively.

[0699] Measurement of Compound Metabolic Stability

[0700] The metabolic stability of compounds is determined in hepatocytes from human, mice and rats. Compounds are diluted to 5 μM in Williams' Medium E from 10 mM stock solutions. 10 μL of each compound is aliquoted into a well of a 96-well plate and reactions are started by aliquoting 40 μL of a 625,000 cells / mL suspension into each well. The plate is incubated at 37°C with 5% CO2. At each corresponding time point, the reaction is stopped by quenching with ACN containing internal standards (IS) at a 1 :3. Plates are shaken at 500 rpm for 10 min, and then centrifuged at 3,220 x g for 20 minutes. Supernatants are transferred to another 96-well plate containing a dilution solution. Supernatants are analyzed by LC / MS / MS.

[0701] The remaining percent of compound after incubation is calculated using the following equation:

[0702] % Remaining Compound =

[0703] Peak Area Ratios of Tested Compound vs. Internal Standard at End Point Peak Area Ratios of Tested Compound vs. Internal Standard at Start Point

[0704] Compound half-life and CLintare calculated using the following equations:

[0705] Ct= C0*e-k*t(first order kinetics); when Ct= ½C0, t½= ln2 / k = 0.693 / k; and CLint= k / (1,000,000 cells / mL)

[0706] The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods described will become apparent from the description and teachings herein. Such variations may be practiced without departing from the true scope and spirit of the disclosure and are intended to fall within the scope of the present disclosure.

[0707] Cell Viability Assay

[0708] AGS, GP2D, HP AC, AsPC-1, Panc04.03, or HCC1937 cells were seeded into clear bottom white 384-well plates (Falcon #353963) at 500-1500 cells per well and a final volume of 50 uL / well. AGS and HP AC cells were cultured in DMEM / F12 + 1% penicillin / streptomycin + 10% fetal bovine serum. GP2d cells were cultured in DMEM, high-glucose + 1% penicillin / streptomycin + 10% fetal bovine serum. AsPC-1, Panc04.03, and HCC1937 cells were cultured in RPMI-1640 + 1% penicillin / streptomycin + 10% fetal bovine serum. 16-24 hours later, a Multidrop Pico8 digital dispenser (Thermo Fisher Scientific) was used to dispense test compounds in duplicate starting from 5 μM in a 1 :3 dilution series for a 9-point dose titration (3 -fold serial dilution; final concentrations were 5 μM, 1.67 μM, 0.556 μM, 0.185 μM, 0.0617 μM, 0.0206 μM, 0.00685 μM, 0.00229 μM and 0.000762 μM) with a maximum final DMSO concentration of 0.5%. Cells were incubated at 37°C, in 5% CO2for 72 hours. At this time, 20 μL CellTiter-Glo 2.0 (Promega #G9243) luminescent cell viability detection reagent was added to each well. Cells were incubated at RT with shaking at 525 RPM for 5 minutes. Luminescence was measured using a Biotek Synergy Neo2 (Agilent, USA) using filter cube set 3: Single PMT / LUM (top) and 114: LUM 1536 / LUM (bottom) with an integration time (s) = 0.2, and measurement height (mm) = 6.0. Technical replicates were averaged then normalized to the untreated control wells, and relative IC50values were calculated by nonlinear least squares fit using a 3-parameter dose-response curve (Graphpad Prism). Average IC50values were then calculated from all available experimental replicates. See Table D2. “A” represents an IC50of 100 nM or less, “B” represents an IC50between 100 nM and 500 nM, “C” represents an IC50between 500 nM and 1 μM, and “D” represents an IC50of 1 μM or greater.

[0709] Cellular pERK Assay

[0710] AGS, AsPC-1, GP2D, or Panc04.03 cells were seeded at 15,000 cells per well in 384-well tissue culture plates. After 16 to 24 hours, test compounds were dispensed from a Multidrop Pico8 digital dispenser (Thermo Fisher Scientific) in duplicate starting at 10 μM in a 1 :3 dilution series for a 9-point dose response curve (3-fold serial dilution; final concentrations were 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.0412 μM, 0.0137 μM, 0.00457 μM, 0.00152 μM and 0.000508 μM). All treatment groups were done in triplicate. All groups were incubated for 3 hours. After the 3-hours treatment, all wells were fixed with 20 μL of 4% paraformaldehyde at RT with shaking at 525 RPM for 10 minutes. After removing the paraformaldehyde, cells were permeabilized with 20 μL Triton X-100 at RT with shaking at 525 RPM for 10 min. After removal of Triton X-100, cells were incubated with blocking buffer (5% bovine serum albumin (BSA), 0.05% sodium azide (NaN3)) at RT with shaking at 525 RPM for 1 hour. Primary antibody (phospho-ERK; Cell Signaling Technologies #9101) was prepared at 1 : 100 in antibody dilution buffer (1% BSA, 0.05% NaN3). Blocking Buffer was removed from wells, 20 μL of diluted primary antibody was added to each well and the plate was incubated at least 16 hours at 4°C. After the primary antibody incubation, wells were washed 3 times with 50 μL of wash buffer (lx phosphate buffered saline, 0.1% Tween 20). A solution of secondary antibody (goat antirabbit HRP; Invitrogen #31460) was prepared in wash buffer at 1 :5000. Wash buffer was removed from wells, 20 μL of diluted secondary antibody solution was added to each well and the plate was incubated for 2 hours at RT. After the secondary antibody incubation, wells were washed 5 times with 50 μL of wash buffer. After the last wash was removed, 25 uL Ultra TMB ELISA Substrate (Thermo Scientific #34028) was added to each well and incubated at RT with shaking at 525 RPM for 15 minutes. Then 25 uL of 2M sulfuric acid (H2SO4) was added to each well and incubated at RT with shaking at 525 RPM for 5 minutes. Once the ELISA reaction was quenched, ELISA signal was measured colorimetrically at 450 nm using a Biotek Synergy Neo2 (Agilent, USA). After ELISA signal was measured and the quenched reaction was removed from each well, each well was washed 5x with wash buffer. After the fifth wash was removed, 25 μL Pierce 660 nm Protein Assay Reagent (Thermo Scientific #22660) was added and incubated at RT with shaking at 525 RPM for 15 minutes. Total protein concentration was measured by absorbance at 660 nm using a Biotek Synergy Neo2 (Agilent, USA). The average signal and standard deviation were calculated for all samples. The dose response curves were plotted on a semi-log axis using the calculation:

[0711] (Sample signal at 450 nm / Sample signal at 660 nm) (average [vehicle control signal at 450 nm / vehicle control signal at 660 nm]) to normalize the high (vehicle control) signal to 1. IC50values were calculated by fitting the data of each test compound to a 3 -parameter dose-response curve by Graphpad Prism software. See Table D3. “A” represents an IC50of 100 nM or less, “B” represents an IC50between 100 nM and 500 nM, “C” represents an IC50between 500 nM and 1 μM, and “D” represents an IC50of 1 μM or greater.

[0712] Cellular Degradation of KRAS G12D Protein

[0713] AGS, AsPC-1, GP2D, or Panc04.03 cells were seeded at 15,000 cells per well in 384-well tissue culture plates. After 16 to 24 hours, test compounds were dispensed from a Multidrop Pico8 digital dispenser (Thermo Fisher Scientific) in duplicate starting at 10 μM in a 1 :3 dilution series for a 9-point dose response curve (3-fold serial dilution; final concentrations were 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.0412 μM, 0.0137 μM, 0.00457 μM, 0.00152 μM and 0.000508 μM). All treatment groups were done in triplicate. All groups were incubated for 6 to 24 hours. After treatment, all wells were fixed with 20 μL of 4% paraformaldehyde at RT with shaking at 525 RPM for 10 minutes. After removing the paraformaldehyde, cells were permeabilized with 20 μL Triton X-100 at RT with shaking at 525 RPM for 10 min. After removal of Triton X-100, cells were incubated with blocking buffer (5% bovine serum albumin (BSA), 0.05% sodium azide (NaN3)) at RT with shaking at 525 RPM for 1 hour. Primary antibody (KRas G12D; Cell Signaling Technologies #14429) was prepared at 1 : 100 in antibody dilution buffer (1% BSA, 0.05% NaN3). Blocking Buffer was removed from wells, 20 μL of diluted primary antibody was added to each well and the plate was incubated at least 16 hours at 4°C. After the primary antibody incubation, wells were washed 3 times with 50 μL of wash buffer (lx phosphate buffered saline, 0.1% Tween 20). A solution of secondary antibody (goat anti-mouse HRP; Invitrogen #31430) was prepared in wash buffer at 1 :5000. Wash buffer was removed from wells, 20 μL of diluted secondary antibody solution was added to each well and the plate was incubated for 2 hours at RT. After the secondary antibody incubation, wells were washed 5 times with 50 μL of wash buffer. After the last wash was removed, 25 μL Ultra TMB ELISA Substrate (Thermo Scientific #34028) was added to each well and incubated at RT with shaking at 525 RPM for 15 minutes. Then 25 μL of 2M sulfuric acid (H2SO4) was added to each well and incubated at RT with shaking at 525 RPM for 5 minutes. Once the ELISA reaction was quenched, ELISA signal was measured colorimetrically at 450 nm using a Biotek Synergy Neo2 (Agilent, USA). After ELISA signal was measured and the quenched reaction was removed from each well, each well was washed 5x with wash buffer. After the fifth wash was removed, 25 uL Pierce 660 nm Protein Assay Reagent (Thermo Scientific #22660) was added and incubated at RT with shaking at 525 RPM for 15 minutes. Total protein concentration was measured by absorbance at 660 nm using a Biotek Synergy Neo2 (Agilent, USA). The average signal and standard deviation were calculated for all samples. The dose response curves were plotted on a semi-log axis using the calculation:

[0714] (Sample signal at 450 nm / Sample signal at 660 nm) (average [vehicle control signal at 450 nm / vehicle control signal at 660 nm]) to normalize the high (vehicle control) signal to 1. DC50values were calculated by fitting the data of each test compound to a 3 -parameter dose-response curve by Graphpad Prism software. See Table D4. “A” represents an IC50of 100 nM or less, “B” represents an IC50between 100 nM and 500 nM, “C” represents an IC50between 500 nM and 1 μM, and “D” represents an IC50of 1 μM or greater. Surface Plasmon Resonance (SPR) Assay

[0715] A Biacore 8K+ (GE Healthcare) was used to acquire SPR measurements at 25 °C, a flow rate of 50 μL / mL, and biotinylated KRAS-G12D-GDP (MW 23 KDa, 5 mg / mL) recombinant protein was used for the assay. KRAS-G12D-GDP protein was diluted to 5pg / mL and captured on a neutravidin pre-coated CM5 sensor chip for a 350 seconds contact at 5 μL / min to reach an immobilization level of 1400-1900 response units (RU) and using Running Buffer (10 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, 0.5 mM TCEP, IμM GDP). During the course of the assay, different concentrations of compounds were injected, and the compounds were serially diluted (3- fold) in Dilution Buffer (10 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, 0.5 mM TCEP, IμM GDP, pH7.4, 2% DMSO). In each cycle, association time was 60 seconds, and dissociation time was 120 seconds. The final response was obtained by subtracting the blank channel (without KRAS-G12D-GDP protein, a buffer injection across the sample channel was measured). Raw data were analyzed in Biacore Insight Evaluation program by fitting the data to a simple 1 : 1 equilibrium and kinetic model.

[0716] Mouse Pharmacokinetic (PK) Assays

[0717] Female CFW mice (8-18 weeks) were housed under a 12hr light / 12hr dark cycle and were equilibrated for at least 7 days prior to the experiment. Inhibitors were formulated in 80: 15:4: 1 (v:w:v:v) 30 mM sodium citrate buffer pH 6.0 ± 0.2, hydroxypropyl beta cyclodextrin (HPβCD), propylene glycol, and polyethylene glycol 12-hydroxy stearate (Solutol® HS-15) at a final concentration of 0.20 mg / mL or 4.0 mg / mL (free basis) for 1 mg / kg or 20 mg / kg experiments, respectively. Test articles were administered to 3 animals by intravenous injection via the tail vein at a dosing volume of 5 mL / kg. Serial blood collections (20 μL) were made from the lateral or medial saphenous vein at 0.05, 0.17, 0.5, 1, 1.5, 2, and 3 hours post dose for 1 mg / kg doses or 0.05, 0.17, 0.5, 1, 2, 4, 8 and 16 hours post dose for 20 mg / kg doses and were collected into K2-EDTA coated polypropylene microcentrifuge tubes. Blood samples were centrifuged (2,000xg, 10 min) immediately after each collection and the plasma fraction was transferred and stored at -20 °C.

[0718] Plasma samples (5-10μL) were aliquoted and precipitated by the addition of 3 volumes of ACN internal standard solution containing 1 ng / mL verapamil, 1 ng / mL imipramine, and 300 ng / mL Ref. 2 (except in PK studies of Ref. 2) then vortexed for 10 min. Where necessary, samples were diluted (2 - 40x) with blank matrix to reach a concentration within the method calibration range. The samples were centrifuged at 10,000xg for 10min at rt then a portion of the supernatant was transferred to a glass vial insert for analysis and diluted with 2 volumes of 0.1% formic acid in water. Samples were analyzed using an Agilent 1290 HPLC system equipped with a Restek Raptor FluoroPhenyl, 2.7 μm, 50 x 2.1 mm column (heated to 50 °C) and coupled to a G6460A triple-quadrupole mass spectrometer with an electrospray ionization source. The injection volume was 5 μL. An elution gradient of 5-60% ACN in H2O + 0.1% formic acid and 0.6 to 0.8 mL / min over 4.5 min was used, followed by 0.4 min column wash with 100% ACN and 0.5min re-equilibration with 5% ACN. A matrix blank, eight matrix-matched calibrators (1200, 480, 192, 76.8, 30.7, 12.3, 4.92, 1.97 ng / mL), and three QC standards (750, 94, 12 ng / mL) were processed in the same manner. Calibrators and QC standards were analyzed at the beginning and end of the analytical run, and a QC standard was analyzed after every 6 unknown samples. Quantitation was done by fitting the relative response (RR) of unknowns to the external calibration line as implemented in MassHunter Workstation B.09.00. The ULOQ and LLOQ were defined by a back fit accuracy of 80-120%.

[0719] Actualized dosage was determined by triplicate analysis of dosing solutions and test article master stock solutions in by HPLC-UV (254 nm) and the solution concentration was determined using a triplicate single-point calibration.

[0720] PK parameters were determined by non-compartmental analysis of mean plasma drug concentrations versus time using the linear trapezoidal method as implemented in PK Solver 2.0. Key parameters determined include Clearance (CL), terminal half-life (t1 / 2), and steady-state volume of distribution (Vss). See Table D5 for parameters measured following 1 mg / kg I.V. See Table D6 for parameters measured following 20 mg / kg I.V.

[0721] Activity-Guided Selection of Inhibitors

[0722] Subgenera of KRAS G12D inhibitors having desirable properties were identified using one or more types of in vitro data.

[0723] In particular, the results from the assays described above (e.g., KRasG12D (GDP- bound) Competitive Binding Assay, SPR Assay, Cellular pERK Assay, Cell Viability Assay, Caco-2 Assay (PappA to B) and Measurement of Compound Metabolic Stability) were used to select compounds.

[0724] A desirable property for compounds of the invention is having an average IC50of about 100 nM or less for binding of GDP -bound KRASG12Dprotein (as measured, for example, by the KRasG12D (GDP-bound) Competitive Binding Assay disclosed herein). A desirable property for compounds of the invention is having an IC50of about 500 nM or less for cellular pERK (as measured, for example, by the Cellular pERK Assay disclosed herein). A more desirable property for compounds of the invention is having an IC50of about 100 nM or less for cellular pERK.

[0725] A desirable property for compounds of the invention is having an average IC50of about 500 nM or less (as measured, for example, by the Cell Viability Assay disclosed herein) against the group of cell lines AsPC-1, AGS, GP2D, and Panc04.03. In some instances, the group of cell lines is AsPC-1, AGS, and GP2D. In other instances, the group of cell lines is AGS and GP2D. A more desirable property for compounds of the invention is having an average IC50of about 100 nM or less (as measured, for example, by the Cell Viability Assay disclosed herein) against the group of cell lines AsPC-1, AGS, GP2D, and Panc04.03. In some instances, the group of cell lines is AsPC-1, AGS, and GP2D. In other instances, the group of cell lines is AGS and GP2D.

[0726] The skilled artisan would readily recognize that the results of additional in vitro assays (e.g., CYP enzymatic inhibition, hERG inhibition, compound solubility, targetspecificity analysis, Compound Metabolic Stability Assay, Caco-2 Assay), as well as the results of in vivo assays (e.g., rodent xenograft studies, rodent pharmacokinetic and pharmacodynamic studies, rodent maximum tolerated dose studies, and oral bioavailability) could be used to identify other subgenera of KRAS G12D inhibitors, or to narrow subgenera determined using other results, for example, the subgenera identified with the average IC50values for the group of cell lines AGS, AsPC-1, and GP2D.

[0727] Table DI.

[0728] Table D2.

[0729] Table D3.

[0730] Table D4.

[0731] Table D5.

[0732] Table D6.

Claims

CLAIMSWe claim:

1. A compound having the structure of Formula I:or a pharmaceutically acceptable salt thereof, wherein:A1is selected from:wherein eachdenotes a point of attachment; orA1is an optionally substituted 6 to 12-membered saturated or partially unsaturated heterocycle;A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;X1is O, a bond, CH2, S, N(H), or N(C1-3alkyl);X2is OC(RXa)2, C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2C(RXa)2, C(RXa)2OC(RXa)2, SC(RXa)2, SC(RXa)2C(RXa)2, or C(RXa)2SC(RXa)2;X3is O, a bond, S, S(O), S(O)2, N(H), C1-3alkyl, C2-3alkenyl, C2-3alkynyl, or (CH2)qO(CH2)qCH3;RXain each instance is independently H, C1-3alkyl, halogen (e.g., F), hydroxyl, cyano, , C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;R1is selected from:denotes the point of attachment; orR1is an optionally substituted 4 to 6-membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4-membered carbocycle, or an optionally substituted 5 to 6- membered heteroaryl; R1a, when present, in each instance is independently optionally substituted C1-3alkyl, halogen, hydroxyl, optionally substituted (e.g., F) C1-3alkoxyl, , or C1-3haloalkyl (e g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);R2is halogen (e.g., Cl), cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;R3is selected from:whereindenotes the point of attachment;R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), F, Cl, C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;R3dis F, H, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);R4is an optionally substituted C1-4 alkyl (e.g. isopropyl), an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R5bis optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl, e.g., CH2OH) or H; or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;R6is selected from:denotes the point of attachment;R6aeach independently is optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; orR6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;R7a, when present, in each instance is independently H or C1-3alkyl;RPin each instance is independently OH, F, Cl, or CH3;W-Y-Z is selected from:denote the points of attachment and * denotes the end that attaches to the X3; or W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);RY, when present, in each instance is independently H or C1-3alkyl;Z is selected from:denote the points of attachment and * denotes the end that attaches to Y; orZ is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q in each instance is independently 0, 1, 2, or 3.

2. The compound of claim 1, having the structure of Formula I: wherein:A1is selected from:wherein eachdenotes a point of attachment;R1is selected from:denotes the point of attachment; orR1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; R1a, when present, in each instance is independently optionally substituted C1-3alkyl, halogen, hydroxyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3);R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;R6is selected from:whereindenotes the point of attachment; or W-Y-Z is selected from:wherein denote the points of attachment and * denotes the end that attaches to the X3.

3. The compound of claim 1, wherein:A1is selected from: wherein eachdenotes the point ofattachment;A2is optionally substituted phenyl;X1is O;X2is C(RXa)2C(RXa)2, C(RXa)2C(RXa)2C(RXa)2, OC(RXa)2, or OC(RXa)2C(RXa)2;X3is O;RXain each instance is H;R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R2is halogen (particularly F or Cl) or cyclopropyl; R3isR3cC1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), orC2-3alkynyl (e.g., ethynyl and propargyl);R3dis F or Cl;R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl;R6is selected from:whereindenotes the point of attachment; andR6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl).

4. A compound having the structure of Formula II:or a pharmaceutically acceptable salt thereof, wherein:A1ais selected from:wherein eachdenotes a point of attachment;A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;X1is O, a bond, CH2, S, N(H), or N(C1-3alkyl);X2ais O, C(RXa)2, or S;X2bis C(RXa)2;RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;R1is selected from:wherein denotes the point of attachment; orR1is an optionally substituted 4 to 6-membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl, pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, or an optionally substituted 5 to 6-membered heteroaryl; R1a, when present, in each instance is independently optionally substituted C1-3alkyl, halogen, hydroxyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);R2is halogen (e.g. Cl), cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;R3is selected from:whereindenotes the point of attachment;R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3bis H, F, Cl, Br, CH3, or OH; or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), F, Cl, C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;R3dis F, H, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);R4is an optionally substituted C1-4 alkyl(e.g. isopropyl), an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R5bis optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;R6is selected from:whereindenotes the point of attachment;R6a, when present, is optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; orR6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;R7a, when present, in each instance is independently H or C1-3alkyl;RP1is OH, H, F, Cl, or CH3;RP2is H, F, Cl, OH, or CH3; orRP1is OH and RP2is H or F; W-Y-Z is selected from:denote the points of attachment and * denotes the end that attaches to the oxygen; orW is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);RY, when present, in each instance is independently H or C1-3alkyl;Z is selected from:denote the points of attachment and * denotes the end that attaches to Y; orZ is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5- membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

5. A compound having the structure of F ormula II- 1 :or a pharmaceutically acceptable salt thereof, wherein:A1ais selected from:w denotes a point ofherein eachattachment;X2bis C(RXa)2; one instance of RXais C1alkyl (i.e., CH3) and the other is H; orRXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;R3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), F, Cl, C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;R3dis F, H, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);R6is selected from: whereindenotes the point ofattachment; orR6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R6a, when present, is optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H;R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;RP2is H, F, Cl, OH, or CH3, preferably H or F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

6. The compound of claim 3, wherein:A1is selected from:wherein eachdenotes the point of attachment;A2is optionally substituted phenyl;X1is O;X2ais C(RXa)2or O;X2bis C(RXa)2; orX2ais O and X2bis C(RXa)2;RXain each instance is H;R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R2is halogen (particularly F or Cl) or cyclopropyl; R3isR3cC1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);R3dis F or Cl;R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl;R6is selected from:whereindenotes the point of attachment; andR6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl).

7. The compound of claim 6, wherein X2ais O and X2bis C(RXa)2, and wherein one instance of RXais H and the other is C1alkyl (i.e., CH3).

8. The compound of claim 6, wherein X2ais C(RXa)2, wherein each instance of RXais H, and X2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3).

9. The compound of claim 6, wherein X2ais O; X2bis C(RXa)2; and RXain one instance is C1alkyl (i.e., CH3) and in the other is H.

10. A compound having the structure of Formula III:or a pharmaceutically acceptable salt thereof,wherein:A1ais selected from:wdenotes a point ofherein each attachment;A2is optionally substituted phenyl, optionally substituted 5-membered heteroaryl, or optionally substituted 6-membered heteroaryl containing one, two or three nitrogen atoms;X1is a bond, CH2, O, S, N(H), or N(C1-3alkyl);X2ais C(RXa)2, O, or S,X2bis C(RXa)2, O, or S, andX2cis C(RXa)2, with the proviso that X2aand X2bcannot both be heteroatoms;RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;R1is optionally substituted C1-6alkyl, optionally substituted (CH2)qO(CH2)qCH3, C1-6alkyl substituted with one C1-3aminoalkyl group, an optionally substituted 4 to 6- membered saturated heterocycle (e.g., morpholinyl, piperidinyl, hexahydro- 1H-pyrrol izinyl,pyrrolidinyl, oxetanyl, furanyl, pyranyl, tetrahydropyranyl, and oxepanyl), or an optionally substituted 5 to 6-membered heteroaryl; or R1is selected from:whereindenotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3); or two instances of R1acombine, together with the two different carbon atoms to which they are bonded, along with any intervening atoms, to form an optionally substituted C4-7cycloalkyl or an optionally substituted 5 to 7-membered heterocycle; or two instances of R1acombine, together with the carbon to which they are bonded, to form an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle; R1b, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, C1-3haloalkyl (e.g., CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., =CF2, CHCHF, and CHCF2);R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;R3is selected from:whereindenotes the point of attachment;R3ais H, halogen, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3bis H, F, Cl, Br, CH3, or OH;or, together with the carbon to which they are each bonded, R3aand R3bform an optionally substituted C5-6cycloalkyl, an optionally substituted 5 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propynyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl);R3eis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C1-3haloalkyl, C3-5cycloalkyl, or optionally substituted (e.g., F) C1-3alkoxy;R3fand R3gare each independently H, F, Cl, or C1-3alkyl (e.g., methyl, ethyl, and propyl);R3hand R31are each independently H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), or C1-3haloalkyl (e.g., CF3and CH2CF3);R4is an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, or an optionally substituted 4 to 6-membered heterocycle;R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl); or, together with the carbon to which they are bonded, R5aand R5bform an optionally substituted C3-6cycloalkyl or an optionally substituted 4 to 6-membered heterocycle;R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from:whereindenotes the point of attachment;R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, (CH2)qO(CH2)qCH3, (CH2)qS(O)(CH2)qCH3, (CH2)qS(O)2(CH2)qCH3, (CH2)qS(O)N(R7a)2, and (CH2)qS(O)2N(R7a)2;R7a, when present, in each instance is independently H or C1-3alkyl;RP1is H, F, Cl, OH, or CH3;RP2is H, F, Cl, OH, or CH3; orRP1is OH and RP2is H or F;W is phenylene, pyridinediyl, pyrimidinyl, thiophenyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, or oxadiazolyl, wherein any of the aforementioned is optionally substituted and, more particularly, the phenylene is optionally substituted with F;Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are each independently a bond, O, NRY, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3alkylene, or C(O);RY, when present, in each instance is independently H or C1-3alkyl;Z is N(H), optionally substituted C1-6alkyl, or an optionally substituted 5-membered heteroaryl; or Z is selected from:denote the points of attachment and * denotes the end that attaches to Y; or W-Y-Z is selected from:denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

11. A compound having the structure of F ormula III- 1 :or a pharmaceutically acceptable salt thereof, wherein:A1ais selected from:wherein eachdenotes a point of attachment;X2bis C(RXa)2;X2cis C(RXa)2;RXain each instance is independently H, halogen (e.g., F), hydroxyl, cyano, C1-3alkyl, C1-3hydroxyalkyl, C1-3haloalkyl, or C1-3cyanoalkyl;R2is halogen, cyano, CH2F, CHF2, CF3, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl, wherein each of C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, and cyclobutyl is optionally substituted with one, two or three groups independently selected from F, hydroxyl, cyano, C1-3alkyl, and C1-3haloalkyl;R3cis F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), C2-3alkynyl (e.g., ethynyl and propargyl), C1-3haloalkyl, C1-3alkylthio, C1-3alkyoxy, CF3, CHF2, CF2CH3, OCH3, (CH2)qO(CH2)qCH3, OCHF2, OCF3, or SCH3;R3dis H, F, Cl, C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);R6is H, C1-3alkyl, C3-6cycloalkyl, an optionally substituted 4 to 6-membered heterocycle, or an optionally substituted 5 to 6-membered heteroaryl; or R6is selected from: whereindenotes the point ofattachment;R6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;RP2is H, F, Cl, OH, or CH3; orRP2is H; orRP2is F; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and q in each instance is independently 0, 1, 2, or 3.

12. The compound of claim 10, wherein:A1is selected from: wherein eachdenotes the point ofattachment;A2is optionally substituted phenyl;X1is O;X2ais C(RXa)2or O,X2bis C(RXa)2or O, andX2cis C(RXa)2, with the proviso that X2aand X2bcannot both be O;RXain each instance is H;R1is an optionally substituted 4 to 6-membered saturated heterocycle, or an optionally substituted 5 to 6-membered heteroaryl;R2is halogen (particularly F or Cl) or cyclopropyl;R3isR3cis C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl);R3dis F or Cl;R4is an optionally substituted C1-3alkyl; one of R5aand R5bis H and the other is optionally substituted C1-3alkyl;R6is selected from:whereindenotes the point of attachment; andR6a, when present, is H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl).

13. The compound of claim 12, wherein X2ais O andX2bis C(RXa)2, wherein one instance of RXais H and the other is C1alkyl (i.e., CH3).

14. The compound of claim 12, wherein X2ais C(RXa)2, wherein each instance of RXais H, and X2bis C(RXa)2, and wherein one instance of RXais H and the other is C1alkyl (i.e., CH3).

15. The compound of claim 1, 4, 5, 10 or 11, wherein:A1is selected from:wherein eachdenotes the point of attachment;X1, when present, is O;R1is selected from: denotes thepoint of attachment; R1a, when present, in each instance is independently halogen, optionally substitutedC1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3);R2is Cl or cyclopropyl;R6is selected from: denotes the point ofattachment; and m is 0 or 1.

16. The compound of claim 15, wherein m is 0.

17. The compound of claim 15, wherein m is 1.

18. The compound of claim 1, 4, 5, 10, 11 or 15, wherein A1is19. The compound of claim 18, wherein m is 0.

20. The compound of claim 18, wherein m is 1.

21. The compound of claim 1, 4, 5, 10 or 11, wherein m is 2.

22. The compound of claim 1, 4 or 10, wherein R1is selected from: denotes thepoint of attachment; and R1a, when present, in each instance is independently halogen, optionally substituted C1-3alkyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3).

23. The compound of claim 22, wherein R1is24. The compound of claim 22, wherein R1isand n is 0.

25. The compound of claim 1, 4 or 10, wherein R1is and R1b, when present, in each instance is independently halogen, C1-3haloalkyl (e.g., =CF2, CH2F, CHF2, and CF3), or C2-3haloalkenyl (e.g., CHCHF and CHCF2).

26. The compound of claim 25, wherein n is 0.

27. The compound of claim 25, wherein n is 1 or 2.The compound of cla28. im 1, 4, 5, 10 or 11, wherein R6is selected from whereindenotes the point of attachment.

29. The compound of claim 28, wherein R6is30. The compound of claim 28, wherein R6isand R6ais optionally substitutedC1-3alkyl.

31. The compound of claim 28, wherein R6isR6ais C1-3alkyl, and C1-3alkyl is C1alkyl (i.e., methyl).

32. The compound of claim 1, 4 or 10, wherein R3is R3ais C1-3alkyl (e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propynyl); and R3bis F, Cl, Br, or CH3.

33. The compound of claim 32, wherein R3ais C2-3alkynyl (e.g., ethynyl and propargyl), and R3bis F, Cl, or Br.

34. The compound of claim 32, wherein R3ais ethynyl, and R3bis F.

35. The compound of claim 1, 4 or 10, wherein R3is R3cis C1-3alkyl(e.g., methyl, ethyl, and propyl), C2-3alkenyl (e.g., vinyl and allyl), or C2-3alkynyl (e.g., ethynyl and propargyl); and R3dis F or Cl.

36. The compound of claim 35, wherein R3cC1alkyl (i.e., CH3) and R3dis F.

37. The compound of claim 1, 4 or 10, wherein W-Y-Z is:denote the points of attachment and * denotes the end that attaches to the oxygen.

38. The compound of claim 37, wherein W-Y-Z is39. The compound of claim 1, 4 or 10, wherein:W is phenyl;Y is -(Y1-Y2-Y3-Y4)-, wherein Y1, Y2, Y3, and Y4are all a bond; andZ is selected from:denote the points of attachment and * denotes the end that attaches to Y.

40. The compound of claim 39, wherein Z is41. The compound of claim 39, wherein Z is42. The compound of claim 39, wherein Z is43. The compound of claim 39, wherein Z is44. The compound of claim 4, 5, 10 or 11, wherein R2is Cl or cyclopropyl.

45. The compound of claim 4, 5, 10 or 11, wherein R2is Cl.

46. The compound of claim 4, 5, 10 or 11, wherein R2is cyclopropyl.

47. The compound of claim 4, 5, 10 or 11, wherein RP2is H or F.

48. The compound of claim 4, 5, 10 or 11, wherein RP2is H.

49. The compound of claim 4, 5, 10 or 11, wherein RP2is F.

50. The compound of claim 1, 4, 5, 10 or 11, wherein m is 0, 1, or 2, and n is 0, 1, or 2.

51. The compound of claim 1, 4, 5, 10 or 11, wherein m is 1 and n is 1.

52. The compound of claim 1, 4, 5, 10 or 11, wherein m is 0 and n is 0.

53. The compound of claim 1, 4, 5, 10 or 11, wherein m is 1 and n is 0.

54. The compound of claim 1, 4, 5, 10 or 11, wherein m is 0 and n is 1.

55. The compound of claim 1, wherein p is 1 or 2.

56. The compound of claim 1, wherein p is 1 and the one instance of RPis OH.

57. The compound of claim 1, wherein p is 2, wherein one instance of and RPis OH and the other is F.

58. The compound of claim 1, 4, 5, 10 or 11, wherein q in each instance is independently either 1 or 2.

59. The compound of claim 1, 4, 5, 10 or 11, wherein q in each instance is 1.

60. The compound of claim 1, 4, 5, 10 or 11, wherein q is 1 in one instance and is 2 in another.

61. A compound having the structure of F ormula II- 1or a pharmaceutically acceptable salt thereof, wherein: A1ais:wherein eachdenotes the point of attachment;X2bis CH2;R2is halogen (preferably Cl), C1-3alkyl, C2-3alkenyl, C2-3alkynyl, cyclopropyl, or cyclobutyl;R3cis C1-3alkyl, preferably methyl;R3dis F, H, Cl, or C1-3alkyl, preferably F;R6is: whereindenotes the point of attachment, and R6ais C1-3alkyl(preferably methyl) or H ; andRP2is H, F, Cl, OH, or CH3, preferably H.

62. The compound of claim 61, wherein the compound is a single atropisomer.

63. A compound having the structure:or pharmaceutically acceptable salt thereof.

64. The compound of claim 63 having the structure:, or a pharmaceutically acceptable salt thereof.

65. A compound having the structure:, or a pharmaceutically acceptable salt thereof.

66. The compound of claim 65 having the structure:, or a pharmaceutically acceptable salt thereof.

67. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.21568. The compound of claim 4, having the structure of Formula IIor a pharmaceutically acceptable salt thereof, wherein: A1ais:wherein eachdenotes the point of attachment;A2is phenyl, optionally substituted with C1-3alkoxyl;X1is O;X2ais O;X2bis C(RXa)2;RXain each instance is independently H, halogen (e.g., F), C1-3alkyl, C1-3hydroxyalkyl, or C1-3haloalkyl;R1is selected from:denotes the point of attachment; R1a, when present, in each instance is independently halogen, hydroxyl, optionally substituted C1-3alkyl, optionally substituted (e.g., F) C1-3alkoxyl, or C1-3haloalkyl (e.g., CH2F, CHF2, and CF3);R2is halogen (preferably Cl), C1-3alkyl, cyclopropyl, or cyclobutyl;denotes the point of attachment;R3cis C1-3alkyl, preferably methyl, F, Cl, C1-3haloalkyl, or C1-3alkyoxy;R3dis F, H, Cl, or C1-3alkyl, preferably F;R4is an optionally substituted C1-4 alkyl, preferably propyl or butyl; or an optionally substituted C3-6cycloalkyl, preferably cyclobutyl;R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl);R5bis optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl) or H; R6is: whereindenotes the point ofattachment, and R6a, when present, is H or optionally substituted C1-3alkyl;R7, when present, in each instance is independently selected from optionally substituted C1-3alkyl, optionally substituted C2-3alkenyl, optionally substituted C2-3alkynyl (e.g., ethynyl and propargyl), hydroxyl, halogen, cyano, C1-3haloalkyl, C1-3cyanoalkyl, C1-3hydroxyalkyl, C1-3alkoxy, and (CH2)qO(CH2)qCH3;RP1is H, F, Cl, OH, or CH3, preferably OH;RP2is H;W-Y-Z is selected from:wherein denote the points of attachment and * denotes the end that attaches to the oxygen; m is 0, 1, 2, 3, or 4; preferably 0; and n is 0, 1, 2, 3, or 4; preferably 0 or 1.

69. The compound of claim 68, wherein A1ais70. The compound of claim 68, wherein A2is71. The compound of claim 68, wherein X2bis CH2or CH(CH3).

72. The compound of claim 68, wherein R1is selected from:

73. The compound of claim 68, wherein R2is halogen(preferably Cl) or cyclopropyl.

74. The compound of claim 68, wherein R3is75. The compound of claim 68, wherein R4is propyl (preferably isopropyl), butyl, (preferably sec-butyl), or cyclobutyl.

76. The compound of claim 68, wherein R6a, when present, is H, methyl or ethyl.

77. The compound of claim 68, wherein R6is78. The compound of claim 68, wherein R5ais H and R5bis CH3, CH2OH, or CH(OH)CH3.

79. The compound of claim 68, wherein RP1is OH.

80. The compound of claim 1, having the structure of Formula IIor a pharmaceutically acceptable salt thereof, wherein:A1ais:wherein eachdenotes the point of attachment;A2is phenyl;X1is O;X2ais O;X2bis C(RXa)2; wherein RXain each instance is independently H, or C1-3alkyl;R1is: wherein denotes the point of attachment;R2is halogen, preferably Cl, C1-3alkyl, or cyclopropyl;R3iswhereindenotes the point of attachment;R4is an optionally substituted C1-3alkyl, preferably isopropyl;R5ais H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl), preferably H;R5bis H or optionally substituted C1-3alkyl (e.g., optionally substituted with hydroxyl), preferably CH2OH;R6is:whereindenotes the point of attachment;RP1is OH;RP2is H; andW-Y-Z is selected from:wherein denote the points of attachment and * denotes the end that attaches to the oxygen.

81. The compound of claim 68, having the structure selected from:,or a pharmaceutically acceptable salt thereof.

82. The compound of claim 68, having the structure selected from:or a pharmaceutically acceptable salt thereof.

83. The compound of claim 1 or 68 having the structure:or a pharmaceutically acceptable salt thereof.

84. A compound selected from Table 1 A, or a pharmaceutically acceptable salt thereof.

85. The compound of claim 68, wherein the compound is a single atropisomer.

86. A pharmaceutical composition comprising the compound of any one of claims 1-85 and a pharmaceutically acceptable diluent or excipient.

87. A method of treating a disease or disorder mediated by KRAS G12D in a subject afflicted therewith, comprising administering to the subject a compound of any one of claims 1-85.

88. The method of claim 87, wherein the disease mediated by KRAS G12D is a cancer selected from pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, lung adenocarcinoma (particularly, non-small cell lung carcinoma), endometrioid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, and cholangiocarcinoma.

89. The method of claim 87, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, and lung adenocarcinoma (particularly, non-small cell lung adenocarcinoma).

90. A method of treating a cancer in a subject afflicted therewith, comprising administering to the subject a compound of any one of claims 1-85 or a pharmaceutical composition of claim 86.

91. The method of claim 90, wherein the disease mediated by KRAS G12D is a cancer selected from pancreatic adenocarcinoma, mucinous ovarian cancer, appendiceal adenocarcinoma, ampullary carcinoma, small intestinal carcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, lung adenocarcinoma (particularly, non-small cell lung carcinoma), endometrioid ovarian cancer, low grade serous ovarian cancer, endometrial carcinoma, and cholangiocarcinoma.

92. The method of claim 91, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal adenocarcinoma, bladder adenocarcinoma, and lung adenocarcinoma (particularly, non-small cell lung adenocarcinoma).

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