WO2025226861A1

WO2025226861A1 - Cyclin inhibitors

Info

Publication number: WO2025226861A1
Application number: PCT/US2025/026045
Authority: WO
Inventors: Andrew T. BOCKUS; Breena F. WALTON; Constantine Kreatsoulas; James B. Aggen; Justin A. SHAPIRO; Megan DEMART; Nathan J. Dupper; Sik Fai Siegfried LEUNG; Chinmay Bhatt; Samuel Metobo; Kai Yang; Ming Hsun Ho; Rajinder Singh
Original assignee: Circle Pharma Inc
Current assignee: Circle Pharma Inc
Priority date: 2024-04-24
Filing date: 2025-04-23
Publication date: 2025-10-30
Anticipated expiration: 2026-10-24

Abstract

Disclosed herein are compounds of Formula (I), intermediates thereof, and methods for making the same. Also described herein are the use of such compounds and compositions for the treatment of diseases and disorders that are mediated, at least in part, by one or more cyclins, including cancer.

Description

PATENT Attorney Docket No.052687-508001WO CYCLIN INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/637,995, filed April 24, 2024, which is incorporated herein in its entirety for all purposes. 5 BACKGROUND [0002] Cyclins are a family of proteins that play a central role in the regulation of the cell cycle. Specific cyclins, including Cyclins D, E, A and B, are expressed at the different stages of the cell cycle, during which they bind and activate their cognate cyclin dependent kinases (CDKs), including CDKs 1, 2, 4 and 6, to form cyclin-CDK complexes that orchestrate 10 progression and transitions through the different stages of the cell cycle. Disruptions of the normal regulatory functions of cyclin-CDK complexes are common drivers of oncogenesis and the rapid proliferation of cancer cells. The central role of cyclins and CDKs in the cell cycle makes these proteins and their complexes attractive targets for treating proliferative disorders and cancer. To date, most inhibitors of cyclin-CDK complexes target the kinase 15 activity of CDKs (“CDK inhibitors”) and include therapeutics both in development and approved for clinical use. Alternative approaches could include disrupting the association of cyclins with CDKs or the interaction of a particular cyclin-CDK complex with its substrates or regulators. [0003] Although CDK inhibitors have been developed and proven successful in certain 20 cancers, they are currently limited by their relative lack of selectivity, small therapeutic window, and ultimately the development of resistance. As such, there is a need to develop agents that offer alternative approaches to inhibiting the function of cyclin-CDK complexes as a means to modulate the cell cycle. Such agents could provide new tools in the treatment of proliferative diseases. The present disclosure addresses this need by providing compounds 25 that inhibit the binding of substrates to various cyclins, thereby disrupting the function of cyclin-CDK complexes. BRIEF SUMMARY [0004] In one embodiment, provided herein is a compound of Formula (I): 1 PATENT Attorney Docket No.052687-508001WO (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 5 4, or 5 R^3a, (b) C3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R^3b, or (c) heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 R^3c; 10 (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 R^3g; each R^3a is independently –OH, C1-6 alkoxy, C1-6 haloalkoxy, –O–(CH2CH2O)1-4–C1-4 alkyl, –O–(CH2CH2O)1-4–heterocycloalkyl, C1-3 haloalkoxy, –NR^3a1R^3a2, –O–C(O)C1-6 alkyl, C3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 15 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3b is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, cyano, –OH, C1-6 alkoxy, C1-6 haloalkoxy, –NR^3b1R^3b2, –N(R^3b3)C(O)R^3b4, phenyl, or 20 heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3c is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, cyano, oxo, or C_3-6 cycloalkyl; each R^3g is independently C1-6 alkyl, halo, C1-6 haloalkyl, or C3-6 cycloalkyl; each R^3a1, R^3a2, R^3b1, R^3b2, and R^3b3 is independently H or C_1-6 alkyl; 25 each R^3b4 is C1-6 alkyl or C1-6 haloalkyl; R^4a is H or C_1-6 alkyl; 2 PATENT Attorney Docket No.052687-508001WO R^4b and R^4c are each independently H, C_1-6 alkyl, –C_1-6 alkyl–OH, C_1-6 haloalkyl, –NR^4c1R^4c2, C1-6 alkyl–NR^4c1R^4c2, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 5 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is 10 substituted with 0, 1, 2, 3, or 4 R^4a1; each R^4c1 and R^4c2 are independently C_1-6 alkyl or C_2-6 alkoxyalkyl; each R^4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or –N(R^4a2)S(O)₂–C_1-4 alkyl; R^4a2 is H or C1-6 alkyl; 15 alternatively, two R^4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R^4a3; each R^4a3 is independently C_1-6 alkyl, –OH, –C_1-6 alkyl–OH, C_1-6 alkoxy, or halo; R^5a is H or C1-6 alkyl; R^5b and R^5c are each independently H, C_1-6 alkyl, –C_1-6 alkyl–OH, C_2-6 alkoxyalkyl, ₂₀ C_1-6 haloalkyl, –C_1-6 alkyl–NR^5b1R^5b2, –C_1-6 alkyl–C(O)NR^5b1R^5b2, –C_1-6 alkyl–N(R^5b1)C(O)R^5b3, –C_1-6 alkyl–C(O)OR^5b1, C_3-6 cycloalkyl, –C_1-6 alkyl–C_3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently 25 N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^5b5; each R^5b1 and R^5b2 are independently H, C_1-6 alkyl, or C_1-6 haloalkyl; alternatively, R^5b1 and R^5b2 on the same nitrogen atom combine to form a heterocycloalkyl 30 having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^5b5; each R^5b3 is C_1-6 alkyl, C_1-6 haloalkyl, or a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, substituted with 0, 1, 2, or 3 R^5b4; 3 PATENT Attorney Docket No.052687-508001WO each R^5b4 is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, –NH₂, –N(C_1-6 alkyl)₂, or –NH(C1-6 alkyl); each R^5b5 is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, –NH₂, –N(C_1-4alkyl)₂, or –NH(C1-4 alkyl); 5 R^6a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each 10 independently N, O, or S; R^6b is H or C_1-6 alkyl; R^6d is H, C1-6 alkyl, C1-6 deuteroalkyl, –OH, or C2-6 alkoxyalkyl; L^6a is C_1-5 alkylene or C_2-5 alkenylene, wherein C_1-5 alkylene and C_2-5 alkenylene is substituted with 0, 1, 2, or 3 R^L6a; 15 L^6b is C_1-5 alkylene or C_2-5 alkenylene, wherein C_1-5 alkylene and C_2-5 alkenylene is substituted with 0, 1, 2, or 3 R^L6b; Y⁶ is a bond, O, NH, S, S(O), or S(O)₂, wherein when Y⁶ is a bond, then i) L^6a and L^6b combine to form C8-10 alkylene or C_8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b; or ii) L^6a is ₂₀ substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C_3-6 cycloalkyl; each R^L6a and R^L6b is independently C_1-4 alkyl, –OH, or halo; alternatively, an R^L6a and R^6b on adjacent atoms combine to form a C_3-6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 R^6e; 25 alternatively, an R^L6a and R^6a on non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e; alternatively, two R^L6b moieties on the same atom or on adjacent atoms combine to form a ₃₀ C_3-6 cycloalkyl or a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the cycloalkyl and heterocycloalkyl is substituted with 0, 1, or 2 R^6e; alternatively, an R^L6b and R^6d on adjacent or non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 4 PATENT Attorney Docket No.052687-508001WO heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e; each R^6e is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; R^7a is H or C1-6 alkyl; 5 R^7b and R^7c are each independently H, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C1-6 alkyl–OH, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R^8a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R^8b, R^8d, and R^8e are each independently H or C_1-6 alkyl; 10 alternatively R^8b and R^8d together with the carbons to which each is attached combine to form a C_3-6 cycloalkyl; ring B is C6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; the subscript m8 is 0, 1, 2, 3, 4, or 5; 15 each R^8f is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C1-6 deuteroalkoxy, C2-6 alkoxyalkyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, –X^8f–cyano, –NR^8f1R^8f2, –C(O)NR^8f1R^8f2, –N(R^8f1)C(O)R^8f2, C_3-12 cycloalkyl, –X^8f–C3-6 cycloalkyl, heterocycloalkyl, –X^8f–heterocycloalkyl, C6-12 aryl, –X^8f–C _6-12 aryl, heteroaryl, or –X^8f–heteroaryl, wherein each heterocycloalkyl has 3 20 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; alternatively, two R^8f groups on adjacent ring vertices combine to form a C_3-6 cycloalkyl or a 25 heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3; each X^8f is independently C_1-6 alkylene, C_2-6 alkenylene, –O–C_1-6 alkylene, C(O), O, or S; each R^8f1 and R^8f2 are independently H or C1-6 alkyl; ₃₀ each R^8f3 is independently C_1-6 alkyl, –Y⁸–C_1-6 alkyl, C_1-6 deuteroalkyl, –Y⁸–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y⁸–C1-6 alkyl–OH, –C_1-6 alkyl–Y⁸–C_1-6 alkyl, –(C_1-2 alkyl–O)_1-4–C_1-2 alkyl, C_1-6 alkoxy, halo, C_1- 6 haloalkyl, –Y⁸–C1-6 haloalkyl, cyano, –C1-6 alkyl–cyano, –C1-6 alkyl–NR^8gR^8h, oxo, C_3-6 cycloalkyl, –X^8f3–C_3-6 cycloalkyl, heterocycloalkyl, –X^8f3– heterocycloalkyl, 5 PATENT Attorney Docket No.052687-508001WO phenyl, –X^8f3–phenyl, heteroaryl, or –X^8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are 5 substituted with 0, 1, or 2 C_1-4 alkyl or halo; alternatively, two R^8f3 groups on the same or adjacent ring vertices combine to form a C_3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in the heterocycloalkyl are substituted with 0 or 1 C_1-4 alkyl; 10 each X^8f3 is independently C1-6 alkylene, O, C(O), or S(O)2; each Y⁸ is independently C(O), C(O)O, N(R^8f4)C(O), O, S, or S(O)₂; each R^8g and R^8h is independently H, C1-6 alkyl, or C1-6 haloalkyl; each R^8f4 is independently H or C_1-6 alkyl; and ring A comprises 13 to 21 ring atoms; 15 or a pharmaceutically acceptable salt thereof. [0005] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient. [0006] In another embodiment, the present disclosure provides a method of treating a 20 disease or disorder mediated at least in part by cyclin activity, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the disorder or condition. [0007] In another embodiment, the present disclosure provides a method of treating a 25 cancer mediated at least in part by cyclin A, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. [0008] In another embodiment, the present invention provides intermediates useful in the 30 preparation of compounds of Formula (I). [0009] Other objects, features, and advantages of the present disclosure will be apparent to one of skill in the art from the following detailed description and figures. 6 PATENT Attorney Docket No.052687-508001WO BRIEF DESCRIPTION OF THE DRAWINGS [0010] NOT APPLICABLE DETAILED DESCRIPTION I. General 5 [0011] Provided herein are compounds and compositions that disrupt the typical cellular function of cyclins. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by cyclin activity. [0012] Complexes between cyclins and cyclin dependent kinases (CDKs) are responsible for phosphorylating a wide range of substrates, thereby modulating the activity of the 10 substrates. Many of these substrates are important in the cell cycle and the cyclin and CDKs that regulate these substrates therefore play key roles in regulating the cell cycle, including Cyclins D, A, E and B, and CDKs 1, 2, 4 and 6. Without being bound to any particular theory, certain substrates, including p21, p27, Rb, E2F and CDC6, first bind to the cyclin- CDK complex via a conserved RxL motif within the substrate (Adams et al. Mol Cell Biol. 15 1996.16(12):6223-33.) and bind to a region with the cyclin that is referred to as an RxL binding domain or a “hydrophobic patch” (Brown et al. Nat Cell Biol.1999.1(7):438-43) and contains a highly conserved MRAIL motif. Compounds that disrupt the binding of substrates to cyclins have been posited to be of potential therapeutic utility, including in the disruption of cancer cell proliferation (Chen et al. Proc Natl Acad Sci U S A.1999.96(8):4325-9). 20 [0013] Without being bound to any particular theory, it is believed that compounds of the present disclosure inhibit the binding of substrates to the hydrophobic patch region of cyclins including, but not limited to, Cyclins A, E and B. Compounds of the present disclosure include compounds that bind more potently to one or more cyclins. II. Definitions 25 [0014] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, about means a range extending to +/- 10% of the specified value. In some embodiments, about means the 30 specified value. 7 PATENT Attorney Docket No.052687-508001WO [0015] “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_1-7, C_1-8, C_1-9, C_1-10, C_2-3, C_2-4, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C5-6. For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, 5 butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. [0016] “Alkylene” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent 10 hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of –(CH₂)_n–_, where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. Alkylene groups can be substituted or 15 unsubstituted. [0017] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C₆. Alkenyl groups can have any suitable number of double bonds, including, but not 20 limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. 25 [0018] “Alkenylene” refers to a straight or branched hydrocarbon having at least 2 carbon atoms, one double bond, and linking at least two other groups, i.e., a divalent hydrocarbon radical. Alkenylene can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4, C_3-5, C_3-6, C_3-6, C_3-7, C₄, C_4-5, C_4-6, C_4-7, C_6-7, C₅, C₆ and C_7. The two moieties linked to the alkenylene can be linked to the same atom or different atoms of the30 alkenylene group. Representative alkenylene groups include, but are not limited to, (E)-hex- 2-enylene, (Z)-hex-2-enylene, (E)-hept-2-enylene, (Z)-hept-2-enylene, (E)-hept-3-enylene, 8 PATENT Attorney Docket No.052687-508001WO and (Z)-hept-3-enylene. Alkenylene moieties can be in the E or Z isomer. Alkenylene groups can be substituted or unsubstituted. [0019] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such 5 as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C₆. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or 10 unsubstituted. [0020] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C_1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, 15 tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be substituted or unsubstituted. [0021] “Alkoxyalkyl” refers to alkyl group connected to an oxygen atom that is further connected to an second alkyl group, the second alkyl group being the point of attachment to the remainder of the molecule: alkyl-O-alkyl. The alkyl portion can have any suitable number of carbon atoms, such as C2-6. Alkoxyalkyl groups include, for example, 20 methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. The alkoxy groups can be substituted or unsubstituted. [0022] “Halo” or “halogen” refers to fluorine, chlorine, bromine and iodine. [0023] “Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any 25 suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, flouromethyl, etc. In some instances, the term “perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. [0024] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms 30 are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C_1-6. The alkoxy groups can be substituted with 1, 9 PATENT Attorney Docket No.052687-508001WO 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc. [0025] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, spirocyclic, 5 fused or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C_3-6, C_4-6, C_5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] 10 bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring, but cycloalkyl groups are not aromatic. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobuteneyl, cyclopenteneyl, cyclohexeneyl, cyclohexadieneyl (1,3- and 1,4-isomers), cyclohepteneyl, cycloheptadieneyl, cycloocteneyl, 15 cyclooctadieneyl (1,3-, 1,4- and 1,5-isomers), norborneneyl, and norbornadieneyl. When cycloalkyl is a C_3-6 monocyclic cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexeneyl, cyclohexadieneyl (1,3- and 1,4-isomers). When cycloalkyl is a C_5-10 fused bicyclic cycloalkyl, exemplary groups include, but are not limited to bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, 20 bicyclo[4.2.0]octanyl, and octahydro-1H-indenyl. When cycloalkyl is a C_5-10 bridged polycyclic cycloalkyl, exemplary groups include, but are not limited to bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.1.1]hexane. When cycloalkyl is a C_5-10 spirocycloalkyl, exemplary groups include, but are not limited to spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonanyl, spiro[2.5]octane, and spiro[2.4]heptane. Cycloalkyl groups can be 25 substituted or unsubstituted. [0026] “Heterocycloalkyl” refers to a saturated or partially unsaturated, monocyclic, spirocyclic, fused or bridged polycyclic ring assembly having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)₂-. Heterocycloalkyl groups can include any number of ring 30 atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, 10 PATENT Attorney Docket No.052687-508001WO piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), tetrahydropyridine, oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, 5 dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can be unsubstituted or substituted. [0027] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2- azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 10 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine, piperazine can be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine. 15 [0028] When heterocycloalkyl is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also be monocyclic 20 heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine. [0029] “Aryl” refers to an aromatic ring system having any suitable number of ring atoms 25 and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene 30 linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. 11 PATENT Attorney Docket No.052687-508001WO Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted. [0030] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 12 ring atoms, where from 1 to 6 of the ring atoms are a heteroatom 5 such as N, O or S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)₂-. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12, or 9 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, 5, or 6, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, or 3 to 6. Heteroaryl groups 10 can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, 15 isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include 20 heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. [0031] The heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole 25 includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5- 30 oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline 12 PATENT Attorney Docket No.052687-508001WO includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran. [0032] Some heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, 5 pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, 10 pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 15 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. [0033] As used herein, the term “oxo” refers to an oxygen atom connected to the point of attachment by a double bond (=O). [0034] “Pharmaceutically acceptable excipient” refers to a substance that aids the 20 formulation and/or administration of an active agent to a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. [0035] “Subject” refers to animals such as mammals, including, but not limited to, primates 25 (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. [0036] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release 30 device e.g., a mini-osmotic pump, to the subject. 13 PATENT Attorney Docket No.052687-508001WO [0037] “Therapeutically effective amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of 5 Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins) [0038] “Treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any 10 objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination. 15 III. Compounds [0039] In some embodiments, the present disclosure provides a compound of Formula (I): (I) wherein R³ is 20 (a) C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, or C_1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R^3a, (b) C_3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R^3b, or (c) heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 25 4, or 5 R^3c; 14 PATENT Attorney Docket No.052687-508001WO (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 R^3g; each R^3a is independently –OH, C_1-6 alkoxy, C_1-6 haloalkoxy, –O–(CH₂CH₂O)_1-4–C_1-4 alkyl, –O–(CH2CH2O)1-4–heterocycloalkyl, C1-3 haloalkoxy, –NR^3a1R^3a2, 5 –O–C(O)C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3b is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, halo, C_1-6 haloalkyl, cyano, 10 –OH, C1-6 alkoxy, C1-6 haloalkoxy, –NR^3b1R^3b2, –N(R^3b3)C(O)R^3b4, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3c is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, cyano, oxo, or C_3-6 cycloalkyl; each R^3g is independently C1-6 alkyl, halo, C1-6 haloalkyl, or C3-6 cycloalkyl; 15 each R^3a1, R^3a2, R^3b1, R^3b2, and R^3b3 is independently H or C_1-6 alkyl; each R^3b4 is C1-6 alkyl or C1-6 haloalkyl; R^4a is H or C_1-6 alkyl; R^4b and R^4c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C1-6 haloalkyl, –NR^4c1R^4c2, C_1-6 alkyl–NR^4c1R^4c2, C_3-6 cycloalkyl, –C_1-6 alkyl–C_3-6 cycloalkyl, heterocycloalkyl, ₂₀ –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached 25 combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, or 4 R^4a1; each R^4c1 and R^4c2 are independently C_1-6 alkyl or C_2-6 alkoxyalkyl; each R^4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or ₃₀ –N(R^4a2)S(O)₂–C_1-4 alkyl; R^4a2 is H or C1-6 alkyl; alternatively, two R^4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R^4a3; each R^4a3 is independently C_1-6 alkyl, –OH, –C_1-6 alkyl–OH, C_1-6 alkoxy, or halo; 15 PATENT Attorney Docket No.052687-508001WO R^5a is H or C_1-6 alkyl; R^5b and R^5c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C2-6 alkoxyalkyl, C_1-6 haloalkyl, –C_1-6 alkyl–NR^5b1R^5b2, –C_1-6 alkyl–C(O)NR^5b1R^5b2, –C1-6 alkyl–N(R^5b1)C(O)R^5b3, –C1-6 alkyl–C(O)OR^5b1, C3-6 cycloalkyl, 5 –C_1-6 alkyl–C_3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and wherein each cycloalkyl, heterocycloalkyl, phenyl, and 10 heteroaryl is substituted with 0, 1, 2, or 3 R^5b5; each R^5b1 and R^5b2 are independently H, C_1-6 alkyl, or C_1-6 haloalkyl; alternatively, R^5b1 and R^5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^5b5; 15 each R^5b3 is C_1-6 alkyl, C_1-6 haloalkyl, or a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, substituted with 0, 1, 2, or 3 R^5b4; each R^5b4 is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, –NH₂, –N(C_1-6 alkyl)₂, or –NH(C1-6 alkyl); each R^5b5 is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, –NH₂, –N(C_1-4alkyl)₂, or ₂₀ –NH(C_1-4 alkyl); R^6a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, –C_1-6 alkyl–C_3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently 25 N, O, or S, and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; R^6b is H or C_1-6 alkyl; R^6d is H, C_1-6 alkyl, C_1-6 deuteroalkyl, –OH, or C_2-6 alkoxyalkyl; L^6a is C1-5 alkylene or C2-5 alkenylene, wherein C1-5 alkylene and C2-5 alkenylene is ₃₀ substituted with 0, 1, 2, or 3 R^L6a; L^6b is C1-5 alkylene or C2-5 alkenylene, wherein C1-5 alkylene and C2-5 alkenylene is substituted with 0, 1, 2, or 3 R^L6b; Y⁶ is a bond, O, NH, S, S(O), or S(O)2, wherein when Y⁶ is a bond, then i) L^6a and L^6b combine to form C_8-10 alkylene or 16 PATENT Attorney Docket No.052687-508001WO C_8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b; or ii) L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C_3-6 cycloalkyl; each R^L6a and R^L6b is independently C1-4 alkyl, –OH, or halo; 5 alternatively, an R^L6a and R^6b on adjacent atoms combine to form a C_3-6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 R^6e; alternatively, an R^L6a and R^6a on non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is 10 substituted with 0, 1, or 2 R^6e; alternatively, two R^L6b moieties on the same atom or on adjacent atoms combine to form a C3-6 cycloalkyl or a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the cycloalkyl and heterocycloalkyl is substituted with 0, 1, or 2 R^6e; 15 alternatively, an R^L6b and R^6d on adjacent or non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e; each R^6e is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; ₂₀ R^7a is H or C_1-6 alkyl; R^7b and R^7c are each independently H, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C_1-6 alkyl–OH, C_3-6 cycloalkyl, or –C_1-6 alkyl–C_3-6 cycloalkyl; R^8a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, or –C_1-6 alkyl–C_3-6 cycloalkyl; 25 R^8b, R^8d, and R^8e are each independently H or C_1-6 alkyl; alternatively R^8b and R^8d together with the carbons to which each is attached combine to form a C_3-6 cycloalkyl; ring B is C_6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; 30 the subscript m8 is 0, 1, 2, 3, 4, or 5; each R^8f is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C_1-6 deuteroalkoxy, C_2-6 alkoxyalkyl, halo, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, –X^8f–cyano, –NR^8f1R^8f2, –C(O)NR^8f1R^8f2, –N(R^8f1)C(O)R^8f2, C3-12 cycloalkyl, –X^8f–C_3-6 cycloalkyl, heterocycloalkyl, –X^8f–heterocycloalkyl, C_6-12 aryl, 17 PATENT Attorney Docket No.052687-508001WO –X^8f–C _6-12 aryl, heteroaryl, or –X^8f–heteroaryl, wherein each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 5 substituted with 0, 1, 2, or 3 R^8f3; alternatively, two R^8f groups on adjacent ring vertices combine to form a C3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3; 10 each X^8f is independently C1-6 alkylene, C2-6 alkenylene, –O–C1-6 alkylene, C(O), O, or S; each R^8f1 and R^8f2 are independently H or C_1-6 alkyl; each R^8f3 is independently C1-6 alkyl, –Y⁸–C1-6 alkyl, C1-6 deuteroalkyl, –Y⁸–C_1-6 deuteroalkyl, –OH, –C_1-6 alkyl–OH, –Y⁸–C_1-6 alkyl–OH, –C1-6 alkyl–Y⁸–C1-6 alkyl, –(C1-2 alkyl–O)1-4–C1-2 alkyl, C1-6 alkoxy, halo, 15 C_1-6 haloalkyl, –Y⁸–C_1-6 haloalkyl, cyano, –C_1-6 alkyl–cyano, –C_1-6 alkyl–NR^8gR^8h, oxo, C3-6 cycloalkyl, –X^8f3–C3-6 cycloalkyl, heterocycloalkyl, –X^8f3– heterocycloalkyl, phenyl, –X^8f3–phenyl, heteroaryl, or –X^8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each 20 independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C_1-4 alkyl or halo; alternatively, two R^8f3 groups on the same or adjacent ring vertices combine to form a C_3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in 25 the heterocycloalkyl are substituted with 0 or 1 C_1-4 alkyl; each X^8f3 is independently C_1-6 alkylene, O, C(O), or S(O)₂; each Y⁸ is independently C(O), C(O)O, N(R^8f4)C(O), O, S, or S(O)₂; each R^8g and R^8h is independently H, C_1-6 alkyl, or C_1-6 haloalkyl; each R^8f4 is independently H or C1-6 alkyl; and 30 ring A comprises 13 to 21 ring atoms; or a pharmaceutically acceptable salt thereof. [0040] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 13 to 21 ring atoms. In 18 PATENT Attorney Docket No.052687-508001WO some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 14 to 20 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 16 to 18 ring atoms. In some 5 embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 13 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 14 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A 10 comprises 15 ring atoms. In some embodiment ring A comprises 16 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 17 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 18 ring atoms. In some embodiments, the compound, or the 15 pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 19 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 20 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 21 ring atoms. 20 Residue 3 [0041] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (a) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or C1-6 haloalkyl substituted with 0, 1, 2, 3, 4, or 5 R^3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 25 wherein R³ is (a) C1-6 alkyl or C1-6 haloalkyl substituted with 0, 1, or 2 R^3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (a) C1-6 alkyl substituted with 0, 1, or 2 R^3a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (a) C1-6 haloalkyl substituted with 0, 1, or 2 R^3a. 30 These embodiments of R³ can be combined with any of the embodiments described herein for R^3a. 19 PATENT Attorney Docket No.052687-508001WO [0042] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3a is –OH or C1-6 alkoxy. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3a is –OH. These embodiments of R^3a can be 5 combined with any of the relevant embodiments described herein for R³. [0043] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (b) C3-12 cycloalkyl substituted with 0, 1, 2, or 3 R^3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (b) C3-7 cycloalkyl substituted with 0, 10 1, 2, or 3 R^3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (b) C5-6 cycloalkyl substituted with 0, 1, or 2 R^3b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (b) C3-4 cycloalkyl substituted with 0, 1, or 2 R^3b. These embodiments of R³ can be combined with any of the embodiments 15 described herein for R^3b. [0044] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3b is halo, C_1-4 haloalkyl, or cyano. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3b is halo or C_1-4 haloalkyl. In some embodiments, 20 the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3b is fluoro or trifluoromethyl. These embodiments of R^3b can be combined with any of the relevant embodiments described herein for R³. [0045] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (c) heterocycloalkyl having 3 to 6 ring 25 members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 R^3c. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (c) heterocycloalkyl having 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^3c. 30 These embodiments of R³ can be combined with any of the relevant embodiments described herein for R^3c. 20 PATENT Attorney Docket No.052687-508001WO [0046] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^3c is halo or C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3c is fluoro or trifluoromethyl. These embodiments 5 of R^3c can be combined with any of the embodiments described herein for R³. [0047] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 R^3g. In some embodiments, the compound, or the 10 pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is (g) heteroaryl having 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, or 2 R^3g. These embodiments of R³ can be combined with any of the relevant embodiments described herein for R^3g. [0048] In some embodiments, the compound, or the pharmaceutically acceptable salt 15 thereof, is the compound of Formula (I), wherein R^3g is halo or C_1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^3g is chloro, fluoro, or trifluoromethyl. These embodiments of R^3g can be combined with any of the embodiments described herein for R³. [0049] In some embodiments, the compound, or the pharmaceutically acceptable salt 20 thereof, is the compound of Formula (I), wherein R³ is , [0050] Any of the embodiments described herein for residue 3 can be combined with any of the embodiments described herein for residues 4, 5, 6, 7, and 8. For example, any of the 25 embodiments of R³ as described herein, can be combined with any of the embodiments described herein for R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^6a, R^6b R^6d, L^6a, Y⁶, L^6b, R^7a, R^7b, R^7c, R^8a, R^8b, R^8d, R^8e, ring B, m8, R^8f, and ring A. 21 PATENT Attorney Docket No.052687-508001WO Residue 4 [0051] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a, R^4b, and R^4c are each independently H or C1-6 alkyl; 5 alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^4a1; and each R^4a1 is independently halo. 10 [0052] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a, R^4b, and R^4c are each independently H or C_1-6 alkyl. [0053] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein 15 R^4b is H or C_1-6 alkyl; and R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^4a1. 20 [0054] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a and R^4b are each H; and R^4c is ethyl; alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached 25 combine to form a pyrrolidinyl, substituted with 0, 1, or 2 fluoro. [0055] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4b is H; and R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form 30 a pyrrolidinyl, substituted with 0, 1, or 2 R^4a1. 22 PATENT Attorney Docket No.052687-508001WO [0056] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a1 is C1-6 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a1 is halo. In some embodiments, the compound, or the 5 pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^4a1 is fluoro. These embodiments of R^4a1 can be combined with any of the relevant embodiments described herein for R⁴. [0057] The embodiments described herein for R^4a, R^4b and R^4c can be present in any combination. In addition, the embodiments described herein for residue 4 can be present in 10 combination with any of the embodiments described herein for residues 3, 5, 6, 7, and 8. For example, any of the embodiments of R^4a, R^4b and R^4c as described herein, can be combined with any of the embodiments described herein for R³, R^5a, R^5b, R^5c, R^6a, R^6b R^6d, L^6a, Y⁶, L^6b, R^7a, R^7b, R^7c, R^8a, R^8b, R^8d, R^8e, ring B, m8, R^8f, and ring A. Residue 5 15 [0058] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^5a is H or C_1-6 alkyl; R^5b and R^5c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C2-6 alkoxyalkyl, C1-6 haloalkyl, C_3-6 cycloalkyl, or C_1-4 alkyl–C_3-6 cycloalkyl, wherein each cycloalkyl is 20 substituted with 0, 1, 2, or 3 R^5b5; and each R^5b5 is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl. [0059] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^5a is H or C_1-6 alkyl; and 25 R^5b and R^5c are each independently H, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkyl–C3-6 cycloalkyl. [0060] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^5a is H or C1-6 alkyl; R^5b is H; and 30 R^5c is C3-6 cycloalkyl or C1-4 alkyl–C3-6 cycloalkyl. 23 PATENT Attorney Docket No.052687-508001WO [0061] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^5a and R^5b are each H; and R^5c is H, methyl, ethyl . 5 [0062] In some emb r the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^5a and R^5b are each H; and R^5c is methyl . [0063] The em o iments described herein for R^5a, R^5b and R^5c can be present in any 10 combination. In addition, the embodiments described herein for residue 5 can be present in combination with any of the embodiments described herein for residues 3, 4, 6, 7, and 8. For example, any of the embodiments of R^5a, R^5b and R^5c as described herein, can be combined with any of the embodiments described herein for R³, R^4a, R^4b, R^4c, R^6a, R^6b R^6d, L^6a, Y⁶, L^6b, R^7a, R^7b, R^7c, R^8a, R^8b, R^8d, R^8e, ring B, m8, R^8f, and ring A. 15 Residue 6 [0064] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^6a is H, C_1-4 alkyl, or –C_1-4 alkyl–C_3-6 cycloalkyl; and R^6b and R^6d are each independently H or C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula 20 (I), wherein R^6a is H or C1-4 alkyl; R^6b is H; and R^6d is C1-4 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^6a is H or C1-4 alkyl; and R^6b and R^6d are each H. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^6a, R^6b, and R^6d are each H. These embodiments of R^6a, R^6b and R^6d can be 25 combined with any of the embodiments described herein for L^6a, Y⁶, and L^6b. [0065] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^6a is H, methyl, n-propyl, o ; R^6b is H; and R^6d is H, methyl, ethyl, isopropyl, or 24 PATENT Attorney Docket No.052687-508001WO –CD₃. This embodiment of R^6a, R^6b and R^6d can be combined with any of the embodiments described herein for L^6a, Y⁶, and L^6b. [0066] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein 5 R^6a is H, methyl, n-propyl, or ; R^6b is H; and R^6d is H or methyl. This embodiment of R^6a, R^6b and mbined with any of the embodiments described herein for L^6a, Y⁶, and L^6b. [0067] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is C_1-5 alkylene substituted with 0, 1, 2, 10 or 3 R^L6a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is C_2-5 alkenylene substituted with 0, 1, 2, or 3 R^L6a. These embodiments of L^6a can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, Y⁶, and L^6b. [0068] In some embodiments, the compound, or the pharmaceutically acceptable salt 15 thereof, is the compound of Formula (I), wherein L^6a is substituted with 0 R^L6a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is substituted with 1 R^L6a. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is substituted with 2 R^L6a. In some embodiments, the compound, or the 20 pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is substituted with 3 R^L6a. These embodiments of L^6a and R^L6a can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, Y⁶, and L^6b. [0069] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^L6a is C1-4 alkyl, –OH, or halo. In 25 some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^L6a is C1-4 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^L6a is C1-4 alkyl. These embodiments of R^L6a can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, Y⁶, and L^6b. 30 [0070] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6b is C1-5 alkylene substituted with 0, 1, 2, 25 PATENT Attorney Docket No.052687-508001WO or 3 R^L6b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6b is C2-5 alkenylene substituted with 0, 1, 2, or 3 R^L6b. These embodiments of L^6b can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, and Y⁶. 5 [0071] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6b is substituted with 0 R^L6b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6b is substituted with 1 R^L6b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 10 wherein L^6b is substituted with 2 R^L6b. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6b is substituted with 3 R^L6b. These embodiments of L^6b and R^L6b can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, and Y⁶. [0072] In some embodiments, the compound, or the pharmaceutically acceptable salt 15 thereof, is the compound of Formula (I), wherein each R^L6b is C_1-4 alkyl, –OH, or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^L6b is C_1-4 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^L6b is C_1-4 alkyl. These embodiments of R^L6b can be combined with any of the 20 embodiments described herein for R^6a, R^6b, R^6d, L^6a, Y⁶, and L^6b. [0073] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Y⁶ is a bond and L^6a and L^6b combine to form C8-10 alkylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b. This embodiment of Y⁶ can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, R^L6a, 25 and R^L6b. [0074] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Y⁶ is a bond and L^6a and L^6b combine to form C8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b. This embodiment of Y⁶ can be combined with any of the embodiments described herein for R^6a, 30 R^6b, R^6d, R^L6a, and R^L6b. [0075] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Y⁶ is a bond and L^6a is substituted with at 26 PATENT Attorney Docket No.052687-508001WO least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C_3-6 cycloalkyl. This embodiment of Y⁶ can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, and L^6b. [0076] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein Y⁶ is O, NH, S, S(O), or S(O)2. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Y⁶ is O, S, S(O), or S(O)2. These embodiments of Y⁶ can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, and L^6b. [0077] In some embodiments, the compound, or the pharmaceutically acceptable salt 10 thereof, is the compound of Formula (I), wherein L^6a is C_1-5 alkylene substituted with 0, 1, 2, or 3 R^L6a; L^6b is C1-5 alkylene substituted with 0, 1, 2, or 3 R^L6b, Y⁶ is a bond, O, S, S(O), or S(O)₂, wherein when Y⁶ is a bond, L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C3-6 cycloalkyl. 15 This embodiment of L^6a, Y⁶, and L^6b can be combined with any of the embodiments described herein for R^6a, R^6b, and R^6d. [0078] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L^6a is C2-5 alkenylene substituted with 0, 1, 2, or 3 R^L6a; 20 L^6b is C_1-5 alkylene substituted with 0, 1, 2, or 3 R^L6b; Y⁶ is a bond, O, NH, S, S(O), or S(O)2, wherein when Y⁶ is a bond, L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C_3-6 cycloalkyl. This embodiment of L^6a, Y⁶, and L^6b can be combined with any of the embodiments described herein for R^6a, R^6b, and R^6d. 25 [0079] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein an R^L6a and R^6b on adjacent atoms combine to form a C_3-6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 R^6e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein an R^L6a and R^6b on adjacent atoms combine to form 30 cyclopropyl. These embodiments of R^L6a and R^6b can be combined with any of the embodiments described herein for R^6a, R^6d, L^6a, Y⁶, and L^6b. 27 PATENT Attorney Docket No.052687-508001WO [0080] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein an R^L6a and R^6a on non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the 5 heterocycloalkyl is substituted with 0, 1, or 2 R^6e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein an R^L6a and R^6a on non-adjacent atoms combine to form a piperidinyl. These embodiments of R^L6a and R^6a can be combined with any of the embodiments described herein for R^6b, R^6d, L^6a, Y⁶, and L^6b. 10 [0081] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein two R^L6b moieties on the same atom or on adjacent atoms combine to form a C_3-6 cycloalkyl or a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the cycloalkyl and heterocycloalkyl is substituted with 15 0, 1, or 2 R^6e. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein two R^L6b moieties on the same atom or on adjacent atoms combine to form cyclopropyl, cyclopenyl, or tetrahydrofuran. These embodiments of R^L6b can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, Y⁶, and L^6b. 20 [0082] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein an R^L6b and R^6d on adjacent or non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e. In some embodiments, the compound, 25 or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein n R^L6b and R^6d on adjacent or non-adjacent atoms combine to form azetidinyl, pyrrolidinyl, oxazolidinyl, or morpholinyl substituted with 0, 1, or 2, R^6e. These embodiments of R^L6b and R^6d can be combined with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, Y⁶, and L^6b. 30 [0083] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^6e is independently C1-4 alkyl, halo, or C_1-4 haloalkyl. In some embodiments, the compound, or the pharmaceutically acceptable 28 PATENT Attorney Docket No.052687-508001WO salt thereof, is the compound of Formula (I), wherein each R^6e is independently C_1-4 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^6e is independently methyl or fluoro. In some embodiments, each R^6e is independently methyl. These embodiments of R^6e can be combined 5 with any of the embodiments described herein for R^6a, R^6b, R^6d, L^6a, Y⁶, and L^6b. [0084] In some embodiments, the compound, or the pharmaceutically acceptable salt 10 29 PATENT Attorney Docket No.052687-508001WO 6^b can be combined with any of the [0085] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the moiet is 5 . These embodiments of L^6a, Y⁶, L^6b, and R^6b can be described herein for R^6a an ^6d d R . [0086] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the moiet is . These embodiments of L^6a, Y⁶, L^6b, and R^6b can 10 y s described herein for R^6a and R^6d. 30 PATENT Attorney Docket No.052687-508001WO [0087] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the moie is 5 , . These embodiments of L^6a, Y⁶, L^6b, and nts described herein fo ^{6a 6b} r R and R . [0088] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the moiet is 31 PATENT Attorney Docket No.052687-508001WO Y⁶, a. [0089] In some embodiments, the compound, or the pharmaceutically acceptable salt is 5 [0090] The embodiments described herein for R ^a, R R , L ^a, Y , and L can be present in any combination. In addition, the embodiments described herein for residue 6 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 7, and 8. For example, any of the embodiments of R^6a, R^6b R^6d, L^6a, Y⁶, and L^6b as described 10 herein, can be combined with any of the embodiments described herein for R³, R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^7a, R^7b, R^7c, R^8a, R^8b, R^8d, R^8e, ring B, m8, R^8f, and ring A. Residue 7 [0091] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^7a and R^7b are each independently H or C1- 15 ₆ alkyl; and R^7c is C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C_1-6 alkyl–OH, or –C1-6 alkyl–C3-6 cycloalkyl. [0092] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^7a and R^7b are each independently H or C_1- 6 alkyl; and R^7c is C1-6 alkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl. 32 PATENT Attorney Docket No.052687-508001WO [0093] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^7a and R^7b are each independently H or C1- 6 alkyl; and R^7c is C_1-6 alkyl or C_1-6 haloalkyl. [0094] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein R^7a and R^7b are each H; and R^7c is C1-6 alkyl. [0095] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^7a and R^7b are each H; and R^7c is isobutyl, O^H . 10 ompound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^7a and R^7b are each H; and R^7c is isobutyl. [0097] The embodiments described herein for R^7a, R^7b and R^7c can be present in any combination. In addition, the embodiments described herein for residue 7 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 8. For 15 example, any of the embodiments of R^7a, R^7b and R^7c as described herein, can be combined with any of the embodiments described herein for R³, R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^6a, R^6b R^6d, L^6a, Y⁶, L^6b, R^8a, R^8b, R^8d, R^8e, ring B, m8, R^8f, and ring A. Residue 8 [0098] In some embodiments, the compound, or the pharmaceutically acceptable salt 20 thereof, is the compound of Formula (I), wherein R^8a, R^8b, R^8d, and R^8e are each independently H or C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R^8a is H or methyl; and R^8b, R^8d and R^8e are each H. These embodiments of R^8a, R^8b, R^8d, and R^8e can be combined with any of the embodiments described herein for m8, ring B, R^8f, and R^8f3. 25 [0099] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N, O, or S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is phenyl. In some embodiments, the compound, 33 PATENT Attorney Docket No.052687-508001WO or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is biphenyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N, O, or S. In some 5 embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is pyrid-3-yl. In some embodiments, the compound, or the pharmaceutically acceptable salt 10 thereof, is the compound of Formula (I), wherein ring B is phenyl or pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is phenyl or pyrid-3-yl. These embodiments of ring B can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, R^8f, and R^8f3. 15 [0100] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 1, 2, or 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 0. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 20 wherein the subscript m8 is 1. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 2. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 25 wherein the subscript m8 is 4. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 5. These embodiments of m8 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, R^8f, R^8f3, and ring B. [0101] In some embodiments, the compound, or the pharmaceutically acceptable salt 30 thereof, is the compound of Formula (I), wherein the moiety 34 PATENT Attorney Docket No.052687-508001WO . These embodiments ca described herein for R^8a, 8^b, R^8d, R⁸ R ^e, R^8f, R^8f3, m8 and ring B. [0102] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein the moiety . These embodiments escribed herei ^8a n for R , R^8b, R^8d, R^8e, R^8f, R^8f3, m8 and ring B. [0103] In some embodiments, the compound, or the pharmaceutically acceptable salt 10 thereof, is the compound of Formula (I), wherein the moiety . These embodiments ca described herein for R^8a, R^8b, R^8d, R^8e, R^8f, R^8f3, m8 and ring B. [0104] In some embodiments, at least one R^8f is halo. In some embodiments, at least one 15 R^8f is fluoro or chloro. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0105] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently C_1-6 alkyl, C_2-6 35 PATENT Attorney Docket No.052687-508001WO alkenyl, C_1-6 alkoxy, C_1-6 deuteroalkoxy, halo, C_1-6 haloalkyl, cyano, or –X^8f–cyano. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0106] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –X^8f–C_3-6 cycloalkyl, –CH=CR^8f5R^8f6, heterocycloalkyl, –X^8f–heterocycloalkyl, phenyl, –X^8f–phenyl, heteroaryl, or –X^8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein 10 each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; each X^8f is independently C1-6 alkylene, C2-6 alkenylene, O, or S; and each R^8f5 and R^8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be 15 combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0107] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –X^8f–C_3-6 cycloalkyl, –CH=CR^8f5R^8f6, heterocycloalkyl, –X^8f–heterocycloalkyl, 20 heteroaryl, or –X^8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; each X^8f is independently C_1-6 alkylene, C_2-6 alkenylene, O, or S; and each R^8f5 and R^8f6 are combined 25 with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0108] In some embodiments, the compound, or the pharmaceutically acceptable salt 30 thereof, is the compound of Formula (I), wherein each X^8f is independently C_1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f is independently C_2-6 alkenylene. In some 36 PATENT Attorney Docket No.052687-508001WO embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f is independently –O–C1-6 alkylene. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f is independently O. In some embodiments, the 5 compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f is independently C1-6 alkylene or O. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. 10 [0109] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –CH=CR^8f5R^8f6, heterocycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each 15 independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; each R^8f5 and R^8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments 20 described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0110] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently C1-4 alkyl, C2-4 alkenyl, C_1-4 alkoxy, C_1-4 deuteroalkoxy, halo, C_1-4 haloalkyl, cyano, or –C_1-2 alkyl–cyano. These embodiments of R^8f can be combined with any of the embodiments described herein 25 for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0111] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –O–C_3-6 cycloalkyl, heterocycloalkyl, –C_2-4 alkenyl–heterocycloalkyl, –O– heterocycloalkyl, –CH=CR^8f5R^8f6, phenyl, –O–phenyl, heteroaryl, or –O–heteroaryl, wherein 30 each heterocycloalkyl has 3 to 9 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 9 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl 37 PATENT Attorney Docket No.052687-508001WO is substituted with 0, 1, 2, or 3 R^8f3; and R^8f5 and R^8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments 5 described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0112] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –O–C_3-6 cycloalkyl, heterocycloalkyl, –C_2-4 alkenyl–heterocycloalkyl, –O– heterocycloalkyl, phenyl, –O–phenyl, heteroaryl, or –O–heteroaryl, wherein each 10 heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. 15 [0113] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, C3-6 cycloalkyl, –O–C_3-6 cycloalkyl, heteroaryl, or –O–heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can 20 be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0114] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f is independently halo, heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl 25 has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, wherein each heterocycloalkyl and phenyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0115] In some embodiments, the compound, or the pharmaceutically acceptable salt 30 thereof, is the compound of Formula (I), wherein each R^8f is independently halo, heterocycloalkyl, or –O–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, wherein each 38 PATENT Attorney Docket No.052687-508001WO heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. These embodiments of R^8f can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f3. [0116] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein each R^8f3 is independently C1-6 alkyl, –Y⁸– C_1-6 alkyl, C_1-6 deuteroalkyl, –Y⁸–C_1-6 deuteroalkyl, –OH, –C_1-6 alkyl–OH, –Y⁸–C_1-6 alkyl– OH, –C1-6 alkyl–Y⁸–C1-6 alkyl, –(C1-2 alkyl–O)2-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, –Y⁸–C_1-6 haloalkyl, cyano, –C_1-6 alkyl–cyano, –C_1-6 alkyl–NR^8gR^8h, oxo, C_3-6 cycloalkyl, – X^8f3–C3-6 cycloalkyl, heterocycloalkyl, –X^8f3– heterocycloalkyl, phenyl, –X^8f3–phenyl, 10 heteroaryl, or –X^8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C1-4 alkyl or halo [0117] In some embodiments, the compound, or the pharmaceutically acceptable salt15 thereof, is the compound of Formula (I), wherein each R^8f3 is independently C_1-6 alkyl, –Y⁸– C1-6 alkyl, C1-6 deuteroalky, –Y⁸–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y⁸–C1-6 alkyl– OH, –C_1-6 alkyl–Y⁸–C_1-6 alkyl, halo, C_1-6 haloalkyl, –Y⁸–C_1-6 haloalkyl, or oxo; each Y⁸ is independently C(O), C(O)O, N(R^8f4)C(O), O, S, or S(O)2; and each R^8f4 is independently H or C_1-6 alkyl. These embodiments of R^8f3 can be combined with any of the embodiments 20 described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. [0118] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently –Y⁸–C_1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently –Y⁸–methyl. In some 25 embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently C(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently C(O)O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is 30 independently NHC(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the 39 PATENT Attorney Docket No.052687-508001WO compound of Formula (I), wherein each Y⁸ is independently S. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently S(O)₂. These embodiments of Y⁸ can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, R^8f, and R^8f3. 5 [0119] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f3 is independently C_1-6 alkyl, C_1-6 deuteroalky, –OH, –C1-6 alkyl–OH, halo, C1-6 haloalkyl, or oxo. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. 10 [0120] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f3 is independently C_1-6 alkyl or – Y⁸–C1-6 alkyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y⁸ is independently a C(O) or C(O)O. These embodiments of R^8f3 and Y⁸ can be combined with any of the embodiments described 15 herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. [0121] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f3 is independently C3-6 cycloalkyl, – X^8f3–C_3-6 cycloalkyl, heterocycloalkyl, or –X^8f3–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or 20 S(O)₂; and each X^8f3 is independently C_1-6 alkylene, C(O), or S(O)₂. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. [0122] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f3 is independently C1-6 alkylene. In 25 some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f3 is independently C(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each X^8f3 is independently S(O)2. These embodiments of X^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, R^8f, and R^8f3. 30 [0123] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 40 PATENT Attorney Docket No.052687-508001WO heteroatoms, each independently N, O, S, or S(O)₂. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. [0124] In some embodiments, the compound, or the pharmaceutically acceptable salt 5 thereof, is the compound of Formula (I), wherein two R^8f3 groups on adjacent ring vertices combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O or S. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. [0125] In some embodiments, the compound, or the pharmaceutically acceptable salt 10 thereof, is the compound of Formula (I), wherein each R^8f3 is independently C1-4 alkyl, C1-4 alkoxy, C_2-6 alkoxyalkyl, –S(O)₂–C_1-4 alkyl, –C_1-4 alkyl–S(O)₂–C_1-4 alkyl, halo, C_1-4 haloalkyl, oxo, –C(O)–C1-4 alkyl, or –C(O)O–C1-4 alkyl. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, and R^8f. 15 [0126] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R^8f3 is independently C_1-4 alkyl, C_1-4 alkoxy, C2-6 alkoxyalkyl, halo, C1-4 haloalkyl, oxo, –S(O)2–C1-4 alkyl, –C1-4 alkyl–S(O)2–C1-4 alkyl,–C(O)–C_1-4 alkyl, –C(O)O–C_1-4 alkyl, C_3-6 cycloalkyl, –C(O)–C_3-6 cycloalkyl, –S(O)₂– C3-6 cycloalkyl, heterocycloalkyl, –C1-4 alkyl–heterocycloalkyl, or –S(O)2–heterocycloalkyl, 20 wherein each heterocycloalkyl has 4 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2; alternatively, two R^8f3 groups on adjacent ring vertices combine to form a non-aromatic cyclic moiety having 3 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O or S. These embodiments of R^8f3 can be combined with any of the embodiments described herein for R^8a, R^8b, R^8d, R^8e, m8, ring B, 25 and R^8f. [0127] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein m8 is 2; 41 PATENT Attorney Docket No.052687-508001WO each R^8f is independently fluoro, chloro, bromo, , , 5 [0128] , , lt thereof, is the compound of Formula (I), wherein m8 is 2; each R^8f is independently fluoro, chloro, bromo, , 42 PATENT Attorney Docket No.052687-508001WO [0129] ent in any combination. In addition, the embodiments described herein for residue 8 can be 5 present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 7. For example, any of the embodiments of R^8a, R^8b, R^8d, R^8e, m8 and R^8f as described herein, can be combined with any of the embodiments described herein for R³, R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^6a, R^6b R^6d, L^6a, Y⁶, L^6b, R^7a, R^7b, R^7c, and ring A. Residues 3 to 8 10 [0130] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R³ is , 15 R^4b is R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0, 1, or 2 fluoro; R^5a is H; R^5b is H; 43 PATENT Attorney Docket No.052687-508001WO R^5c is methyl or ; R^6a is H, met , opyl, or ; R^6b is H; R^6d is H or methyl; 5 the moiety s , , , 44 PATENT Attorney Docket No.052687-508001WO O , alternatively, the moiety is ; 5 alternatively, the moiety is , 45 PATENT Attorney Docket No.052687-508001WO , 5 alternatively, the moiet is ; 46 PATENT Attorney Docket No.052687-508001WO R^7a is H; R^7b is H; R^7c is isobutyl; R^8a is methyl; 5 R^8b, R^8d and R^8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R^8f is independently fluoro, chloro, bromo, , 10 , [0131] n some emo ments, te compoun, or te parmaceutca y accepta e salt thereof, is the compound of Formula (I), wherein R³ is 15 , R^4b is H ; 47 PATENT Attorney Docket No.052687-508001WO R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0, 1, or 2 fluoro; R^5a is H; R^5b is H; 5 R^5c is methyl ; R^6a is H, met y , n-propyl, or ; R^6b is H; R^6d is H, methyl, ethyl, isopropyl, or –CD3; 10 , , , 48 PATENT Attorney Docket No.052687-508001WO O , alternatively, the moiety is ; 5 alternatively, the moiety is , 49 PATENT Attorney Docket No.052687-508001WO , 5 alternatively, the moiet is ; 50 PATENT Attorney Docket No.052687-508001WO R^7a is H; R^7b is H; R^7c is isobutyl; R^8a is methyl; 5 R^8b, R^8d and R^8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R^8f is independently fluoro, chloro, bromo, 10 [0132] For the above embodiment, R³, R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^6a, R^6b, R^6d, L^6a, Y⁶, L^6b, R^7a, R^7b, R^7c, R^8a, R^8b, R^8d, R^8e, ring B, m8, and R^8f can each independently be as defined for any embodiment of Formula (I) as described herein. 15 [0133] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) having the structure of any one of Examples 1-103. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) having the structure of any one of Examples 1-50. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the 20 compound of Formula (I) having the structure of any one of Examples 51-103 51 PATENT Attorney Docket No.052687-508001WO [0134] The present disclosure includes all tautomers and stereoisomers of the compounds described herein, either in admixture or in pure or substantially pure form. The compounds of Formula (I) can have asymmetric centers at one or more carbon atoms, and therefore compounds of Formula (I) can exist in diastereomeric or enantiomeric forms or mixtures 5 thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, and tautomers are within the scope of the present disclosure. Compounds of Formula (I) can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. Furthermore, diastereomer and enantiomer products can be 10 separated by chromatography, fractional crystallization or other methods known to those of skill in the art. Unless otherwise indicated, when a stereochemical depiction is shown, it is meant that the isomer with the depicted stereochemistry is present and substantially free of the other isomer(s). “Substantially free of” another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more. When a structure includes a wavy 15 bond attached to a double bond, this indicates E, Z, or a mixture of both isomers. [0135] The compounds of Formula (I) can also be in the salt forms, such as acid or base salts of the compounds of Formula (I). Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, 20 quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0136] Pharmaceutically acceptable salts of the acidic compounds of Formula (I) are salts 25 formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. [0137] Similarly acid addition salts, such as of mineral acids, organic carboxylic and 30 organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. 52 PATENT Attorney Docket No.052687-508001WO [0138] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the 5 compound for the purposes of the present disclosure. [0139] The present disclosure also includes isotopically-labeled compounds of Formula(I), wherein one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. Examples of isotopes that can be incorporated into compounds of Formula (I) include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine,10 sulfur, and chlorine (such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, ³⁵S and ³⁶Cl). Isotopically- labeled compounds of Formula (I) can be useful in assays of the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include ³H and ¹⁴C. In addition, in certain circumstances substitution with heavier isotopes, such as deuterium (²H), can provide increased metabolic stability, which offers therapeutic 15 advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically- labeled compounds of Formula (I) can generally be prepared according to methods known in the art. IV. Compositions [0140] The compounds of Formula (I) described herein are useful in the manufacture of a 20 pharmaceutical composition or a medicament for modulating one or more cyclins (e.g. cyclin A, cyclin B, cycline E). In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition or medicament comprising one or more compounds of Formula (I) can be administered to a 25 subject for the treatment of a cancer. [0141] Pharmaceutical compositions or medicaments for use in the present disclosure can be formulated by standard techniques or methods well-known in the art of pharmacy using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in, e.g., “Remington’s Pharmaceutical Sciences” by E.W. 30 Martin. Compounds of Formula (I) and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including, but not limited to, orally, topically, nasally, rectally, pulmonary, parenterally (e.g., intravenously, 53 PATENT Attorney Docket No.052687-508001WO subcutaneously, intramuscularly, etc.), and combinations thereof. In some embodiments, the compounds of Formula (I) is dissolved in a liquid, for example, water. The most suitable route of administration for a compound of Formula (I) in any given case will depend, in part, on the nature, severity, and optionally, and the stage of the cancer. 5 [0142] The pharmaceutical compositions or medicaments of the present disclosure can include a compound of Formula (I) with as an active ingredient and a pharmaceutically acceptable carrier and/or excipient or diluent. Any carrier and/or excipient suitable for the form of preparation desired for administration is contemplated for use with the compounds of Formula (I) disclosed herein. 10 [0143] In some embodiments, the pharmaceutical compositions or medicaments described herein are suitable for systemic administration. Systemic administration includes enteral administration (e.g., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion, or implantation). In some embodiments, the pharmaceutical compositions or medicaments can be administered via a syringe or 15 intravenously. In preferred embodiments, the pharmaceutical compositions or medicaments are injected subcutaneously. [0144] For oral administration, a pharmaceutical composition or a medicament can take the form of, e.g., a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Preferred are tablets and gelatin capsules comprising the active 20 ingredient(s), together with (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, anhydrous colloidal silica, talcum, stearic acid, its magnesium or calcium salt (e.g., magnesium stearate or calcium stearate), metallic stearates, colloidal silicon dioxide, 25 hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethyleneglycol; for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired (d) disintegrants, e.g., starches (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, 30 or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulfate, and/or (f) absorbents, colorants, flavors and sweeteners. In some embodiments, the tablet contains a mixture of 54 PATENT Attorney Docket No.052687-508001WO hydroxypropyl methylcellulose, polyethyleneglycol 6000 and titatium dioxide. Tablets can be either film coated or enteric coated according to methods known in the art. [0145] Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution 5 with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for 10 example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound. [0146] Typical formulations for topical administration include creams, ointments, sprays, 15 lotions, and patches. The pharmaceutical composition can, however, be formulated for any type of administration, e.g., intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, with a syringe or other devices. Formulation for administration by inhalation (e.g., aerosol), or for oral, rectal, or vaginal administration is 20 also contemplated. [0147] Pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein, or a salt thereof, and the powder of a suitable carrier and/or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder 25 inhaler device known to a person skilled in the art. In certain instances, the compositions can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to 30 deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base, for example, lactose or starch. 55 PATENT Attorney Docket No.052687-508001WO [0148] The compounds of Formula (I) can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides. [0149] The compounds of Formula (I) set forth herein can be formulated for parenteral 5 administration by injection, for example by bolus injection. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, 10 wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Alternatively, the compound(s) can be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain 15 about 0.1 to 75%, preferably about 1 to 50%, of the compound(s). [0150] In some embodiments, the compositions described herein are prepared with a polysaccharide such as chitosan or derivatives thereof (e.g., chitosan succinate, chitosan phthalate, etc.), pectin and derivatives thereof (e.g., amidated pectin, calcium pectinate, etc.), chondroitin and derivatives thereof (e.g., chondroitin sulfate), and alginates. 20 [0151] In some embodiments, the compositions described herein further include a pharmaceutical surfactant. In other embodiments, the compositions further include a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HPI3CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof. 25 V. Methods [0152] The present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by one or more cyclins. In some embodiments, the cyclin mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present 30 disclosure provides a method of treating a cancer mediated at least in part by cyclin activity, the method comprising administering to a subject in need there of, a therapeutically effective 56 PATENT Attorney Docket No.052687-508001WO amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. [0153] In some embodiments, provided herein are compounds of Formula (I) for use in 5 therapy. [0154] The present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin A. In some embodiments, the cyclin A mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present disclosure 10 provides a method of treating a cancer mediated at least in part by cyclin A, the method comprising administering to a subject in need there of, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. [0155] In some embodiments, provided herein are methods of treating a proliferative 15 condition or disorder mediated at least in part by cyclin A comprising administering a compound of Formula (I) described herein. [0156] In some embodiments, provided herein are compounds of Formula (I) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin A. [0157] In some embodiments, provided herein are uses of compounds of Formula (I) for 20 the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin A. [0158] The present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin B. In some embodiments, the cyclin B mediated disease is a proliferative 25 condition or disorder, including cancer. In some embodiments, the present disclosure provides a method of treating a cancer mediated at least in part by cyclin B, the method comprising administering to a subject in need there of, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. 57 PATENT Attorney Docket No.052687-508001WO [0159] In some embodiments, provided herein are methods of treating a proliferative condition or disorder mediated at least in part by cyclin B comprising administering a compound of Formula (I) described herein. [0160] In some embodiments, provided herein are compounds of Formula (I) for use in a 5 method for treating a proliferative condition or disorder mediated at least in part by cyclin B. [0161] In some embodiments, provided herein are uses of compounds of Formula (I) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin B. [0162] The present disclosure contemplates the use of the compounds of Formula (I) 10 described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin E. In some embodiments, the cyclin E mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present disclosure provides a method of treating a cancer mediated at least in part by cyclin E, the method comprising administering to a subject in need there of, a therapeutically effective amount of a 15 compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer. [0163] In some embodiments, provided herein are methods of treating a proliferative condition or disorder mediated at least in part by cyclin E comprising administering a compound of Formula (I) described herein. 20 [0164] In some embodiments, provided herein are compounds of Formula (I) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin E. [0165] In some embodiments, provided herein are uses of compounds of Formula (I) for the manufacture of a medicament for the treatment of a proliferative condition or disorder mediated at least in part by cyclin E. 25 [0166] In some embodiments, the compounds of Formula (I) described herein can be used to treat or prevent a proliferative condition or disorder, including a cancer, for example, cancer of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gall bladder, bile ducts, heart, lung (e.g., non- 30 small-cell lung carcinoma, small cell lung cancer), pancreas, salivary gland, adrenal gland, 58 PATENT Attorney Docket No.052687-508001WO thyroid, brain, ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (e.g., spleen or thymus). [0167] The present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions, including, for example, virus-induced cancers (e.g., 5 epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis. [0168] In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast 10 cancer, melanoma, lung cancer, glioblastoma, or leukemia. [0169] In some embodiments, the tumor or cancer is small cell lung cancer (SCLC). [0170] The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia. 15 [0171] In some embodiments, the cancer is a blood cancer (e.g., leukemia, lymphoma, multiple myeloma). [0172] In some embodiments, the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or hairy cell leukemia. 20 [0173] In some embodiments, the lymphoma is non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma. [0174] In some embodiments, the cancer is an Rb mutated cancer. In some embodiments, the cancer has a mutation in the Rb/E2F pathway. VI. Administration 25 [0175] The present disclosure contemplates the administration of compounds of Formula (I) and compositions thereof, in any appropriate manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral 59 PATENT Attorney Docket No.052687-508001WO (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation. [0176] Pharmaceutical compositions comprising compounds of Formula (I) are preferably in unit dosage form. The unit dosage form can be a packaged preparation, the package 5 containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. [0177] Compounds of Formula (I) or pharmaceutical compositions or medicaments thereof can be administered to a subject diagnosed or suspected of having a disease or disorder 10 mediated at least in part by cyclin A in an amount sufficient to elicit an effective therapeutic response in the subject. [0178] The dosage of compounds administered is dependent on a variety of factors including the subject’s body weight, age, individual condition, and/or on the form of administration. The size of the dose will also be determined by the existence, nature, and 15 extent of any adverse effects that accompany the administration of a particular compound in a particular subject. Typically, a dosage of the active compounds is a dosage that is sufficient to achieve the desired effect. Optimal dosing schedules can be calculated from measurements of compound accumulation in the body of a subject. In general, dosage can be given once or more daily, weekly, or monthly. Persons of ordinary skill in the art can easily determine 20 optimum dosages, dosing methodologies, and repetition rates. [0179] In some embodiments, a unit dosage for oral administration of a compound of Formula (I) described herein to a subject (e.g., a human) of about 50 to about 70 kg may contain between about 1 and about 5,000 mg, about 1 and about 3,000 mg, about 1 and about 2,000 mg, or about 1 to about 1,000 mg of the compound(s). 25 [0180] In some embodiments, a unit dosage for subcutaneous administration of a compound of Formula (I) described herein to a subject (e.g., human) of about 50 to about 70 kg may contain between about 0.1 and about 500 mg, about 0.5 and about 300 mg, about 0.5 and about 200 mg, about 0.5 and about 100 mg, or about 0.5 and about 50 mg. [0181] The dose can be administered once per day or divided into sub-doses and 30 administered in multiple doses, e.g., twice, three times, or four times per day. However, as 60 PATENT Attorney Docket No.052687-508001WO will be appreciated by a skilled artisan, depending on the route of administration different amounts can be administered at different times. [0182] In some embodiments, the compounds are administered for about 1 to 31 days, or for about 1 to 12 months. In some embodiments, the compounds are administered for one or more 5 weeks, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more weeks. In some embodiments, the compounds are administered for one or more months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. [0183] Optimum dosages, toxicity, and therapeutic efficacy of such compounds may vary depending on the relative potency of individual compounds and can be determined by standard 10 pharmaceutical procedures in experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side-effects can be used, care should be 15 taken to design a delivery system that targets such compounds to the affected site to minimize potential damage to normal cells and, thereby, reduce side-effects. [0184] The dosage of a pharmaceutical composition or medicament of the present disclosure can be monitored and adjusted throughout treatment, depending on severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic 20 regimen. Those of skill in the art commonly engage in such adjustments in therapeutic regimens. [0185] Single or multiple administrations of the pharmaceutical compositions or medicaments can be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition or medicament should provide a 25 sufficient quantity of the compounds of the disclosure to effectively treat the patient. Generally, when treating cancer, the dose is sufficient to stop tumor growth or cause tumor regression without producing unacceptable toxicity or side-effects to the patient. VII. Intermediates [0186] In some embodiments, the present disclosure provides intermediates useful in the 30 preparation of compounds of Formula (I). Certain intermediates useful in the preparation of a 61 PATENT Attorney Docket No.052687-508001WO compound of Formula (I) can be found, for example, in the Examples section of the current disclosure. [0187] In some embodiments, the intermediate is an External Building Block described herein. In some embodiments the intermediate is a compound produced in one of Methods 5 A-C or Methods 1-7 for any one of the compounds exemplified herein. In some embodiments, the intermediate is one of Int.1-78. [0188] In some embodiments, the intermediate is a combination of one or more covalently linked External Building Blocks. VIII. Kits 10 [0189] The present disclosure contemplates kits comprising a compound of Formula (I) described herein described herein, and pharmaceutical compositions thereof. The kits are generally in the form of a physical structure housing various components, as described below, and can be utilized, for example, in practicing the methods described above. [0190] A kit can include one or more of the compounds disclosed herein (provided in, e.g., 15 a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a form that is ready for use (e.g., a tablet, capsule, syringe) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration. When the compounds described herein are in a form that needs to be reconstituted or diluted by a user, the kit may 20 also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compounds described herein. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. A kit of the present disclosure can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or 25 freezing). [0191] A kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or inserts can 30 include manufacturer information such as lot numbers and expiration dates. The label or packaging insert may be, e.g., integrated into the physical structure housing the components, 62 PATENT Attorney Docket No.052687-508001WO contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial). [0192] Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as 5 CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided. 10 IX. Examples [0193] The following examples illustrate how various intermediates and exemplary compounds of Formula (I) are prepared. The following examples are offered to illustrate, but not to limit the current disclosure. A. External Building Blocks 15 [0194] The compounds of Formula (I) described herein are prepared by covalently linking the external building blocks described in this section. The external building blocks of the present disclosure are identified in Table 1, below, by intermediate number (INT #), IUPAC name, and CAS number, if known. For those without a CAS number, an experimental write- up is provided herein. The order and details related to covalently linking these external 20 building blocks are described in another section. Table 1: External Building Blocks of the Present Disclosure INT # IUPAC CAS Number, if k 63 PATENT Attorney Docket No.052687-508001WO INT # IUPAC CAS Number, if known lll hl h i 64 PATENT Attorney Docket No.052687-508001WO INT # IUPAC CAS Number, if known hl lf l hl 65 PATENT Attorney Docket No.052687-508001WO INT # IUPAC CAS Number, if known l l i Int.2: Preparation of 1-(allyloxy)-2-methylpropan-2-amine: Step 1: tert-butyl (1-(allyloxy)-2-methylpropan-2-yl)carbamate: 66 PATENT Attorney Docket No.052687-508001WO [0195] mol) and allyl ethyl carbonate (6.2 g, 6.2 mL, 3 Eq, 48 mmol) were dissolved in THF (50 mL) and degassed with Ar for 15 min. Pd(Ph₃P)₄ (1.5 g, 0.08 Eq, 1.3 mmol) was quickly added and 5 degassing was continued for an additional 10 min. Next, the flask was sealed and heated to 60 °C. The reaction was continued until the complete consumption of starting material (monitored by LCMS). upon completion, the reaction mixture was concentrated and directly purified by FCC (0 to 30% EtOAc in Hex.) tert-butyl (1-(but-3-en-1-yloxy)-2-methylpropan- 2-yl)carbamate (2.5 g, 10 mmol, 65 %) was isolated as a clear oil. LCMS (ESI+): m/z 230.3 ₁₀ (M+H⁺). Step 2: Int.2: [0196] t ert- uty ( -(a y oxy)- -met y propan- -y )car amate ( . g, q, .7 mmol) was dissolved in 30% TFA in DCM (50 mL). The reaction was continued until the complete 15 consumption of starting materials (monitored by LCMS). Upon completion, the reaction was concentrated. PhMe was added (50 mL) and the reaction was concentrated again to drive off excess TFA. Int.2 (2.1 g, 8.7 mmol, 100 %) was isolated as a clear liquid and used directly in the next reaction. LCMS (ESI+): m/z 130.3 (M+H⁺). Int.4: Preparation of (1S,2S)-2-(allyloxy)cyclopentan-1-amine 20 Step 1: tert-butyl ((1S,2S)-2-(allyloxy)cyclopentyl)carbamate: 67 PATENT Attorney Docket No.052687-508001WO [0197] To a soluti rbamate (10 g, 49.69 mmol, 1 eq) and 3-bromoprop-1-ene (6.31 g, 52.17 mmol, 1.05 eq) in THF (150 mL) was added tBuONa (7.16 g, 74.53 mmol, 1.5 eq) at 0 °C under a N2 atmosphere. The mixture was 5 stirred at 20 °C for 3 hr. Upon the consumption of starting material (monitored by TLC, Pet. ether:EtOAc = 3:1), the reaction mixture was quenched by H2O (250 mL), extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (SiO2, 0-5% EtOAc:Pet. ether) to give tert-butyl 10 ((1S,2S)-2-(allyloxy)cyclopentyl)carbamate (8.86 g, 36.71 mmol, 73.89%) as a light yellow oil. LCMS (ESI+): m/z 242.3 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 6.86 (d, J = 7.0 Hz, 1H), 5.93 - 5.78 (m, 1H), 5.26 - 5.05 (m, 2H), 4.03 - 3.88 (m, 2H), 3.72 - 3.56 (m, 2H), 1.91 - 1.72 (m, 2H), 1.62 - 1.45 (m, 3H), 1.38 (s, 10H). Step 2: Int.4: 15 [0198] Int.4 was synthe sized using the Boc deprotection procedure outlined in Int.2 Step 2., using tert-butyl ((1S,2S)-2-(allyloxy)cyclopentyl)carbamate as starting material. LCMS (ESI+): m/z 242.3 (M+H⁺). Int.6: Preparation of (R)-2-((allyloxy)methyl)pyrrolidine 20 Step 1: tert-butyl (R)-2-((allyloxy)methyl)pyrrolidine-1-carboxylate: 68 PATENT Attorney Docket No.052687-508001WO [0199] To a solut 1-carboxylate (90 g, 447.18 mmol, 1 eq) and allyl bromide (70.33 g, 581.33 mmol, 1.3 eq) in THF (1000 mL) was added 60% NaH (24.5 g, 612.56 mmol, 1.37 eq) at 0°C. The reaction was continued until 5 the consumption of starting material (monitored by LCMS). The reaction mixture was quenched by addition of saturated. NH₄Cl (2000 mL) at 0°C, and then extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by FCC (0~20% EtOAc in pet. ether) to give tert-butyl (R)-2-((allyloxy)methyl)pyrrolidine-10 1-carboxylate (100 g, 414.38 mmol, 92.66%) as a colorless oil. LCMS (ESI+): m/z 142.2 (M- Boc+H⁺).¹H NMR (400 MHz, CDCl3-d): δ 5.98 - 5.80 (m, 1H), 5.27 (dd, J = 1.4, 17.2 Hz, 1H), 5.17 (br d, J = 10.3 Hz, 1H), 4.07 - 3.80 (m, 3H), 3.57 (br s, 1H), 3.33 (br s, 3H), 2.00 - 1.74 (m, 4H), 1.47 (s, 9H) Step 2: Int.6: 15 [0200] A solut ion of tert-butyl (R)-2-((allyloxy)methyl)pyrrolidine-1-carboxylate (100 g, 414.38 mmol, 1 eq) in HCl/EtOAc (2 M, 2000 mL) was stirred at 15 °C for 12 h. The consumption of starting material was observed by LCMS). The reaction mixture was concentrated under reduced pressure to give Int.5 (79 g, crude, HCl) as a yellow oil. The 20 product was used directly in the next reaction without further purification. LCMS (ESI+): m/z 142.2 (M+H⁺). Int.7: Preparation of (S)-2-((allyloxy)methyl)pyrrolidine: 69 PATENT Attorney Docket No.052687-508001WO [0201] Int.7 was synthesized by following the procedure for Int.6 with tert-butyl (S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate as the starting alcohol. LCMS (ESI+): m/z 142.0 (M+H⁺). Int.8: Preparation of (R)-2-((allyloxy)methyl)azetidine: 5 [0202] Int.8 was synthesized by edure for Int.6 with tert-butyl (R)-2- (hydroxymethyl)azetidine-1-carboxylate as the starting alcohol. The following modification was also used: the removal of the Boc group was conducted using the procedure outlined in the synthesis of Int.2 – Step 2. TFA in DCM was used instead of HCl in EtOAc. LCMS 10 (ESI+): m/z 127.0 (M+H⁺). Int.10: Preparation of (R)-2-((allyloxy)methyl)piperidine: [0203] Int.10 was synthesized b y o ow ng e procedure for Int.6 with tert-butyl (R)-2- (hydroxymethyl)piperidine-1-carboxylate as the starting alcohol. LCMS (ESI+): m/z 156.3 15 (M+H⁺). Int.11: Preparation of 2-(allyloxy)-N-methylethan-1-amine [0204] Int.11 was synthesized by following the procedure for Int.6 with tert-butyl (2- hydroxyethyl)(methyl)carbamate as the starting alcohol. The following modification was also 20 used: the removal of the Boc group was conducted using the procedure outlined in the synthesis of Int.2 – Step 2. TFA in DCM was used instead of HCl in EtOAc. LCMS (ESI+): m/z 116.3 (M+H⁺). Int.12: Preparation of (R)-2-((allylthio)methyl)pyrrolidine 70 PATENT Attorney Docket No.052687-508001WO Step 1: tert-butyl (R)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate: [0205] A soluti on of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (200 mg, 0.99 mmol, 1 equiv) in DCM was treated with triethylamine (5.03 g, 49.686 mmol, 2 5 equiv) for 5 min at 25 ℃ under nitrogen atmosphere followed by the addition of methanesulfonic anhydride (8.65 g, 49.69 mmol, 2.00 equiv) at 0 ℃. The resulting mixture was stirred for 3hr at 25℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI+): m/z 224.0 (M+H⁺). 10 Step 2: tert-butyl (R)-2-((allylthio)methyl)pyrrolidine-1-carboxylate: [0206] To a so u on o a y mercap an . g, . mmo , . equ v, n THF was added NaH (4.01 g, 100.2 mmol, 4 equiv, 60% in mineral oil) at 0 ℃. The mixture was stirred for 30 min then tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1- 15 carboxylate (250 mg, 0.895 mmol, 1 equiv) was added. The mixture was allowed to warm to ambient temperature and stirred for 16 hr. The reaction was quenched slowly by the addition of water. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (Pet. Ether / EtOAc (20:1) to afford tert-butyl (R)-2- ((allylthio)methyl)pyrrolidine-1-carboxylate (2.00 g, 7.76 mmol, 73.0 %) as a light 20 yellow liquid. LCMS (ESI+): m/z 258.0 (M+H⁺).¹H NMR (300 MHz, DMSO-d6): δ 1.40 (s, 9H), 1.55 – 2.02 (m, 4H), 2.44 (dd, 1H), 2.72 (dd, 1H), 3.21 (dd, 4H), 5.12 (dd, 2H), 5.80 (dt, 1H). Step 3: Int.12: 71 PATENT Attorney Docket No.052687-508001WO [0207] tert-butyl (R)-2-((allylthio)methyl)pyrrolidine-1-carboxylate (1.0 g, 1 Eq, 3.9 mmol) was dissolved in a mixture of 30% TFA in DCM. upon the consumption of starting material (monitored by LCMS) the volatile solvent was removed. PhMe (~20 mL) was added to the residue and evaporated under reduced pressure to drive off remaining TFA. (R)-2- 5 ((allylthio)methyl)pyrrolidine (0.61 g, 3.9 mmol, 100 %) was used without further purification. LCMS (ESI+): m/z 158.0 (M+H⁺). Int.13: Preparation of (S)-3-((allyloxy)methyl)morpholine: [0208] Int.13 was synthesized edure for Int.6 with tert-butyl (S)-3- 10 (hydroxymethyl)morpholine-4-carboxylate as the starting alcohol. LCMS (ESI+): m/z 158.3 (M+H⁺). Int.14: Preparation of 1-((allyloxy)methyl)cyclopropan-1-amine: [0209] Int.14 was synthesized us ng t e proce ure outlined in Int.4 using tert-butyl (1- 15 (hydroxymethyl)cyclopropyl)carbamate as starting material. LCMS (ESI+): m/z 128.2 (M+H+) Int.15: Preparation of (3S,4R)-4-(allyloxy)tetrahydrofuran-3-amine: [0210] Int.15 was synthesized by following the procedure for Int.2 with tert-butyl- 20 ((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamate as starting material. LCMS (ESI+): m/z 144.3 (M+H⁺). Int.16: Preparation of (R)-2-(allyloxy)propan-1-amine: 72 PATENT Attorney Docket No.052687-508001WO Step 1: tert-butyl (R)-(2-(allyloxy)propyl)carbamate: [0211] Sodiu dded to a solution of tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (2 g, 11.414 mmol, 1 equiv) in THF at 0℃. 5 The mixture was stirred for 15 min then allyl bromide (5.52 g, 45.656 mmol, 4 equiv) was added. The mixture was allowed to warm to ambient temperature and stirred until the consumption of starting material (monitored by LCMS). The reaction was quenched by the addition of sat. NH4Cl (aq.) (2 mL) at 0℃. The resulting mixture was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with an additional 50 10 mL of EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (Hexanes / EtOAc, 17:1) to afford tert-butyl N-[(2R)-2-(prop-2-en-1-yloxy)propyl]carbamate (1.17 g, 45.41%) as a light yellow liquid. LCMS (ESI+): m/z 160.15 (M+H-56⁺).¹H NMR (300 MHz, DMSO-d6): δ 1.03 (d, 3H), 1.38 (s, 9H), 2.83 – 3.06 (m, 2H), 3.45 (p, 1H), 3.95 (ddt, 15 2H), 5.04 – 5.31 (m, 2H), 5.87 (ddt, 1H), 6.79 (s, 1H). Step 2: Int.16: [0212] tert-b utyl (R)-(2-(allyloxy)propyl)carbamate (1.00 g, 1 Eq, 4.64 mmol) was dissolved in a mixture of 30% TFA in DCM. upon the consumption of starting material 20 (monitored by LCMS) the volatile solvent was removed/ PhMe was added to the residue and removed via reduced pressure to drive off additional TFA. (R)-2-(allyloxy)propan-1-amine (535 mg, 4.64 mmol, 100.0 %) was used without further purification. LCMS (ESI+): m/z 115.15 (M+H⁺). Int.17: Preparation of (R)-1-(allyloxy)-N-methylpropan-2-amine: 25 73 PATENT Attorney Docket No.052687-508001WO Step 1: tert-butyl (R)-(1-(allyloxy)propan-2-yl)carbamate: [0213] re of tert- butyl N-[(2R)-1-hydroxypropan-2-yl]carbamate (5 g, 28.534 mmol, 1 equiv) in THF (50 5 mL) at 0^oC under nitrogen. Then the mixture was stirred for 1hr at 0 ^oC under nitrogen atmosphere. To the above mixture was added allyl bromide (10.36 g, 85.6 mmol, 3 equiv) in portions over 10 min at 0 ^oC. The resulting mixture was stirred for an additional 3h at room temperature and then quenched with saturated NH4Cl (25mL). The mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were 10 washed with water (20 mL) and brine (20mL), then dried with MgSO4 and filtered. After the volatile solvents were removed the material was purified by silica gel column chromatography (pet. ether/EtOAc, 10:1) to afford tert-butyl N-[(2R)-1-(prop-2-en-1- yloxy)propan-2-yl]carbamate (3.1 g, 50.46%) as a colorless oil. LCMS (ESI+): m/z 216.0 (M+H⁺).¹H NMR (300 MHz, DMSO-d6): δ 6.67 (d, J = 8.4 Hz, 1H), 5.87 (ddt, J = 17.2, 15 10.5, 5.3 Hz, 1H), 5.36 – 5.07 (m, 2H), 3.93 (dt, J = 5.4, 1.5 Hz, 2H), 3.72 – 3.50 (m, 1H), 3.32 (d, J = 7.6 Hz, 1H), 3.17 (dd, J = 9.4, 6.6 Hz, 1H), 1.38 (s, 9H), 1.01 (d, J = 6.7 Hz, 3H). Step 2: tert-butyl (R)-(1-(allyloxy)propan-2-yl)(methyl)carbamate: [0214] To a stirred mixture of tert-butyl N-[(2R)-1-(prop-2-en-1-yloxy)propan-2- 20 yl]carbamate (3.1 g, 14.4 mmol, 1 equiv) in THF (50 mL) were added NaH (1.73 g, 72.0 mmol, 5 equiv) in portions at 0 ^oC under nitrogen atmosphere. The resulting mixture was stirred for an additional 1hr. MeI (10.22 g, 72.0 mmol, 5 equiv) was added dropwise and the reaction was warmed to ambient temperature. The resulting mixture was stirred for 5hr at room temperature. The reaction was quenched with sat. NH₄Cl (aq.) at 0 ^oC and 25 extracted with EtOAc (100mL). The organics were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (pet. ether / EtOAc 10:1) to afford tert-butyl N-methyl-N-[(2R)-1- (prop-2-en-1-yloxy)propan-2-yl]carbamate (2.8g, 11.81 mmol 82.2%) as a light yellow oil. 74 PATENT Attorney Docket No.052687-508001WO LCMS (ESI+): m/z 230.15 (M+H⁺).¹H NMR (300 MHz, DMSO-d₆): δ 5.87 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.37 – 5.09 (m, 2H), 4.21 (d, J = 37.1 Hz, 1H), 4.06 – 3.80 (m, 2H), 3.44 – 3.26 (m, 2H), 2.64 (s, 3H), 1.39 (s, 9H), 1.01 (d, J = 6.8 Hz, Step 3: Int.17: 5 [0215] Int.1 ined in the synthesis of Int.12 (Step 3). LCMS (ESI+): m/z 130.15 (M+H⁺). Int.18: Preparation (S)-2-(allyloxy)propan-1-amine: 10 Step 1: tert-butyl (S)-(2-(allyloxy)p e: [0216] To a so ut on o tert- uty ( )-( - y roxypropy )car amate ( g, .60 mmol, 1 eq) and 3-bromoprop-1-ene (10.46 g, 86.46 mmol, 1.01 eq) in DMF (300 mL) was added NaI (12.83 g, 85.60 mmol, 1 eq) and Ag₂O (19.84 g, 85.60 mmol, 1 eq). Then, it was stirred at 20 15 °C until the consumption of starting material (monitored by TLC, pet. ether:EtOAc 3:1) The reaction was added into water (300 mL), then extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate. Filtered and concentrated. The residue was purified by flash chromatography (SiO₂, 0-30% EtOAc in pet. ether) to give tert-butyl (S)-(2-(allyloxy)propyl)carbamate (10 g, 45.64 20 mmol, 26.66%) as a colorless oil and to give tert-butyl N-[(2S)-2-allyloxypropyl]carbamate (9.59 g, 44.54 mmol, 52.04%) as a colorless oil. Analytical data give for only desired product: LCMS (ESI+): m/z 216.5 (M+H⁺).¹H NMR (400 MHz, CDCl₃-d): δ 1.07 (d, J = 6.25 Hz, 3 H) 1.38 (s, 9 H) 2.96 (ddd, J = 13.79, 6.91, 4.94 Hz, 1 H) 3.24 (d, J = 11.13 Hz, 1 H) 3.44-3.56 (m, 1 H) 3.82-3.91 (m, 1 H) 3.95-4.03 (m, 1 H) 4.81 (s, 1 H) 5.07-5.25 (m, 2 H) 25 5.77-5.91 (m, 1 H). 75 PATENT Attorney Docket No.052687-508001WO Step 2: Int.18: [0217] Int.18 tlined in the synthesis of Int.2 (Step 2) using tert-butyl (S)-(2-(allyloxy)propyl)carbamate as starting 5 material LCMS (ESI+): m/z 116.5 (M+H⁺). Int.19: Preparation of (R)-3-(allyloxy)pyrrolidine: [0218] Int.19 was synthesized by cedure for Int.6 with tert-butyl (R)-3- hydroxypyrrolidine-1-carboxylate as the starting alcohol. The following modification was 10 also used: the removal of the Boc group was conducted using the procedure outlined in the synthesis of Int.2 – Step 2. TFA in DCM was used instead of HCl in EtOAc. LCMS (ESI+): m/z 128.5 (M+H⁺). Int.20: preparation of 1-((allyloxy)methyl)-N-methylcyclopropan-1-amine: 15 [0219] Int.20 was synthesized fol lowing the procedure outlined in Int.17 (steps 2-3) using tert-butyl (1-((allyloxy)methyl)cyclopropyl)carbamate (Int.14) as starting material. LCMS (ESI+): m/z 142.3 (M+H⁺). Int.21: Preparation of N-methyl-2-((2-methylallyl)oxy)ethan-1-amine: 20 [0220] Int.21 was synthesized by following the procedure for Int.6 with tert-butyl (2- hydroxyethyl)(methyl)carbamate and 3-bromo-2-methylprop-1-ene as starting materials. LCMS (ESI+): m/z 130.5 (M+H⁺). Int.22: Preparation of (3S,4R)-4-(allyloxy)-N-methyltetrahydrofuran-3-amine: 76 PATENT Attorney Docket No.052687-508001WO [0221] Int.22 was synthesized by cedure for Int.6 using tert-butyl ((3S,4R)-4-(allyloxy)tetrahydrofuran-3-yl)carbamate (from the synthesis of Int.15) and MeI as starting materials. The following modification was also used: the removal of the Boc group 5 was conducted using the procedure outlined in the synthesis of Int.2 – Step 2. TFA in DCM was used instead of HCl in EtOAc. LCMS (ESI+): m/z 158.3 (M+H⁺). Int.23: Preparation of (4S,5S)-4-((allyloxy)methyl)-5-methyloxazolidine: Step 1: 3-(tert-butyl) 4-methyl (R) , dicarboxylate: 10 [0222] To a stirred so lution of formaldehyde (8.31 mL, 83.949 mmol, 1.00 equiv, 37% in water) and NaOH (335.77 mg, 8.395 mmol, 0.10 equiv) in H2O (7 mL) was added (2R)-2- amino-3-hydroxybutanoic acid (10 g, 83.949 mmol, 1.00 equiv) at 0°C under nitrogen atmosphere, and the resulting mixture was stirred for 7hr at the 15 0°C. To this solution was added hydroxylamine hydrochloride (583.37 mg, 8.395 mmol, 0.10 equiv), acetone (49.37 mL, 671.592 mmol, 8.00 equiv) and NaOH (335.77 mg, 8.395 mmol, 0.10 equiv) in H₂O (7 mL) at 0°C. The resulting mixture was stirred for 15min. Then Boc₂O (20.15 g, 92.344 mmol, 1.10 equiv) was added at room temperature, and the solution was stirred for another 3hr. Upon completion (monitored by LCMS), the resulting mixture was 20 diluted with water (50mL) and washed with ether (3x100mL). Ether extracts were discarded, and 20% citric acid was added to aqueous layer. The resulting mixture was extracted with EtOAc (3x100mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash 77 PATENT Attorney Docket No.052687-508001WO chromatography (MeCN in water, 40% to 50%) to afford (4R,5S)-3-(tert-butoxycarbonyl)-5- methyl-1,3-oxazolidine-4-carboxylic acid (11.734 g, 60.44%) as a white solid. LCMS (ESI+): m/z 254.0 (M+Na⁺).¹H NMR (300 MHz, D₂O): δ 1.13 – 1.39 (m, 12H), 3.71 (d, J = 7.4 Hz, 1H), 4.09 (t, J = 6.4, 6.4 Hz, 1H), 4.64 (d, J = 4.5 Hz, 1H), 4.91 (d, J = 4.3 Hz, 1H). 5 Step 2: (4R,5S)-3-(tert-butoxycarbonyl)-5-methyloxazolidine-4-carboxylic acid: [0223] K2CO3 (21.04 g, 152.226 mmol, 3.00 equiv) was added to a stirred solution of (4R,5S)-3-(tert-butoxycarbonyl)-5-methyl-1,3-oxazolidine-4-carboxylic acid (11.734 g, 50.742 mmol, 1.00 equiv) and CH3I (8.64 g, 60.890 mmol, 1.20 equiv) in acetone (50 mL) 10 at room temperature under nitrogen atmosphere. The reaction was stirred under nitrogen atmosphere for 16h at reflux. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with EtOAc (3x50mL). The combined organic layers were washed with brine (3x50mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified15 by silica gel column chromatography, eluted with EtOAc: pet. ether (1:3) to afford 3-tert- butyl 4-methyl (4R,5S)-5-methyl-1,3-oxazolidine-3,4-dicarboxylate (8.12 g, 65.21%) as a yellow oil. LCMS (ESI+): m/z 268 (M+Na⁺).¹H NMR (300 MHz, DMSO-d6): δ 1.18 – 1.48 (m, 12H), 3.70 (d, J = 4.6 Hz, 3H), 3.91 (dd, J = 6.5, 11.0 Hz, 1H), 4.15 (p, J = 5.6, 5.6, 5.8, 5.8 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 5.01 (d, J = 4.1 Hz, 1H). 20 Step 3: 3-(tert-butyl) 4-methyl (4R,5S)-5-methyloxazolidine-3,4-dicarboxylate: [0224] NaBH₄ (6.26 g, 165.445 mmol, 5.00 equiv) was added in portions to o a stirred solution of 3-tert-butyl 4-methyl (4R,5S)-5-methyl-1,3-oxazolidine-3,4-dicarboxylate (8.116 g, 33.089 mmol, 1.00 equiv) in THF (50 mL) and MeOH (50 25 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room 78 PATENT Attorney Docket No.052687-508001WO temperature. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column 5 chromatography, eluted with EtOAc:pet. ether (1:1) to afford tert-butyl (4S,5S)-4- (hydroxymethyl)-5-methyl-1,3-oxazolidine-3-carboxylate (6.216 g, 86.46%) as a colorless oil. LCMS (ESI+): m/z 240 (M+Na⁺).¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (d, J = 6.2 Hz, 3H), 1.41 (s, 9H), 3.27 (s, 1H), 3.40 – 3.63 (m, 2H), 4.10 (s, 1H), 4.49 (d, J = 4.5 Hz, 1H), 4.79 – 5.02 (m, 2H). 10 Step 4: tert-butyl (4S,5S)-4-(hydroxymethyl)-5-methyloxazolidine-3-carboxylate: [0225] Step 4 for I . p p d in Step 1 for Int.16. LCMS (ESI+): m/z 280.0 (M+Na⁺).¹H NMR (300 MHz, DMSO-d6): δ 1.27 (d, J = 6.2 Hz, 3H), 1.42 (s, 9H), 3.36 – 3.52 (m, 2H), 3.61 (dd, J = 3.2, 9.1 Hz, 1H), 3.97 (dt, J = 1.6, 1.6, 15 5.3 Hz, 2H), 4.08 (q, J = 6.1, 6.1, 6.1 Hz, 1H), 4.50 (d, J = 4.5 Hz, 1H), 4.98 (d, J = 4.4 Hz, 1H), 5.09 – 5.29 (m, 2H), 5.87 (ddt, J = 5.2, 5.2, 10.4, 17.3 Hz, 1H). Step 5: tert-butyl (4S,5S)-4-((allyloxy)methyl)-5-methyloxazolidine-3-carboxylate: Step 6: Int.23: 20 [0226] Step 6 for Int.23 was performed with the procedure outlined in Step 2 for Int.16. The product was used directly in the next reaction. LCMS (ESI+): m/z 180.0 (M+H⁺). Int.24: Preparation of ((S)-4-((allyloxy)methyl)oxazolidine: 79 PATENT Attorney Docket No.052687-508001WO Step 1: 3-(tert-butyl) 4-methyl (R) dicarboxylate: [0227] To a stirre olidine-4-carboxylic 5 acid (10 g, 46.04 mmol, 1 equiv) and K₂CO₃ (19.09 g, 138.108 mmol, 3 equiv) in acetone (200 mL) was added CH3I (9.80 g, 69.054 mmol, 1.5 equiv). The reaction mixture was stirred for 16hr at 60°C. The resulting mixture was diluted with H₂O (300mL) and extracted with EtOAc (3 x 300mL). The combined organic layers were washed with H2O (3x500mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. 10 The residue was purified by RP flash chromatography (10% - 50% MeCN in Water with 0.1% FA) to afford 3-tert-butyl 4-methyl (4R)-1,3-oxazolidine-3,4-dicarboxylate (8 g, 75.15%) as a white oil. LCMS (ESI+): m/z 132.1 (M+H-100). Step 2: tert-butyl (S)-4-(hydroxymethyl)oxazolidine-3-carboxylate: 15 [0228] To a stir red mixture of 3-tert-butyl 4-methyl (4R)-1,3-oxazolidine-3,4-dicarboxylate (8 g, 34.595 mmol, 1 equiv) in MeOH (70 mL) and THF (70 mL) was added NaBH₄ (6.54 g, 172.975 mmol, 5 equiv) at 0°C. The resulting mixture was stirred for 5hr at 20°C.The reaction was quenched by the addition of Water (70mL) at 0°C. THF was removed under reduced pressure and the resulting mixture was diluted with water (50mL) and extracted with 20 CH₂Cl₂ (3 x 60mL). The combined organic layer was washed with H₂O (3x500mL), dried over anhydrous Na2SO4 and filtered. The residue was purified by RP flash chromatography (MeCN in Water with 0.1% FA, 10% to 50%) to afford tert-butyl (4S)-4-(hydroxymethyl)- 1,3-oxazolidine-3-carboxylate (6 g, 85.34%) as a white solid. LCMS (ESI+): m/z 148.1 (M+H⁺). 80 PATENT Attorney Docket No.052687-508001WO Step 3: tert-butyl (S)-4-((allyloxy)methyl)oxazolidine-3-carboxylate: [0229] Step 3 fo in Step 1 for Int.16. LCMS (ESI+): m/z 244.0 (M+H⁺).¹H NMR (400 MHz, DMSO-d₆) δ: 5.87 (ddt, J = 17.4, 5 10.6, 5.4 Hz, 1H), 5.25 (dq, J = 17.3, 1.8 Hz, 1H), 5.16 (dq, J = 10.4, 1.5 Hz, 1H), 4.81 – 4.77 (m, 1H), 4.60 (d, J = 4.0 Hz, 1H), 4.04 – 3.81 (m, 5H), 3.51 (dd, J = 9.5, 3.9 Hz, 1H), 3.33 (dd, J = 9.2, 8.0 Hz, 1H), 1.41 (s, 9H). Step 4: Int.24: 10 [0230] Step 4 o . was pe o e w e p oce u e ou e Step 2 for Int.16. LCMS (ESI+): m/z 144.0 (M+H⁺). The product was used directly in the next reaction. Int.25: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(2,5- dichlorophenyl)propanoic acid 15 Step 1: Methyl (2S)-2-[(tert-bu toxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate: 81 PATENT Attorney Docket No.052687-508001WO [0231] To a stirred mixture of Zn (29.95 g, 458.06 mmol, 2.5 eq) and TMSCl (1.33 g, 12.28 mmol, 0.067 eq) in DMA was added methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (1.03 g, 3.11 mmol, 1.7 eq) dropwise below 45 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 16 5 h at rt under nitrogen atmosphere. The above mixture was added into a solution of 1,4- dichloro-2-iodo-benzene (50 g, 183.22 mmol, 1 eq), CuI (6.96 g, 36.64 mmol, 0.2 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (14.93 g, 18.32 mmol, 0.10 eq) at rt under nitrogen. The resulting mixture was stirred for additional 16 h at 85 ℃. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (1.5 L) at rt. The aqueous 10 layer was extracted with EtOAc (3 x 500 mL). The combined organics were washed with (5 x 300 mL) of water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (25:1) to afford methyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate (40 g, 63 %) as a white solid. LCMS (ESI+): m/z 292.15 (M-56⁺).¹H NMR (300 MHz, DMSO-d6): δ 1.11 – 1.47 (m, 15 12H), 2.89 (dd, 1H), 3.22 (dd, 1H), 3.64 (d, 4H), 3.91 – 4.37 (m, 1H), 6.87 – 7.89 (m, 4H). Step 2: Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate: [0232] o a st rre so ut on o met y ( S)- -[(tert- utoxycar ony )am no]-3-( ,5- 20 dichlorophenyl)propanoate (200 mg, 0.574 mmol, 1 eq) and methyl iodide (214.00 g, 1507.67 mmol, 15 eq) in DMF (350 mL) was added (argentiooxy)silver (93.17 g, 402.04 mmol, 4 eq) in portions at 25 ℃ under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 25 ℃. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was diluted water 25 (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (4 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 220 nm. 82 PATENT Attorney Docket No.052687-508001WO This resulted in methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate as a white solid. LCMS (ESI+): m/z 262.20 (M+Na⁺). Step 3: Int.25: O O O N (S) O N (S) O LiOH, THF/H₂O OH Cl 5 [0233] 5- dichlorophenyl)propanoate (35 g, 96.62 mmol, 1 eq) and LiOH (4.63 g, 193.24 mmol, 2 eq) in THF (500 mL)/ H2O (300 mg) was stirred for 16 h at 25 ℃. Desired product could be detected by LCMS. The mixture was acidified to pH=4 with diluted HCl (aq.). The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organics was concentrated 10 under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Int.6 (25.26 g, 75.07%) as a light-yellow solid. LCMS (ESI+): m/z 346.00 (M-H-).¹H NMR (400 MHz, DMSO-d6): δ 1.23 (d, 9H), 2.66 (d, 3H), 3.06 – 3.39 (m, 2H), 7.24 – 7.56 (m, 3H), 13.00 (s, 15 1H). Int.26: Preparation of (S)-3-(2-bromo-5-chlorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid Step 1: (2S,5R)-2-(2-bromo-5-chlo robenzyl)-3,6-diethoxy-5-isopropyl-2,5- 20 dihydropyrazine: 83 PATENT Attorney Docket No.052687-508001WO [0234] To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (151 g, 711 mmol, 1.00 eq) in THF (1500 mL) was added n-BuLi (2.5 M, 285 mL, 1.00 eq) at -70 °C under N₂, then to the above solution was added 1-bromo-2-(bromomethyl)-4-chlorobenzene (222.5 g, 782 mmol, 1.10 eq) in THF (220 mL) at -70 °C. The mixture was stirred at 25 °C 5 for 12 hours. TLC indicated 1-bromo-2-(bromomethyl)-4-chlorobenzene was remained, and some new spots was detected. The reaction was poured into sat. NH4Cl (aq.) 6000 mL, the reaction mixture was partitioned between water phase 6000 mL and THF 6000 mL. The organic phase was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,10 PE/EtOAc=100/0 to 1/1) to give desired (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy- 5-isopropyl-2,5-dihydropyrazine (620 g, 1.48 mol, 104 % yield, 99.3% purity) as a yellow gum. LCMS (ESI+): m/z 415/417 (M+H⁺) Step 2: Ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate: 15 [0235] To a solu , y , thoxy-5-isopropyl-2,5- dihydropyrazine (100 g, 240 mmol, 1.00 eq) in ACN (1500 mL) was added HCl (0.20 M, 1.40 L, 1.16 eq) at 0 °C, then was stirred at 25 °C for 48 hours. TLC indicated (2S,5R)-2-(2- bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine was consumed completely. The reaction mixture was concentrated under reduced pressure to remove ACN 20 and extracted with DCM 4000 mL (2000 mL x 2), the organic layers was concentrated under reduced pressure to give a residue. Then the water phase was basified with sat.aq. NaHCO3 to pH=7 and extracted with DCM 4.00 L (2.00 L x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give desired ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate (143 g, 466 mmol, 49 % yield) as a25 white solid and to give (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5- dihydropyrazine (200 g, crude) was obtained as a yellow gum. Step 3: (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid: 84 PATENT Attorney Docket No.052687-508001WO [0236] T oate (143 g, 466 mmol, 1.00 eq) in THF (715 mL) and EtOH (715 mL) was added LiOH^.H2O (58.7 g, 1.40 mol, 3.00 eq) at 0 °C, then the reaction was stirred at 25 °C for 12 hours. TLC indicated 5 ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate was consumed completely. The reaction mixture was concentrated under reduced pressure at 30 °C to remove half of solvent. It was added into a saturated solution of citric acid (1.50 L) at 5-10 °C, to keep all the progress worked under acid condition. Some solid precipitated, then the suspension was filtered, the filter cake was washed with MTBE (1.00 L). The filter cake was collected and 10 dried in vacuum to give desired (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid (130 g, crude) as yellow solid which was confirmed by LCMS and SFC, then was used to the next step without further purification. Step 4: (S)-3-(2-bromo-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid: 15 [0237] To a m xture o (2S)-2-amno-3-(2-bromo-5-c oro-p eny )propano c acid (70.00 g, 251.32 mmol, 1 eq) in THF (750 mL) and NaOH (1 N, 750 mL) was added Boc2O (109.70 g, 502.64 mmol, 115.47 mL, 2 eq) at 0 °C, the mixture was stirred at 20 °C for 12 h. The LCMS showed that the reactant 1 was consumed completely, and the desired product was detected. The mixture was poured into sat. Citric acid (4 L) and extracted with EtOAc (1 L x 3). The 20 organic layer was washed with water (2 L) and brine (2 L), dried over Na₂SO₄, filtered, and concentrated. The mixture was suspended in PE (1 L) and stirred at 20 °C for 0.5 h. Then the mixture was filtered, and the white solid was collected and dried to dryness to give compound 2 (2S)-3-(2-bromo-5-chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (124 g, 320.9 mmol, 64 % yield, 98% purity) as a white solid.¹H NMR: ET53616-98-P1Z (400 25 MHz, MeOD) δ 7.54 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.17-7.15 (m, 1H), 4.49 85 PATENT Attorney Docket No.052687-508001WO (dd, J = 4.4, 10.4 Hz, 1H), 3.39 (br dd, J = 4.4, 9.6 Hz, 1H), 2.94 - 2.88 (m, 1H), 1.36 - 1.28 (m, 9H). LCMS (ESI+): m/z 277.9 / 279.9 (M+H⁺) Step 5: Int.26: 5 [0238] To a butoxycarbonylamino)propanoic acid (3.00 g x 10, 7.92 mmol, 1 eq) in THF (90 mL x 10) was added NaH (1.58 g x 10, 39.61 mmol, 60% purity, 5 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h. Then MeI (11.25 g x 10, 79.23 mmol, 4.93 mL, 10 eq) was added at 0 °C, the mixture was stirred at 15 °C for 12 h. The LCMS showed that the (2S)-3-(2-bromo-5- 10 chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid was consumed completely, and the desired product was detected. The mixture was quenched by sat. Citric acid (1.5 L), extracted with EtOAc (1.5 Lx2). The organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE/EtOAc/THF=20/1/0 to 6/1/1) to give crude product. The mixture was combined 15 with ET53616-100,104. The residue was dissolved in DCM (1 L) and concentrated under reduced pressure to give the desired product Int.26 (114.0 g, 285.70 mmol, 98 % purity) as a yellow solid.¹H NMR: ET53616-105-P1Z2 (400 MHz, CHLOROFORM-d) δ 11.44 (brs, 1H), 7.50 - 7.47 (m, 1H), 7.20 - 7.19 (m, 1H), 7.13 - 7.11 (m, 1H), 4.83 - 4.71 (m, 1H), 3.48- 3.43 (m, 1H), 3.31 - 3.06 (m, 1H), 2.81 - 2.70 (m, 3H), 1.44 - 1.37 (m, 9H). LCMS (ESI+): 20 m/z 291.9/293.9 (M+H⁺). Int.35: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2- cyclobutoxypyridin-3-yl)propanoic acid Step 1: 3-Bromo-5-chloro-2-cyclobutoxypyridine: 86 PATENT Attorney Docket No.052687-508001WO [0239] To a su il) in THF (250 mL) was added cyclobutanol (10.49 g, 145.45 mmol, 1.1 eq) in THF (20 mL) at 0 °C dropwise. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere.3- 5 bromo-2,5-dichloropyridine (30.0 g, 132.23 mmol, 1.0 eq) in THF (30 mL) was added and the mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (100 mL) at 0 °C. The resulting mixture was diluted with water (500 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 300 mL), dried over anhydrous Na2SO4. After 10 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40:1) to afford 3-bromo-5-chloro-2- cyclobutoxypyridine (31.0 g, 89 %) as a colorless oil. LCMS (ESI+): m/z 262 (M+H⁺). Step 2: Methyl (2S)-2-[(tert-butoxycarbonyl) amino]-3-(5-chloro-2-cyclobutoxypyridin- 3-yl) propanoate: 15 [0240] To a st rred mxture o 3-bromo-5-c oro-2-cyc obutoxypyr d ne (15 g, 57.14 mmol, 1.0 eq), Pd(dppf)Cl₂.CH₂Cl₂ (2.33 g, 2.86 mmol, 0.05 eq) and CuI (1.09 g, 5.71 mmol, 0.1 eq) in N, N-dimethylacetamide (300 mL) was added methyl (2R)-2-[(tert-butoxycarbonyl) amino]-3-(iodozincio) propanoate (171.41 mL, 171.41 mmol, 3.00 eq) in one portion at rt 20 under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (600 mL) and EtOAc (200 mL), and then filtered. The filter cake was washed with EtOAc (1 x 20 mL). The filtrate was separated, and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with sat. NH₄Cl(aq.) (2 x 300 mL), brine (1 x 300 mL) and dried 25 over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following 87 PATENT Attorney Docket No.052687-508001WO conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 80% gradient in 20 min; detector, UV 220 nm. This resulted in methyl (2S)-2-[(tert-butoxycarbonyl) amino]- 3-(5-chloro-2-cyclobutoxypyridin-3-yl) propanoate (16.4 g, 75 %) as a colorless oil. LCMS (ESI+): m/z 385 (M+H⁺). 5 Step 3: Methyl (2S)-2-[(tert-butoxycarbonyl) (methyl)amino]-3-(5-chloro-2- cyclobutoxypyridin-3-yl) propanoate: [0241] To -3-(5-chloro-2- cyclobutoxypyridin-3-yl) propanoate (16.4 g, 42.61 mmol, 1 eq) and Ag2O (39.50 g, 170.45 10 mmol, 4.0 eq) in DMF (200 mL) was added CH3I (96.8 g, 681.81 mmol, 16.0 eq) in one portion at rt under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The starting material was transformed completely. The resulting mixture was diluted with water (500 mL) and EtOAc (200 mL) and was then filtered. The filter cake was washed with EtOAc (1 x 20 mL). The resulting mixture was separated, and the 15 aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with sat. NH4Cl(aq.) (2 x 300 mL), brine (1 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford methyl (2S)-2-[(tert-butoxycarbonyl) (methyl)amino]-3-(5-chloro-2-cyclobutoxypyridin-3-yl) 20 propanoate (17.0 g, 95 %) as a colorless oil. Step 4: Int.35: [0242] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl) (methyl)amino]-3-(5- chloro-2-cyclobutoxypyridin-3-yl) propanoate (17 g, 42.62 mmol, 1 eq) in THF (300 mL) 88 PATENT Attorney Docket No.052687-508001WO and H₂O (100 mL) was added LiOH (3.06 g, 127.86 mmol, 3.00 eq) in H₂O (100 mL) dropwise at 0 °C. The resulting mixture was stirred for 16 h at rt. The resulting mixture was diluted with water (300 mL) and then acidified to pH 2 with HCl (2 M aq.). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed 5 with brine (1 x 300 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 60% gradient in 25 min; detector, UV 220 nm. This resulted in Int.35 (15.7 g, 95 %) as a white solid. LCMS (ESI+): m/z 385 (M+H⁺).¹H NMR (300 MHz, DMSO-d₆) δ 10 1.23 (d, J = 21.1 Hz, 9H), 1.54 – 1.88 (m, 2H), 1.93 – 2.20 (m, 2H), 2.28 – 2.47 (m, 2H), 2.68 (d, J = 1.4 Hz, 3H), 2.86 – 3.03 (m, 1H), 3.04 – 3.19 (m, 1H), 4.66 – 5.03 (m, 1H), 5.05 – 5.21 (m, 1H), 7.49 – 7.81 (m, 1H), 7.88 – 8.23 (m, 1H), 12.95 (s, 1H). Int.39: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoic acid 15 Step 1: 3-Bromo-5-chloro-2-c yc op opoxypy e: [0243] Into a 1000 mL round-bottom flask were added 3-bromo-5-chloro-2-fluoropyridine (50 g, 237.61 mmol, 1 eq) in DMF (400 mL), Cs₂CO₃ (232.97 g, 712.83 mmol, 3 eq) was 20 added at rt under nitrogen atmosphere. The mixture was stirred at rt for 50 min. cyclopropanol (9.94 g, 171.08 mmol, 1.2 eq) was added dropwise over 2 min at rt. The resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with ice-water (700 mL) and extracted with EA (3 x 100 mL). The organic layer combined and washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated 25 under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (0~20%).This resulted in 3-bromo-5-chloro-2-cyclopropoxypyridine (40 89 PATENT Attorney Docket No.052687-508001WO g, 68 %) as a colorless oil. LCMS (ESI+): m/z 249.95.¹H NMR (400 MHz, DMSO-d₆) δ 0.76 (ddd, J = 5.7, 4.5, 3.1 Hz, 2H) ,0.96 – 0.78 (m, 2H), 4.32 (tt, J = 6.4, 3.1 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H). Step 2: Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin- 5 3-yl)propanoate: [0244] T . , . , . ) was added 1,2-dibromoethane (6.80 g, 36.22 mmol, 0.15 eq) in one portion under N2. Then chlorotrimethylsilane (2.62 g, 24.15 mmol, 0.1 eq) was added slowly and the mixture was10 stirred for 30 min at 25 ^oC. A solution of methyl 2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (95.36 g, 289.74 mmol, 1.2 eq) in DMA (135mL) was added dropwise slowly (60 min) to maintain temperature below 50 ^oC, the resulting mixture was stirred at rt for 2 h and then added 1000 mL 3-necked round-bottom flask a cannula to a solution of 3- bromo-5-chloro-2-cyclopropoxypyridine (60 g, 241.45 mmol, 1 eq), Pd(dppf)Cl2.CH2Cl2 15 (19.67 g, 24.14 mmol, 0.1 eq) and CuI (9.20 g, 48.29 mmol, 0.2 eq) in DMA (135 ml) under N2, the color of the mixture turned brown, then the mixture was heated and stirred at 80 ^oC for 2 h under N2. The mixture was quenched with ice-water (700 ml) and extracted with EA (3 x 500 ml). The organic layer was combined and washed with brine (300 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the crude product. The crude 20 product was purified by silica gel chromatography eluted with PE/EA (0~50%) to afford methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3- yl)propanoate (30 g, 34 %) as a white solid. LCMS (ESI+): m/z 371.10. Step 3: Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate: 90 PATENT Attorney Docket No.052687-508001WO [0245] Into a 10 -[(tert- butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (25 g, 67.42 mmol, 1 eq) in DMF (400 mL), Ag2O (78.11 g, 337.08 mmol, 5 eq) was added at 0 °C under 5 nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, CH₃I (95.69 g, 674.16 mmol, 10 eq) was added dropwise over 2 min at 0 °C. The resulting mixture was stirred at rt for 16 h. The reaction was quenched with ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The organic layer was combined and washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 10 residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate (22 g, 85 %) as a colorless oil. LCMS (ESI+): m/z 385.10.¹H NMR (400 MHz, DMSO-d6) δ 0.83 – 0.62(m, 2H), 1.19 (t, J = 7.1 Hz, 2H), 1.28 (s, 9H), 2.65 (d, J = 3.3 Hz, 3H), 2.95 (dd, J = 13.6, 10.4 Hz, 1H), 3.07(ddd, J = 14.2, 4.9, 1.9 15 Hz, 2H), 3.73 – 3.61 (m, 3H), 4.69 (dd, J = 10.5, 4.6 Hz, 1H), 8.12 (dd, J = 17.7, 2.6 Hz, 2H). Step 4: Int.39: [0246] Into a 1000 mL round-bottom flask were added methyl (2S)-2-[(tert- butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (20 g, 20 51.97 mmol, 1 eq) in THF (250 ml) and NaOH (10.39 g, 259.84 mmol, 5 eq) in water (50 ml) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at rt for 2 h. The solvent was removed by reduce pressure and the residue was purified by reverse flash chromatography with the following conditions: column, C18; mobile phase, ACN in water (0.5% FA), 0% to 100% gradient in 40 min; detector, UV 254 nm. This 25 resulted in Int.39 (13.95 g, 72%) as a yellow oil. LCMS (ESI+): m/z 371.00.¹H NMR (400 91 PATENT Attorney Docket No.052687-508001WO MHz, DMSO-d₆) δ 0.79 – 0.61 (m, 4H), 1.21 (s, 9H), 2.95 – 2.84 (m, 2H), 3.00 (s, 3H), 3.09 – 3.01 (m, 1H), 4.86 (dd, J = 11.3, 4.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 8.11 (dd, J = 18.4, 2.6 Hz, 1H). Int.45: 1-(2,2-difluoroethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 5 yl)phenyl)piperazine: [0247] 1-(4-( q, 3.5 mmol)was dissolved in DCM (20 ml) and DIPEA (0.49 g, 0.66 mL, 1.1 Eq, 3.8 mmol)was added. The reaction was cooled to 0 °C and DIPEA (0.49 g, 0.66 mL, 1.1 Eq, 3.8 10 mmol)was added. After, 2,2-difluoroethyl methanesulfonate (1.1 g, 2 Eq, 6.9 mmol) was added slowly. The reaction was stirred until the complete consumption of starting material (LCMS). Upon completion, the volatile solvent was removed and Int.45 (1.2 g, 3.3 mmol, 96.2 %)was used in the next reaction without any further purification. LCMS (ESI+): m/z 352.02 (M+H). 15 Int.49: (S)-3-(2-bromo-5-fluorophenyl)-2-((tert- butoxycarbonyl)(methyl)amino)propanoic acid: [0248] This material was synthes ized by following the procedure for Int.49 acid using 1- bromo-2-(bromomethyl)-4-fluorobenzene as the starting material. 20 Int.50: Preparation of (2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1- carbonyl)-4-fluoropyrrolidine-2-carboxylic acid 92 PATENT Attorney Docket No.052687-508001WO Step 1: Methyl (2S,4R)-4-fluoropyr oxylate: [0249] A solution o dine-1,2-dicarboxylate 5 (150 g, 101.1 mmol, 1 eq) and HCl_(gas) in 1,4-dioxane (758.29 mL, 505.53 mmol, 5 eq) was stirred for 0.5 h at rt and then concentrated under vacuum to afford methyl (2S,4R)-4- fluoropyrrolidine-2-carboxylate (110 g, yield, 99%, purity 80%) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI+): m/z 148.15 (M+H⁺). 10 Step 2: Methyl (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidine-2-carboxylate: [0250] To a stir red solution of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (110 g, 103.3 mmol, 1 eq, 80%), 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylic acid 15 (122.06 g, 103.3 mmol, 1 eq) and TCFH (251.69 g, 154.95 mmol, 1.5 eq) in ACN (1100 mL) was added NMI (245.51 g, 516.49 mmol, 5 eq) dropwise in 45 min at 0 °C. The mixture was slowly warmed up to rt and stirred overnight at rt. The mixture was concentrated under vacuum at 28 ^oC and diluted with EtOAc (900 mL) and washed with HCl (0.5N,1400 mL x 1). The aqueous layer was extracted again with EtOAc (1x500 mL). The combined organic 20 layers were washed with saturated NaHCO₃ (1000 mL x1). The aqueous layer was extracted 93 PATENT Attorney Docket No.052687-508001WO with EtOAc (300mL x1) again. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford methyl (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4- fluoropyrrolidine-2-carboxylate 180 g, 81 %) as a light-yellow solid. The crude product was 5 used in the next step directly without further purification. LCMS (ESI+): m/z 334.15 (M+H⁺). Step 3: Int.50: [0251] To a s , , 10 (trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (180 g, 82.15 mmol, 1 eq, 90%) in MeOH (1400 mL) was added dropwise NaOH (58.33 g, 246.45 mmol, 3 eq) in H2O (400 mL) in 30 min at 0-20 ^oC. The mixture was stirred for 2 h at rt. MeOH was evaporated out under vacuum. The residue was diluted with water (2500 mL) and acidified with HCl (3N,400 mL) at 0-20 ^oC. Then the precipitated solids were collected by 15 filtration and washed with water (3x200 mL). The filtrate was added HCl (3N,100 mL). The precipitated solids were collected by filtration and washed with water (3x100 mL). The combined solids were dried in an oven for 16 h at 40 ^oC. This resulted in afford Int.50 (150.7 g, 97 %) as a white solid. LCMS (ESI+): m/z 319.95 (M+H⁺). Int.51: Preparation of (2S,4R)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2- 20 methylpropanoyl)pyrrolidine-2-carboxylic acid [0252] This compound was prepared following the general synthetic sequence described for the preparation of Int.50 with (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid as the starting material. LCMS (ESI+): m/z 421.08. 94 PATENT Attorney Docket No.052687-508001WO Int.52: Preparation of (2S,4R)-1-(1-cyanocyclobutane-1-carbonyl)-4-fluoropyrrolidine- 2-carboxylic acid [0253] This compound was prepar general synthetic sequence described 5 for the preparation of Int.50 with 1-cyanocyclobutane-1-carboxylic acid as the starting material. LCMS (ESI+): m/z 240.09 (M+H⁺). Int. 53: Preparation of (2S,4R)-4-fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4- carbonyl)pyrrolidine-2-carboxylic acid: O F ^(R) (S) OH F 10 Step 1: methyl (2S,4R)-4-fluoro-1-( -( r uoromethyl)tetrahydro-2H-pyran-4- carbonyl)pyrrolidine-2-carboxylate: [0254] A mixture of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (1.6 g, 9.786 mmol, 1 equiv), 4-(trifluoromethyl)oxane-4-carboxylic acid (1.94 g, 9.79 mmol, 1.00equiv), TCFH 15 (4.12 g, 14.679 mmol, 1.5 equiv) and NMI (4.02 g, 48.93 mmol, 5 equiv) in MeCN (30 mL) was stirred for 16h at ambient temperature under nitrogen atmosphere. The reaction mixture was directly purified by RP-flash chromatograph, (5-60% MeCN in water with FA) This resulted in methyl (2S,4R)-4-fluoro-1-[4-(trifluoromethyl)oxane-4-carbonyl]pyrrolidine-2- carboxylate (2.2 g, 68.69%) as a white solid. LCMS (ESI+): m/z 328.0 (M+H⁺). 95 PATENT Attorney Docket No.052687-508001WO Step 2: Int.53: [0255] A mixtu ane-4- carbonyl]pyrrolidine-2-carboxylate (3.4 g, 10.39 mmol, 1 equiv) and NaOH (2.08 g, 51.945 5 mmol, 5.0 equiv) in MeOH (80 mL)/H₂O (30 mL) was stirred for 16hr at 20°C. The organic solvents were evaporated in vacuo and the water was acidified by 1N HCl. The resulting precipitation was collected by filtration and dried in air. This resulted in Int.53 (3.25 g, 97.52%) as a white solid. LCMS (ESI+): m/z 314.0 (M+H⁺).¹H NMR (400 MHz, DMSO- d₆): δ 1.69 (td, J = 12.4, 4.5 Hz, 1H), 1.82 – 1.95 (m, 1H), 1.96 – 2.14 (m, 1H), 2.32 (dq, J = 10 12.9, 2.3 Hz, 1H), 2.45 (d, J = 14.4 Hz, 1H), 2.52 – 2.60 (m, 1H), 3.28 (dd, J = 11.9, 2.0 Hz, 1H), 3.49 – 3.96 (m, 4H), 4.13 (ddd, J = 19.7, 12.4, 2.2 Hz, 1H), 4.52 (dd, J = 10.1, 8.0 Hz, 1H), 5.37 (dt, J = 52.2, 3.1 Hz, 1H), 12.80 (s, 1H). Int.54: Preparation of (2S,4R)-1-(3-(1,1-difluoroethyl)oxetane-3-carbonyl)-4- fluoropyrrolidine-2-carboxylic acid 15 Step 1: Methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate: [0256] The mixture of 1-tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (3 g, 12.133 mmol, 1 equiv) in 4M HCl in 1,4-dioxane (60 mL, 234 mmol, 19.78 equiv) was 20 stirred for 2hr. The resulting mixture was concentrated under vacuum to give crude product 96 PATENT Attorney Docket No.052687-508001WO (2.4g) was used in the next step directly without further purification. LCMS (ESI+): m/z 148.2 (M+H⁺). Step 2: Methyl (2S,4R)-1-(3-(1,1-difluoroethyl)oxetane-3-carbonyl)-4-fluoropyrrolidine- 2-carboxylate 5 [0257] To a st , boxylate (1.2 g, 8.155 mmol, 1 equiv) and 3-(1,1-difluoroethyl)oxetane-3-carboxylic acid (1.35g, 8.16 mmol, 1 equiv) in MeCN (25 mL, 475.61 mmol) were added TCFH (4.58g, 16.31 mmol, 2 equiv) and NMI (2.01g, 24.4 mmol, 3 equiv) in portions at room temperature. The resulting mixture 10 was stirred for an additional 2 hr at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by RP chromatography (MeCN in Water with 0.1 FA, 10% to 100%). This resulted in methyl (2S,4R)-1-[3-(1,1- difluoroethyl)oxetane-3-carbonyl]-4-fluoropyrrolidine-2-carboxylate (1.6 g, 66.45%) as a white oil. LCMS (ESI+): m/z 296.1 (M+H⁺).¹H NMR (300 MHz, DMSO-d₆): δ 4.90 (d, J = 15 6.9 Hz, 1H), 4.78 – 4.54 (m, 4H), 3.67 (s, 6H), 2.59 (dt, J = 14.0, 7.7 Hz, 1H), 2.24 – 1.98 (m, 1H), 1.66 (t, J = 19.5 Hz, 3H). Step 3: Int.54 [0258] To a stirred solution of methyl (2S,4R)-1-[3-(1,1-difluoroethyl)oxetane-3-carbonyl]- 20 4-fluoropyrrolidine-2-carboxylate (2.1 g, 7.11 mmol, 1 equiv) in THF (4 mL) was added NaOH (0.85 g, 21.34 mmol, 3 equiv) in H2O (15 mL) at room temperature. The resulting mixture was stirred for an additional 2hr at room temperature. The reaction was acidified to 97 PATENT Attorney Docket No.052687-508001WO pH 4 with conc. HCl. The resulting mixture was concentrated and was purified by RP chromatography (MeCN in Water with 0.1% FA, 10% to 100%). This resulted in Int.54 (1.61 g, 79.62%) as a white solid. LCMS (ESI+): m/z 282.6 (M+H⁺).¹H NMR (300 MHz, DMSO-d6): δ 12.87 (s, 1H), 5.63 – 5.16 (m, 1H), 5.01 – 4.38 (m, 6H), 3.56 (t, J = 12.6 Hz, 5 1H), 2.70 – 2.53 (m, 1H), 2.08 (dddd, J = 40.4, 14.7, 8.9, 4.0 Hz, 1H), 1.66 (t, J = 19.5 Hz, 3H). Int.55: Preparation of (2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclobutane-1- carbonyl)pyrrolidine-2-carboxylic acid 10 [0259] This compound was prepar general synthetic sequence described for the preparation of Int.50 with 1-(trifluoromethyl)cyclobutane-1-carboxylic acid as the starting material. LCMS (ESI+): m/z 283.08 (M+H⁺). Int.56: Preparation of (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran- 2-carbonyl)pyrrolidine-2-carboxylic acid 15 Step 1: Methyl (2S,4R)-4-fluoropyr rolidine-2-carboxylate: [0260] A mixture of 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (20 g, 80.9 mmol, 1 eq) in HCl/EtOAc (200 mL) (4 M) was stirred at 25 °C for 2 h. LC-MS 20 showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was concentrated to give methyl (2S,4R)-4-fluoropyrrolidine-2- 98 PATENT Attorney Docket No.052687-508001WO carboxylate (15 g, crude, HCl) as a light-yellow solid. This was taken on to the next reaction without further purification. Step 2: (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2- carbonyl)pyrrolidine-2-carboxylate and (2S,4R)-4-fluoro-1-((S)-2- 5 (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate: [0261] acid (13 g, 65.61 mmol, 1 eq) in DCM (200 mL) was added DIEA (8.48 g, 65.61 mmol, 11.43 mL, 1 eq), and the mixture was stirred for 10 min, then BOP-Cl (18.37 g, 72.17 mmol, 1.1 eq), 10 methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, and DIEA (16.96 g, 131.22 mmol, 22.86 mL, 2 eq) were added. The mixture was stirred at 25 °C for 12 h. LC-MS showed one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove DCM, and then EtOAc (30 mL) was added. The solution was washed three times with 5% NaHCO3 solution (15 mL) and once consecutively with water (15 mL), 15 2M HCl solution (15 mL), water (15 mL) and saturated brine (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, PE:EtOAc = 10:1 to 2:1) to give methyl (2S,4R)-4-fluoro-1-((R)-2- (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7 g, 31.720 mmol, 48 % yield, 96.8% purity) as a light yellow oil and to give methyl (2S,4R)-4-fluoro-1- ((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (11 g, 32.0 mmol, 49 % yield, 95.2% purity) as a light yellow oil. Step 3: Int.56: 99 PATENT Attorney Docket No.052687-508001WO [0262] To a soluti methyl)tetrahydro-2H- pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7 g, 31.66 mmol, 96.83% purity, 1 eq) in THF (100 mL) and H2O (100 mL) was added LiOH.H2O (2.66 g, 63.32 mmol, 2 eq). Then 5 the mixture was stirred at 25 °C for 1 hr. LC-MS showed methyl (2S,4R)-4-fluoro-1-((R)-2- (trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate was consumed and one main peak with desired mass was detected. The mixture was acidified at 0 °C with HCl (1 N) until pH = 2~3. Then the mixture was extracted with EtOAc 300 mL (100 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under 10 reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, PE:EtOAc = 10:1 to 2:1) to give Int.56 (8.9 g, 28.33 mmol, 89 % yield, 99 % purity) as a white solid. LCMS (ESI+): m/z 314.0 (M+H⁺). Int. 57 and Int. 58: Preparation of (2S,4R)-4-fluoro-1-((1R,3R)-3-methoxy-1- (trifluoromethyl)cyclopentane-1-carbonyl)pyrrolidine-2-carboxylic acid and (2S,4R)-4-15 fluoro-1-((1S,3S)-3-methoxy-1-(trifluoromethyl)cyclopentane-1-carbonyl)pyrrolidine-2- carboxylic acid Step 1: methyl (2S,4R)-4-fluoro-1-((cis-1,3)-3-methoxy-1-(trifluoromethyl)cyclopentane- 1-carbonyl)pyrrolidine-2-carboxylate: 100 PATENT Attorney Docket No.052687-508001WO [0263] T rochloride (1 g, 5.446 mmol, 1 equiv), TCFH (2.29 g, 8.169 mmol, 1.5 equiv) and (cis-1,3)-3-methoxy-1- (trifluoromethyl) cyclopentane-1-carboxylic acid (1.16 g, 5.446 mmol, 1 equiv) in MeCN (50 5 mL) was added dropwise NMI (2.24 g, 27.23 mmol, 5 sequiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 50°C. The resulting mixture was concentrated under reduced pressure and the residue was purified by RP flash chromatography (MeCN in Water with 0.1% FA, 5% to 100%) to afford methyl (2S,4R)-4- fluoro-1-[(cis1,3)-3-methoxy-1-(trifluoromethyl) cyclopentanecarbonyl] pyrrolidine-2- ₁₀ carboxylate (1.1 g, 59.18%) as a white solid. LCMS (ESI+): m/z 342.0 (M+H⁺). Step 2: Int.57 and Int.58: [0264] To a stirred solution of methyl (2S,4R)-4-fluoro-1-[(cis-1,3)-3-methoxy-1- (trifluoromethyl)cyclopentanecarbonyl]pyrrolidine-2-carboxylate (2.2 g, 6.446 mmol, 1 15 equiv) in THF (10 mL) was added LiOH (0.77 g, 32.230 mmol, 5 equiv) in H₂O (10 mL) at 0°C . The resulting mixture was stirred for 6 hr at room temperature. The mixture was then acidified with 1N HCl to pH~3. The resulting mixture was concentrated under reduced pressure and directly purified by RP chromatography (MeCN in Water with 0.1% FA, 5% to 100%). To afford a mixture of Int.57 and Int 58. The diastereomers were separated using 20 Chiral SFC. 101 PATENT Attorney Docket No.052687-508001WO Column: CHIRALPAK IC, 2x25 cm, 5 μm; Mobile Phase A: EtOH, Mobile Phase B: Hex(0.1% FA); Flow rate: 20 mL/min; Gradient: 1:9 A:B over 12 min; Int. 57 7.9 min; Int. 58 10.5 min; Injection Volume: 0.3 mL; Number Of Runs: 134. Int. 57 (0.95 g, 45%) was obtained as a white solid. LCMS (ESI+): m/z 328.0 (M+H⁺).¹H NMR (300 MHz, DMSO-d6): 5 δ 1.66 – 1.79 (m, 2H), 1.80 (d, J = 8.3 Hz, 3H), 1.96 (ddd, J = 14.0, 9.3, 3.9 Hz, 1H), 2.03 – 2.22 (m, 5H), 2.29 – 2.50 (m, 3H), 2.62 (t, J = 12.3 Hz, 2H), 3.10 (s, 6H), 3.35 (s, 1H), 3.59 (d, J = 13.1 Hz, 1H), 3.72 (d, J = 12.9 Hz, 1H), 4.04 – 4.21 (m, 2H), 4.41 (t, J = 8.8 Hz, 2H), 5.27 (s, 1H), 5.45 (s, 1H), 12.64 (s, 2H).¹⁹F NMR (282 MHz, DMSO): δ -70.222, -179.113. [0265] Int.58 (0.95 g, 45%) was obtained as a white solid.. LCMS (ESI+): m/z 328.0 10 (M+H⁺). ¹H NMR (300 MHz, DMSO-d6): δ 1.79 (dq, J = 13.4, 7.7 Hz, 2H), 1.91 – 2.05 (m, 1H), 2.10 (dd, J = 13.8, 4.5 Hz, 1H), 2.17 (td, J = 6.9, 6.3, 4.2 Hz, 2H), 2.31 (td, J = 14.6, 14.2, 5.8 Hz, 4H), 2.43 – 2.50 (m, 2H), 2.57 (d, J = 9.0 Hz, 0H), 3.18 (s, 6H), 3.57 (d, J = 12.9 Hz, 1H), 3.69 (d, J = 12.9 Hz, 1H), 3.83 (t, J = 4.8 Hz, 2H), 4.07 – 4.23 (m, 1H), 4.42 (t, J = 8.7 Hz, 2H), 5.28 (s, 1H), 5.45 (s, 1H), 12.70 (s, 2H).¹⁹F NMR (282 MHz, DMSO): δ - 15 69.918, -178.564. Int.59: Preparation of (2S,4R)-1-(1-(difluoromethyl)-3-fluorocyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylic acid: Step 1: Diisopropyl 3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1,1-dicarboxylate: 20 [0266] To a stirred solution of 1,1-diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate (10 g, 40.935 mmol, 1 equiv) and imidazole (8.36g, 122.8 mmol, 3 equiv) in THF (200 mL) was added TBDPSCl (11.25 g, 40.935 mmol, 1 equiv) in portions at 0°C under argon atmosphere. The resulting mixture was stirred overnight, then, was concentrated under reduced pressure. 102 PATENT Attorney Docket No.052687-508001WO The residue was purified by silica gel column chromatography (pet. ether / EtOAc 50:1) to afford 1,1-diisopropyl 3-[(tert-butyldiphenylsilyl)oxy]cyclobutane-1,1-dicarboxylate (16.7 g, 80.3%) as a colorless oil. LCMS (ESI+): m/z 483.0 (M+H⁺). Step 2: Isopropyl 3-((tert-butyldiphenylsilyl)oxy)-1-formylcyclobutane-1-carboxylate: 5 [0267] To a stir lyl)oxy]cyclobutane- 1,1-dicarboxylate (17.7 g, 36.67 mmol, 1 equiv) in DCM (400 mL) was added DIBAl-H (1M in DCM, 73.34 mL, 73.338 mmol, 2 equiv) dropwise at -60°C under an atmosphere of Ar. The resulting mixture was stirred for 3hr at -60°C. The reaction was quenched by the addition 10 of 1N HCl (2 mL) at 0 °C. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layer was washed with brine, dried with MgSO_4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2, 100% CH₂Cl₂) to afford isopropyl 3-[(tert-butyldiphenylsilyl)oxy]-1-formylcyclobutane-1- carboxylate (12.6 g, 72.83%) as a colorless oil. LCMS (ESI+): m/z 425.0 (M+H⁺). 15 Step 3: Isopropyl 3-((tert-butyldiphenylsilyl)oxy)-1-(difluoromethyl)cyclobutane-1- carboxylate: O O D_{AST, DCM F F} [0268] To a stirred solution of isopropyl 3-[(tert-butyldiphenylsilyl)oxy]-1- formylcyclobutane-1-carboxylate (12.8 g, 30.145 mmol, 1 equiv) in DCM (400 mL) was 20 added DAST (14.58 g, 90.435 mmol, 3 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (200mL) at 0°C.The aqueous layer was extracted with CH2Cl2 (200 mL). The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (pet25 ether:EtOAc, 30:1) to afford isopropyl 3-[(tert-butyldiphenylsilyl)oxy]-1- 103 PATENT Attorney Docket No.052687-508001WO (difluoromethyl)cyclobutane-1-carboxylate (8.4 g, 53.03%) as a colorless oil. LCMS (ESI+): m/z 447.0 (M+H⁺). Step 4: 3-((tert-butyldiphenylsilyl)oxy)-1-(difluoromethyl)cyclobutane-1-carboxylic acid: 5 [0269] 3-[(t carboxylate (8.0 g, 15.23 mmol, 1 equiv) in THF (50 mL) /H₂O (50 mL) /MeOH (50 mL) was added NaOH (1.83 g, 45.678 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to remove MeOH. The resulting mixture was diluted with water (100 mL). The 10 mixture was acidified to pH 4 with HCl (aq.). The aqueous layer was extracted with EtOAc (2 x 150 mL). The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (40%- 100% MeCN in water with 0.1% FA) This resulted in 3-[(tert-butyldiphenylsilyl)oxy]-1- (difluoromethyl)cyclobutane-1-carboxylic acid (3.7 g, 57.07%) as a colorless oil. LCMS 15 (ESI+): m/z 403.0 (M+H⁺). Step 5: Methyl (2S,4R)-1-(3-((tert-butyldiphenylsilyl)oxy)-1- (difluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylate: [0270] To a stirred solution of 3-[(tert-butyldiphenylsilyl)oxy]-1- 20 (difluoromethyl)cyclobutane-1-carboxylic acid (3.7 g, 9.146 mmol, 1 equiv) and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (1.48 g, 10.061 mmol, 1.1 equiv) in MeCN (68 mL) were added TCFH (3.85 g, 13.719 mmol, 1.5 equiv) and NMI (5.63 g, 68.595 mmol, 7.5 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The 104 PATENT Attorney Docket No.052687-508001WO residue was purified by reverse flash chromatography (50-100% MeCN in water with 0.1% FA). This resulted in methyl (2S,4R)-1-{3-[(tert-butyldiphenylsilyl)oxy]-1- (difluoromethyl)cyclobutanecarbonyl}-4-fluoropyrrolidine-2-carboxylate (4.5 g, 87.6%) as a colorless oil. LCMS (ESI+): m/z 534.0 (M+H⁺). 5 Step 6: Methyl (2S,4R)-1-(1-(difluoromethyl)-3-hydroxycyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylate: [0271] To a stirred so , phenylsilyl)oxy]-1- (difluoromethyl)cyclobutanecarbonyl}-4-fluoropyrrolidine-2-carboxylate (4.5 g, 8.43 mmol, 10 1 equiv) in THF (45 mL) was added TBAF (8.43 mL, 32.242 mmol, 3.82 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of water and then extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (0%-15 100% MeCN in water with 0.1% FA). This resulted in methyl (2S,4R)-1-[1-(difluoromethyl)- 3-hydroxycyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (3.2 g, 96.40%) as a colorless oil. LCMS (ESI+): m/z 296.0 (M+H⁺). Step 7: Methyl (2S,4R)-1-(1-(difluoromethyl)-3-fluorocyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylate: 20 [0272] To a stirred solution of methyl (2S,4R)-1-[1-(difluoromethyl)-3- hydroxycyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (3.2 g, 8.13 mmol, 1 equiv, 105 PATENT Attorney Docket No.052687-508001WO 75%) in DCM (60 mL) was added DAST (3.93 g, 24.384 mmol, 3 equiv) dropwise at -78°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature under Ar atmosphere. The resulting mixture was quenched by the addition of NaHCO₃ and then extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried with 5 MgSO_4, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (0-80% MeCN in water with 0.1% FA)This resulted in methyl (2S,4R)-1-[1- (difluoromethyl)-3-fluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (1.4 g, 46.35%) as a white solid. LCMS (ESI+): m/z 298.0 (M+H⁺). Step 8: Int.59: 10 [0273] (2S,4R)-1 y y y -4-fluoropyrrolidine-2- carboxylate (1.4 g, 3.768 mmol, 1 equiv) in THF (15 mL) /H2O (15 mL) was added LiOH (0.27 g, 11.304 mmol, 3 equiv) in portions at 0°C.The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (15mL) and was 15 concentrated under reduced pressure to remove MeOH. The aqueous layer was extracted with EtOAc (2x30 mL). The mixture was acidified to pH 4 with HCl (aq.). The aqueous layer was again extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by RP- HPLC to afford Int.59 (569.9 mg, 52.12%) as a white solid. LCMS (ESI+): m/z 282.0 20 (M+H⁺).¹H NMR (300 MHz, DMSO-d6): δ 12.76 (s, 1H), 6.38 (t, J = 55.9 Hz, 1H), 5.38 (dt, J = 3.1, 52.6 Hz, 1H), 5.16 – 4.82 (m, 1H), 4.43 (t, J = 8.7 Hz, 1H), 3.95 – 3.50 (m, 2H), 3.07 – 2.84 (m, 1H), 2.72 (d, J = 13.2 Hz, 1H), 2.59 (dt, J = 5.0, 17.9 Hz, 2H), 2.48 – 2.38 (m, 1H), 2.06 (dddd, J = 4.0, 8.9, 14.7, 40.2 Hz, 1H). Int. 64: Preparation of (S)-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pent-4- 25 enoic acid: 106 PATENT Attorney Docket No.052687-508001WO Step 1: methyl (S)-2-aminopent-4-e [0274] To a sol ) in MeOH (250 mL) 5 was added TMSCl (59.0 g, 543 mmol, 68.9 mL) at 0°C under N₂. The mixture was stirred at 25°C for 12 hr. Upon consumption of starting material (TLC, Pet. ether:EtOAc 50%), the reaction mixture was concentrated under reduced pressure to remove most of the solvent. The residue was triturated with hexane (50 mL) at 0^oC for 0.5 hour. Then, the mixture was filtered and the filter cake was collected, dried in vacuum to give desired methyl (S)-2-aminopent-4- 10 enoate (35 g, crude, HCl) as a white solid, which was used to next step without further purification. LCMS (ESI+): m/z 130.1 (M+H⁺), Step 2: methyl (S)-2-((cyclopropylmethyl)amino)pent-4-enoate: [0275] To a solution of methyl (S)-2-aminopent-4-enoate (13.3 g, 1 Eq, 103 mmol) and 15 cyclopropanecarbaldehyde (36.1 g, 5 Eq, 515 mmol) in MeOH (50 mL) was added TEA (20.8 g, 28.7 mL, 2 Eq, 206 mmol) at 0^oC under N₂. The mixture was stirred for 5 min. Then AcOH was added dropwise to adjust pH 5-6. The mixture was warmed to 25 ^oC and stirred for another 12 hr. To the mixture NaBH₃CN (16.2 g, 2.5 Eq, 257 mmol) was added in portions at 0°C. The mixture warmed to ambient temperature and stirred. Upon the 20 consumption of starting material (LCMS), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl (S)-2- 107 PATENT Attorney Docket No.052687-508001WO ((cyclopropylmethyl)amino)pent-4-enoate (13.6 g, 74.4 mmol, 72.3 %) as a yellow oil. LCMS (ESI+): m/z 183.2 (M+H⁺). Step 3: methyl (S)-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pent-4-enoate: 5 [0276] To a mi 4-enoate (28 g, 152 mmol) in DCM (300 mL) was added TEA (23.19 g, 229 mmol, 31.9 mL) and Boc₂O (35.0 g, 160 mmol, 36.9 mL) at 25°C. Then the mixture was stirred for 1 hour. Upon the consumption of starting material (TLC, 20% EtOAc in pet. ether) The mixture was concentrated under reduced pressure and was purified by column chromatography (SiO2, EtOAc in pet. ether 0-10 10%) to give desired methyl (S)-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pent-4- enoate (26 g, 91.76 mmol, 60.05%) as a yellow oil. LCMS (ESI+): m/z 284.2 (M+H⁺), Step 4: Int.64: [0277] To a so lution of methyl (S)-2-((tert- 15 butoxycarbonyl)(cyclopropylmethyl)amino)pent-4-enoate (26 g, 91.8 mmol) in MeOH (130 mL) and THF (130 mL) was added LiOH (3.30 g, 137 mmol). The mixture was stirred at 25 °C Upon the consumption of starting material (monitored by LCMS), the reaction mixture was slowly added into 0.1 M of HCl (800 mL). It was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (300mL), dried over Na2SO4, filtered, 20 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, EtOAc in pet. ether 10-30%) to afford desired product Int.64 (11 g, 40.8 mmol, 44.51%) as a white solid. LCMS (ESI+): m/z 270.1 (M-H-) ¹H NMR (400 MHz, DMSO-d6): δ 0.11-0.24 (2 H, m) 0.40 (2 H, br d, J = 8.0 Hz) 0.95 (1 H, br s) 1.31-1.54 (9 H, m) 2.53-2.69 (2 H, m) 2.92-3.14 (2 H, m) 3.96-4.28 (1 H, m) 4.93-5.14 (2 H, m) 5.70- 25 5.94 (1 H, m) 11.82-13.22 (1 H, m). 108 PATENT Attorney Docket No.052687-508001WO Int. 65 and Int. 66 : Preparation of S-allyl-N-(tert-butoxycarbonyl)-L-cysteine and S- allyl-N-(tert-butoxycarbonyl)-N-methyl-L-cysteine Step 1: S-allyl-N-(t 5 [0278] S-allyl-L ater (50 mL). Na₂CO₃ (33 g, 10 Eq, 0.31 mol) was added and the mixture was stirred to dissolve. Boc2O (14 g, 14 mL, 2 Eq, 62 mmol) was dissolved in THF (25 mL) and this solution was added to the reaction mixture. The reaction was stirred for 2 hours and diluted in water. The aqueous 10 phase was washed with hexanes (2 x 50 mL) and then acidified with citric acid. The aqueous phase was extracted EtOAc (3 x 50mL). The combined organics were washed with brine, dried over MgSO₄, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to yield Int.65 (5.01 grams, 19 mmol, 61%). LCMS (ESI+): m/z 207.4 (M-55+H⁺). 15 Step 2: Int.66: [0279] S-allyl-N-(tert-butoxycarbonyl)-L-cysteine (5.0 g, 1 Eq, 19 mmol) was dissolved in THF (30 mL). The solution was degassed for 10 minutes, followed by the addition of NaH (0.92 g, 2 Eq, 38 mmol) in small portions. MeI (16 g, 7.2 mL, 6 Eq, 0.11 mol) was added and 20 the reaction stirred overnight. The reaction was quenched with water (50 mL) and washed with hexanes (2 x 50 mL). The aqueous phase was then acidified with 1M HCl to pH~3 and extracted with EtOAc (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel 109 PATENT Attorney Docket No.052687-508001WO chromatography (0 to 100% EtOAc in hexanes) to yield Int.66 (5.01 grams, 18.2 mmol, 94%). LCMS (ESI+): m/z 221.5 (M-55+H⁺). Int.67: Preparation of (S)-2-((tert-butoxycarbonyl)(propyl)amino)pent-4-enoic acid: 5 Step 1: Int.67 [0280] L-all y g y . g, q, 35 mL). Water (15 mL) was added, followed by DIPEA (25.9 mL3 Eq, 150 mmol). The solution was sparged with argon. Propionaldehyde (4.3 mL, 1.2 Eq, 60 mmol) was added, and the reaction 10 was cooled to 0 ˚C. NaBH4 (3.8g, 2 Eq, 100 mmol) was added in small portions and the reaction was allowed to warm to room temperature while stirring overnight. The next day, the reaction was concentrated by rotary evaporation and the residue was diluted in water (50 mL). Na₂CO₃ (10.5 g, 2 Eq, 100 mmol) was added. Boc₂O (13.1 g, 1.2 Eq, 60 mmol) was dissolved in THF and the solution was added to the reaction mixture and the reaction was 15 stirred for 4 hr. The reaction was acidified with 1M HCl and extracted EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to yield Int.67 (10 g, 38.9 mmol, 77%) Int.68: Preparation of (1S,2R)-1-((S)-2-((tert-butoxycarbonyl)amino)-N- 20 methylpropanamido)-2-vinylcyclopropane-1-carboxylic acid : 110 PATENT Attorney Docket No.052687-508001WO Step 1: Methyl (1S,2R)-1-((tert-butoxycarbonyl)(methyl)amino)-2-vinylcyclopropane-1- carboxylate: [0281] To solutio ylcyclopropane-1- 5 carboxylic acid (5.7 g, 1 Eq, 25 mmol) in DMF (50 mL), NaH (3.0 g, 60% Wt, 3 Eq, 75 mmol) was added in portions at 0°C. After 30 mins, MeI (14 g, 6.3 mL, 4 Eq, 0.10 mol) was added dropwise and the reaction was warmed to room temperature overnight. The reaction was added into ice water (100 mL), then extracted with EtOAc (150 mL × 2), the combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was 10 concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO2, EtOAc in hexanes; 0-60%) to yield methyl (1S,2R)-1-((tert- butoxycarbonyl)(methyl)amino)-2-vinylcyclopropane-1-carboxylate (5.3 g, 21 mmol, 82 %). LCMS (ESI+): m/z 256.3 (M+H+) Step 2: (1-Methyl (1S,2R)-methylamino)-2-vinylcyclopropane-1-carboxylate TFA salt: 15 [0282] To a solutio n of methyl (1S,2R)-1-((tert-butoxycarbonyl)(methyl)amino)-2- vinylcyclopropane-1-carboxylate (5.5 g) in DCM (80 mL) was added TFA (16 mL) at 0 °C. The mixture was removed from the cooling bath and stirred at 25 °C until LCMS analysis showed the complete consumption of starting material. The reaction mixture was 20 concentrated under reduced pressure to give methyl (1S,2S)-1-(methylamino)-2- vinylcyclopropane-1-carboxylate (3.3 g, 22 mmol, 100 %, TFA). The crude product was used directly in the next step. LCMS (ESI+): m/z 156.6 (M+H⁺) Step 3: Methyl (1S,2R)-1-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N- methylpropanamido)-2-vinylcyclopropane-1-carboxylate: 111 PATENT Attorney Docket No.052687-508001WO [0283] To g, 1 Eq, 64 mmol) in DCM (60 mL), SOCl₂ (23 g, 14 mL, 3 Eq, 0.19 mol) was added dropwise at 0 °C. The reaction was heated to reflux. Upon the consumption of starting material (LCMS), the 5 DCM was concentrated and to afford (9H-fluoren-9-yl)methyl (S)-(1-chloro-1-oxopropan-2- yl)carbamate (21 g, 64 mmol) as a yellow solid. The crude product was used directly in the next step. LCMS (ESI+): m/z 326.3 (M+H⁺). (When sample prep was performed in MeOH, the methyl ester is observed) [0284] Methyl (1S,2R)-1-(methylamino)-2-vinylcyclopropane-1-carboxylate (3.0 g, 1 Eq, 10 19 mmol) was dissolved in DCM (60 mL) and 2M Na₂CO₃ (20 mL) at 0 °C for 10 mins. A solution of (9H-fluoren-9-yl)methyl (S)-(1-chloro-1-oxopropan-2-yl)carbamate (16 g, 2.5 Eq, 48 mmol) in DCM (60 mL) was added slowly. The mixture was warmed to ambient temperature and stirred overnight. Then, the organic layer was separated, and the water layer was washed with DCM (50 mL). The combined organic layers were washed with brine, dried 15 over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO₂, EtOAc in Hexanes; 0-100%) to yield methyl (1S,2R)-1-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N- methylpropanamido)-2-vinylcyclopropane-1-carboxylate (3.7 g, 8.3 mmol, 43 %). LCMS (ESI+): m/z 449.4 (M+H+) 20 Step 4: Int.68: [0285] To a solution of methyl (1S,2R)-1-((S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-N-methylpropanamido)-2-vinylcyclopropane-1-carboxylate (3.7 g, 1 Eq, 8.2 mmol) in THF (33 mL), H2O (15 mL) and MeOH (9 mL), LiOH (0.99 g, 3 112 PATENT Attorney Docket No.052687-508001WO Eq, 25 mmol) was added at 0 °C and the mixture was stirred at 25 °C overnight until the starting material was consumed, LCMS (ESI+): m/z 213.4 (M+H+). [0286] The reaction mixture was neutralized with 3M HCl, then, Na2CO3 (5.5 g, 3 Eq, 52 mmol) was added to adjust the pH to ~8. Boc₂O (4.2 g, 4.4 mL, 1.1 Eq, 19 mmol) was added 5 and the reaction was stirred at 25 °C overnight. Upon the consumption of starting material (LCMS), the mixture was quenched with saturated citric acid solution and concentrated to remove THF and MeOH, then extracted with EtOAc (70 mL × 2), the combined organic layers were washed with brine, dried over MgSO₄ and filtered. The filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography 10 (SiO₂, EtOAc in Hexanes; 0-100 %) to yield Int.68 (2.8 g, 9.1 mmol, 52 %). LCMS (ESI+): m/z 313.4 (M+H+) Int.69: Preparation of (1S,2R)-1-((S)-2-((tert-butoxycarbonyl)amino)-2- cyclopropylacetamido)-2-vinylcyclopropane-1-carboxylic acid: 15 Step 1: Methyl (1S,2R)-1-((tert- u oxycar ony )am no)-2-vinylcyclopropane-1- carboxylate: [0287] To solution of (1S,2R)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropane-1- carboxylic acid (4.0 g, 1 Eq, 18 mmol) in DMF (30 mL), K2CO3 (7.3 g, 3 Eq, 53 mmol) was 20 added in portion at 0 °C. After 30 mins, MeI (2.7 g, 1.2 mL, 1.1 Eq, 19 mmol) was added slowly at 0 °C and the reaction was warmed to ambient temperature and stirred overnight. Upon consumption of starting material (LCMS), the reaction was added into ice water (100 mL), then extracted with EtOAc (60 mL × 2), the combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to 25 give crude product which was purified by column chromatography (SiO2, EtOAc in Hexanes; 113 PATENT Attorney Docket No.052687-508001WO 0-60%) to yield methyl (1S,2R)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropane-1- carboxylate (3.3 g, 14 mmol, 78%). LCMS (ESI+): m/z 242.6 (M+H+) Steps 2-4: Int.69: Cl (S) NHF oc 5 [ . . eps 2-4) using the product from the previous reaction and (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2-cyclopropylacetic acid as starting material. LCMS (ESI+): m/z 325.4 (M+H+) Int. 70: Preparation of (1S,2R)-1-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropyl-N- 10 methylacetamido)-2-vinylcyclopropane-1-carboxylic acid: [0289] Int.70 was prepared using the procedure outlined in the synthesis of Int.68 using (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-cyclopropylacetic acid as starting material. LCMS (ESI+): m/z 339.4 (M+H+) 15 Int.71: Preparation of (1S,2R)-1-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-2- vinylcyclopropane-1-carboxylic acid: 114 PATENT Attorney Docket No.052687-508001WO [0290] Int.71 was prepared using the procedure outlined in the synthesis of Int.69 using (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine as starting material. LCMS (ESI+): m/z 299.3 (M+H+). Int.72: Preparation of Cis-1-(tert-butoxycarbonyl)-3-vinylpiperidine-2-carboxylic acid: 5 Step 1: 1-(tert-butyl) 2-methyl 5,6-di ine-1,2(4H)-dicarboxylate: [0291] To a mi , ylate (10 g, 41.10 mmol, 1 eq) in THF (50 mL) was added LiHMDS (1 M, 45.21 mL, 1.1 eq) at -30 ℃ under N2 10 atmosphere, then the mixture was stirred at -30 ℃ for 1.5 hr, then the yellow solution was cooled -78 ℃, and Br2 (7.23 g, 45.21 mmol, 2.33 mL, 1.1 eq) was added dropwise. Afterwards the cooling bath was removed allowing the mixture to warm to room temperature, then the mixture was stirred for 0.5 hr. Upon the consumption of starting material (LCMS), the reaction mixture was quenched with aqueous citric acid (56 mL, 1 M) and stirred at 25 ℃ 15 for 30 min, then the mixture was diluted with EtOAc (250 mL), the organic layer was washed with H2O (2 x 250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc in pet. ether 0-10%) to give 1-(tert-butyl) 2-methyl 5,6-dihydropyridine-1,2(4H)-dicarboxylate (6 g, 24.87 mmol, 60.50% yield) as a white solid. LCMS (ESI+): m/z 242.1 (M+H-).¹H NMR 20 (400 MHz, MeOD-d4): δ 6.04 (t, J = 3.9 Hz, 1H), 3.75 (s, 3H), 3.58-3.51 (m, 2H), 2.25 (t, J = 3.9, 6.7 Hz, 2H), 1.83-1.76 (m, 2H), 1.42 (s, 9H). Step 2: Cis-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate: 115 PATENT Attorney Docket No.052687-508001WO [0292] To a mixture of bromocopper;methylsulfanylmethane (1.02 g, 4.97 mmol, 0.2 eq) in THF (60 mL) was added vinylmagnesiumbromide (1 M, 49.73 mL, 2 eq) at -35 ℃ under argon, then the mixture was stirred at -35 ℃ for 15 min, 1-(tert-butyl) 2-methyl 5,6- dihydropyridine-1,2(4H)-dicarboxylate (6 g, 24.87 mmol, 1 eq) in THF (30 mL) was slowly 5 added to the above mixture. The solution was stirred at -35 °C for 6 hr. Upon consumption of starting material (TLC 20% EtOAc in pet. ether), the reaction mixture was quenched with a sat. NH₄Cl (60 mL) at 0 ℃. After extraction with MTBE (3 x 100 mL), the organic layer was washed with aqueous saturated NH4Cl solution (60 mL) and brine (60 mL). The combined organic layers were then dried over anhydrous Na₂SO₄, filtered, and concentrated under 10 reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc in pet. ether 0-5%) to give Trans-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate (4.8 g, 17.82 mmol, 71.67%) as a colourless oil; ¹H NMR (400 MHz, MeOD-d4): δ 5.92 (d, J = 6.3, 10.7, 17.2 Hz, 1H), 5.23-5.11 (m, 2H), 4.77 (s, 1H), 3.94 (d, J = 11.9 Hz, 1H), 3.75 (s, 3H), 2.99 (s, 2H), 1.71-1.64 (m, 2H), 1.64-1.50 (m, 2H), 1.45 (s, 9H); LCMS (ESI+): m/z 270.2 15 (M+H-).And to give cis-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate carboxylate (400 mg, 1.49 mmol, 5.97%) as a colourless oil.¹H NMR (400 MHz, MeOD - d₄): δ 5.88 (d, J = 7.3 Hz, 1H), 5.18-4.98 (m, 2H), 4.82-4.65 (m, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.66 (s, 3H), 3.28-3.03 (m, 1H), 2.46 (d, J = 1.1 Hz, 1H), 1.86-1.67 (m, 2H), 1.63-1.50 (m, 2H), 1.45 (s, 9H); LCMS (ESI+): m/z 270.2 (M+H-). 20 Step 3: Int.72: [0293] To a solution of cis-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate carboxylate (400 mg, 1.49 mmol, 1 eq) in MeOH (1.5 mL) and THF (4.5 mL) was added LiOH in H2O (2 M, 1.49 mL, 2 eq). Then the mixture was stirred at 50 °C for 3 hr. The 25 reaction mixture was next cooled to room temperature. The aqueous phase was washed with MTBE (5 mL) and acidified with 1M HCl. After extraction with DCM (3 x 5 mL), the organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, EtOAc in Pet. ether 0-10%) to give Compound Int.72 (204 mg, 745.50 μmol, 50.20% yield) as a colourless oil. LCMS30 (ESI+): m/z 156.1 (M+H-Boc).¹H NMR (400 MHz, MeOD-d₄): δ 6.13-5.75 (m, 1H), 5.20- 116 PATENT Attorney Docket No.052687-508001WO 4.95 (m, 2H), 4.79-4.55 (d, 1H), 3.92 (d, J = 12.6 Hz, 1H), 3.26-3.04 (m, 1H), 2.44 (s, 1H), 1.83-1.51 (m, 4H), 1.45 (s, 9H). Int.74: Preparation of (S)-4,4-difluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2- methylpropanoyl)pyrrolidine-2-carboxylic acid: 5 Step 1: 1-(tert-butyl) 2-methyl (S idine-1,2-dicarboxylate: [0294] To a sti e u e o - - e - u o yca o y - , - uo opyrrolidine-2- carboxylic acid (15 g, 59.71 mmol, 1.00 equiv) and K2CO3 (16.50 g, 119.41 mmol, 2 equiv) 10 in DMF (150 mL) was added MeI (21.19 g, 149.3 mmol, 2.5 equiv) dropwise at 25^oC under nitrogen atmosphere. The mixture was stirred for 21 h. Upon consumption of starting material (LCMS), The resulting mixture was diluted with water (500 mL). The mixture was extracted with EtOAc (400 mL). The organic layer was washed with water (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified15 by silica gel column chromatography (0-100% EtOAc in pet. ether) to afford 1-tert-butyl 2- methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (14.6 g, 88.13%) as a yellow oil. LCMS (ESI+): m/z 266.11 (M+H⁺). Step 2: methyl 4,4-difluoropyrrolidine-2-carboxylate: 20 [0295] Into a 250 mL flask were added 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine- 1,2-dicarboxylate (14.6 g, 55.0 mmol, 1.0 equiv) and 4M HCl in 1,4-dioxane (146 mL) at 117 PATENT Attorney Docket No.052687-508001WO 15~25^oC. The resulting mixture was stirred for 2.5 hr at 25^oC. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in methyl (2S)-4,4-difluoropyrrolidine-2-carboxylate (quant.) as a white solid. The product was used without further purification. LCMS (ESI+): m/z 166.1 (M+H⁺). 5 Step 3: methyl (S)-4,4-difluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2- methylpropanoyl)pyrrolidine-2-carboxylate: [0296] To a s rre mx ure o me y - , - uoropyrro ne- -car oxylate (6 g, 36.3 mmol, 1.00 equiv) and (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (8.62 g, 54.5 10 mmol, 1.50 equiv) in DMF (60 mL) were added HATU (27.63 g, 72.7 mmol, 2 equiv) and DIPEA (23.48 g, 181.7 mmol, 5 equiv) dropwise at 0^oC under nitrogen atmosphere. The resulting mixture was stirred for 48 hr at 25^oC under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (400 mL). and washed with water (3 x 300 mL). The aqueous phase was extracted with again with EtOAc (200 mL). The combined 15 organic layer was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, 30% EtOAc in pet. ether) to afford methyl (2S)-4,4-difluoro-1-[(2R)- 3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidine-2-carboxylate (11.6 g, quant.) as a yellow oil. LCMS (ESI+): m/z 302.1 (M+H⁺). 20 Step 4: Int.74: [0297] To a stirred mixture of methyl (2S)-4,4-difluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy- 2-methyl propanoyl] pyrrolidine-2-carboxylate (6.9 g, 12.7 mmol, 1.00 equiv) in MeOH (56 118 PATENT Attorney Docket No.052687-508001WO mL, 1383.14 mmol, 109 equiv), THF (56 mL) and H₂O (56 mL) was added LiOH (0.61 g, 25.3 mmol, 2 equiv) at 0^oC under nitrogen atmosphere. The reaction was stirred for 3 hr. The resulting mixture was concentrated under reduced pressure to remove volatile solvents. The residue was then acidified to pH 2~3 with 4 N HCl. The crude product was collected by 5 filtration and purified by RP flash chromatography (C18, 10-100% MeCN in water) to afford Int.74 (1.56 g, 24.05%) as a white solid. LCMS (ESI+): m/z 292.0 (M+H⁺).¹H NMR (400 MHz, DMSO-d₆): δ 12.93 (s, 1H), 7.27 (s, 1H), 5.26 – 4.56 (m, 1H), 4.45 – 3.65 (m, 2H), 3.11 – 2.73 (m, 1H), 2.39 (qd, J = 13.7, 5.0 Hz, 1H), 1.52 (d, J = 17.1 Hz, 3H). Int.75: Preparation of tert-butyl (S)-2-((((9H-fluoren-9- 10 yl)methoxy)carbonyl)(methyl)amino)pent-4-enoate o a so u o o - - e - u o yca o y e y a o pe -4-enoic acid (250 15 g, 1.09 mol, 1 eq) in HCl/EtOAc (2500 mL). The mixture was stirred at 25 °C for 12 hour. The reaction mixture was concentrated under reduced pressure to remove solvent to give the deprotected HCl salt (180.5 g, crude, HCl) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 14.33-13.58 (m, 1H), 10.10-8.94 (m, 2H), 5.84-5.69 (m, 1H), 5.31-5.11 (m, 2H), 3.99 (br t, J = 5.2 Hz, 1H), 2.68 (br t, J = 6.4 Hz, 2H), 2.60-2.52 (m, 3H). 20 To a solution of the crude HCl salt (170 g, 1.03 mol, 1 eq) in H2O (860 mL) and dioxane (1140 mL) was added FmocOSu (346 g, 1.03 mol, 1 eq) and DIEA (398 g, 3.08 mol, 536 mL, 3 eq). The mixture was stirred until the LCMS showed consumption of starting material. The reaction was quenched with citric acid solution (800 mL) at 25 °C, and then extracted with EtOAc (500 mL x 4). The combined organic layers were washed with brine (500 mL x 2), 25 dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0~40% EtOAc/PE) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)pent-4-enoic 119 PATENT Attorney Docket No.052687-508001WO acid (290 g, 815 mmol, 80 % yield, 99% purity) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 13.13-12.72 (m, 1H), 7.89 (dd, J = 3.7, 7.2 Hz, 2H), 7.63 (br d, J = 7.6 Hz, 2H), 7.45-7.27 (m, 4H), 5.73-5.46 (m, 1H), 5.17-4.95 (m, 2H), 4.67-4.44 (m, 1H), 4.40-4.21 (m, 3H), 2.80-2.70 (m, 3H), 2.53 (br s, 1H), 2.48-2.32 (m, 1H). 5 Step 2: Int.75: [0299] Dissolve (S -4-enoic acid (10 g, 1 Eq, 28 mmol) in DCM (20 mL), bring to 0 °C under argon. Add DCC (6.5 g, 1.1 Eq, 31 mmol) and DMAP (0.35 g, 0.1 Eq, 2.8 mmol) as solids. Add tert-butanol (8.4 g, 11 10 mL, 4 Eq, 0.11 mol) by syringe. Stir at rt overnight. Dilute in water and DCM, extract 3X DCM. Wash combined organic layers with water and brine, dry over MgSO₄, filter, concentrate. Purify by normal phase chromatography (0 to 100% EtOAc in hexanes) to yield Int.75 (9.8 g, 24 mmol, 85 %) as a pale oil. Int.76: Preparation of (R)-3,3-difluorohept-6-en-2-amine: 15 Step 1: Tert-butyl (R)-(1-(methoxy(m ethyl)amino)-1-oxopropan-2-yl)carbamate: [0300] To a mixture of (2R)-2-[(tert-butoxycarbonyl) amino] propanoic acid (50 g, 264.255 mmol, 1 equiv) and N, O-dimethylhydroxylamine hydrochloride (25.78 g, 264.255 mmol, 1 20 equiv) in DMF (2000 mL) were added T₃P (252.24 g, 396.382 mmol, 1.5 equiv, 50% in EtOAc) and DIEPA (102.46 g, 792.765 mmol, 3.0 equiv) at 0°C under an atmosphere of ntrogen. The resulting mixture was stirred overnight at room temperature. The reaction was extracted with EtOAc (2 x 500 mL), the combined organic layers were washed with water (3 x 1000 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated 120 PATENT Attorney Docket No.052687-508001WO under reduced pressure. The residue was purified by RP flash chromatography (C18, 10 to 50% MeCN in Water with 0.1% FA) to afford tert-butyl (R)-(1-(methoxy(methyl)amino)-1- oxopropan-2-yl)carbamate (42 g, 68.4 %) as a white solid. LCMS (ESI+): m/z 233.0 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 1.14 (d, J = 7.2 Hz, 3H), 1.37 (s, 9H), 3.10 (s, 3H), 3.72 (s, 5 3H), 4.40 (p, J = 7.2 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H). Step 2: tert-butyl (R)-(3-oxohept-6-en-2-yl)carbamate: [0301] To a sti o)-1-oxopropan-2- yl)carbamate (30 g, 129.154 mmol, 1 equiv) in THF (600 mL) was added bromo (but-3-en-1- 10 yl) magnesium (645.77 mL, 645.770 mmol, 5 equiv) dropwise at 0°C under nitrogen atmosphere. Then the mixture was stirred for 16 hr at ambient temperature. The reaction was quenched with sat. NH₄Cl (aq.)/ NH₄.OH (9:1) at -10 °C. The resulting mixture was filtered. The filter cake was washed with EtOAc (2 x 20 mL). The filtrate was diluted with water (1200 mL) and the resulting mixture was extracted with EtOAc (3 x 500 mL). The combined 15 organic layers were washed with brine (1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP flash chromatography (C18, 10 to 100% MeCN in water with 0.1% FA) to afford tert- butyl N-[(2R)-3-oxohept-6-en-2-yl] carbamate (26.5 g, 71.26%) as a yellow oil. LCMS (ESI+): m/z 172.02 [M-tBu+2H] 20 Step 3: tert-butyl (R)-(3,3-difluorohept-6-en-2-yl)carbamate: [0302] To a stirred solution of tert-butyl (R)-(3-oxohept-6-en-2-yl)carbamate (10.0 g, 43.994 mmol, 1 equiv) in DCM (120 mL) was added BAST (38.93 g, 175.976 mmol, 4 equiv) in DCM (120 mL) dropwise at 0 °C under an atmosphere of nitrogen. The resulting 25 mixture was stirred for 16 h at room temperature. The reaction was then poured into Ice/sat. NaHCO3(aq.). The resulting mixture was separated, and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (200 mL) and 121 PATENT Attorney Docket No.052687-508001WO dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by FCC (SiO2, 2% EtOAc in pet. ether) to afford tert-butyl (R)-(3,3-difluorohept-6-en-2-yl)carbamate (4.44 g, 40.52%) as a yellow oil. LCMS (ESI+): m/z 194.10 [M-tBu+2H].¹H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J = 7.0 Hz, 3H), 1.39 (s, 5 9H), 1.81 – 2.01 (m, 2H), 2.11 – 2.30 (m, 2H), 3.80 – 4.01 (m, 1H), 4.93 – 5.14 (m, 2H), 5.76 – 5.93 (m, 1H), 7.22 (d, J = 9.3 Hz, 1H). Step 4: Int.76: [0303] Step 4 f Step 2 for Int.16. 10 LCMS (ESI+): m/z 150.20 (M+H⁺). The product was used directly in the next reaction. Int.77: Preparation of (R)-N-methylhept-6-en-2-amine: Step 1: (R)-4-benzyl-3-(hept-6-eno y )oxazo - -one: 15 [0304] A solution of 6-heptenoic acid (17 g, 132.635 mmol, 1 equiv), (4R)-4-benzyl-1,3- oxazolidin-2-one (23.50 g, 132.635 mmol, 1 equiv) in THF (200 mL) was treated with pivaloyl chloride (1.60 g, 13.264 mmol, 0.1 equiv) for 1 hr at -10 °C under nitrogen atmosphere followed by the addition of lithium chloride (5.62 g, 132.635 mmol, 1 equiv) in portions at -10 °C. The resulting mixture was stirred overnight at room temperature under a 20 nitrogen atmosphere. The reaction was quenched with sat. NH₄Cl (50 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 100 mL). The residue was purified by column chromatography (SiO₂, 20% EtOAc in pet. ether) to afford (R)-4-benzyl-3-(hept-6- enoyl)oxazolidin-2-one (20 g, 52.47%) as a white oil. LCMS (ESI+): m/z 288.10 (M+H⁺). 122 PATENT Attorney Docket No.052687-508001WO Step 2: (R)-4-benzyl-3-((R)-2-methylhept-6-enoyl)oxazolidin-2-one: [0305] A s 69.6 mmol, 1 equiv) in THF (400 mL) was treated with NaHMDS (68 mL, 68 mmol, 0.98 equiv, 1M in 5 THF) for 30 min at 0 °C under nitrogen atmosphere followed by the addition of methyl iodide (29.6g, 208.8 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 3 h at - 78 °C under nitrogen atmosphere. The reaction was quenched with sat. NH₄Cl (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced 10 pressure. The residue was purified by column chromatography (SiO2, 20% EtOAc in pet. ether) to afford (R)-4-benzyl-3-((R)-2-methylhept-6-enoyl)oxazolidin-2-one (19 g, 90.58%) as a yellow oil. LCMS (ESI+): m/z 302.30 (M+H⁺). Step 3: (R)-2-methylhept-6-enoic acid: 15 [0306] (R) -4-benzyl-3-((R)-2-methylhept-6-enoyl)oxazolidin-2-one (19 g, 63.042 mmol, 1 equiv) was dissolved in tetrahydrofuran (700 mL) and cooled in an ice-water bath. Hydrogen peroxide (60 mL, 1763.980 mmol, 30%) was added, followed by a solution LiOH (4.53 g, 189.126 mmol, 3 equiv) in water (10 mL). The reaction was allowed to slowly warm up to room temperature. After 16hr, the reaction was cooled in an ice/water bath and was quenched 20 by the addition of water (200mL).The stirring was maintained for 10 minutes, then the mixture was poured into a separation funnel, diluted with DCM (200 mL). The layers were separated, and the aqueous phase was acidified with 1N HCl and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated to obtain (R)-2-methylhept-6-enoic acid (8.3 g, 92.59%) as 25 a yellow oil. LCMS (ESI+): m/z 143.40 (M+H⁺). Step 4: tert-butyl (R)-hept-6-en-2-ylcarbamate: 123 PATENT Attorney Docket No.052687-508001WO [0307] To a 27 mmol, 1 equiv) in anhydrous tBuOH (100 mL) was added TEA (9.96 g, 98.454 mmol, 2 equiv) and DPPA (14.90 g, 54.150 mmol, 1.1 equiv). The reaction mixture was stirred at 5 90°C overnight. The reaction mixture was quenched by addition of water (200 mL). The aqueous layer was extracted with EtOAc (300 mL). The organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 10-20% EtOAc in Pet. ether) to afford tert-butyl (R)-hept-6-en-2-ylcarbamate (3.5 g, 33.33%) as a yellow oil. 10 LCMS (ESI+): m/z 214.05 (M+H⁺). Step 5: tert-butyl (R)-hept-6-en-2-yl(methyl)carbamate: [0308] To a so u o e - u y - ep - -e - -y ca a a e . g, . 7 mmol, 1 equiv) in THF (80 mL) was added NaH (1.61 g, 40.314 mmol, 2 equiv, 60%) in portions. The 15 reaction was stirred at 0°C for 30 min. Then, MeI (28.61 g, 201.570 mmol, 10 equiv) was added dropwise. The reaction was warmed to room temperature and stirred overnight under an atmosphere of nitrogen. The reaction was again cooled in an ice/water bath and quenched with water (100 mL). The mixture was then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and 20 concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 15% EtOAc in pet. ether) to afford tert-butyl (R)-hept-6-en-2- yl(methyl)carbamate (3.86 g, 84.29%) as a yellow oil. LCMS (ESI+): m/z 172.0 (M-tBu⁺). 1H NMR (400 MHz, Chloroform-d) δ 5.78 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 – 4.86 (m, 2H), 4.17 (s, 1H), 2.66 (s, 3H), 2.15 – 2.00 (m, 2H), 1.46 (s, 11H), 1.34 (tq, J = 11.6, 5.9 Hz, 25 3H), 1.07 (d, J = 6.8 Hz, 3H). Step 6: Int.77 124 PATENT Attorney Docket No.052687-508001WO [0309] Step 6 for Int.77 was performed with the procedure outlined in Step 2 for Int.16. LCMS (ESI+): m/z 128.50 (M+H⁺). The product was used directly in the next reaction. Int.78: Preparation of N,2,2-trimethylhex-5-en-1-amine: 5 Step 1: 2,2-dimethylhex-5-enenitril 1 g, 444.432 mmol, 3 equiv) in THF (500 mL) under an atmosphere of nitrogen was treated with LDA (592 mL, 592. mmol, 4 equiv, 1M in THF) at -78°C. After 1 hr, 4-bromo-1-butene (20 g, 148.144 mmol, 1 equiv) was 10 added slowly. The mixture was stirred for 4 hr at -78 °C. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with ether (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 50% DCM in pet. ether) to afford 2,2-dimethylhex-5-enenitrile (11 g, 60.27%) as a yellow oil. 15 71.36%) as a clear oil. GCMS: 123.0 Step 2: 2,2-dimethylhex-5-en-1-amine: [0311] To a solution of 2,2-dimethylhex-5-enenitrile (11 g, 89.286 mmol, 1 equiv) in THF (200 mL) was added LiAlH4 (357.15 mL, 357.144 mmol, 4 equiv) in portions at 0 °C under 20 an atmosphere of nitogn. The mixture was heated 50 °C and stirred overnight. The reaction was quenched with ice at 0 °C. The aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure.2,2-dimethylhex-5-en-1-amine (10 g, 88.03%) was isolated as a yellow oil and used in the next step with no additional purification. GCMS: 25 127.0 Step 3: tert-butyl (2,2-dimethylhex-5-en-1-yl)carbamate: 125 PATENT Attorney Docket No.052687-508001WO [0312] A mix l, 1 equiv) and triethylamine (8.35 g, 82.527 mmol, 3 equiv) in DCM (200 mL) was cooled to 0°C. Boc₂O (9.01 g, 41.264 mmol, 1.5equiv) was added in portions and the reaction was 5 stirred at room temperature for 5 hr. The resulting mixture was concentrated under reduced pressure and was directly purified by column chromatography (SiO₂, 20% EtOAc in pet. ether) to afford tert-butyl (2,2-dimethylhex-5-en-1-yl)carbamate (3.7 g, 59.15%) as a yellow oil. LCMS (ESI+): m/z 172.30 (M-56).¹H NMR (400 MHz, Chloroform-d): δ 5.81 (ddt, J = 16.8, 10.3, 6.5 Hz, 1H), 5.09 – 4.87 (m, 2H), 4.57 (s, 1H), 2.95 (d, J = 5.6 Hz, 2H), 10 2.02 (q, J = 7.3 Hz, 2H), 1.47 (s, 9H), 1.33 – 1.24 (m, 2H), 0.87 (s, 6H). Step 4: tert-butyl (2,2-dimethylhex-5-en-1-yl)(methyl)carbamate: [0313] To a sol u on o er - u y , - me y ex- -en- -y car amate (5.4 g, 23.752 mmol, 1 equiv) in DMF (80 mL) was added NaH (1.43 g, 35.628 mmol, 1.5 equiv, 60%) at 0 15 °C under a nitrogen atmosphere. After 15 min, MeI (6.74 g, 47.504 mmol, 2 equiv) was added and the mixture was warmed to room temperature and continued overnight. The resulting mixture was quenched with sat. NH4Cl (aq.) at 0°C. The reaction was then extracted with EtOAc (100 mL). The organic layer was washed with brine (25 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Tert-butyl (2,2-dimethylhex- 20 5-en-1-yl)(methyl)carbamate (5.07 g, 88.40%) was isolated as a yellow oil. LCMS (ESI+): m/z 242.30 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 1.25 (t, J = 8.7 Hz, 2H), 1.39 (s, 9H), 2.00 (q, J = 7.2 Hz, 2H), 2.83 (d, J = 7.9 Hz, 3H), 3.03 (s, 2H), 4.92 (d, J = 8.7 Hz, 1H), 5.01 (d, J = 17.1 Hz, 1H), 5.81 (d, J = 6.8 Hz, 1H). Step 5: Int.78: 25 [0314] Step 5 for Int.78 was performed with the procedure outlined in Step 2 for Int.16. LCMS (ESI+): m/z 143.30 (M+H⁺). The product was used directly in the next reaction. 126 PATENT Attorney Docket No.052687-508001WO B. Representative Procedures for Preparing Compounds of Formula (I) [0315] The following subsections describe procedures for preparing compounds of Formula (I). It is understood that compounds of Formula (I) can be prepared using variety of synthetic routes. The following procedures are meant to be illustrative, not limiting. 5 Generally, compounds of Formula (I) are prepared by synthesizing a macrocyclic portion of the compound and completing final synthetic steps to obtain compounds of Formula (I). The final synthetic steps include optional modifications (e.g., reduction, Phe Suzuki coupling) and tail addition (comprising the R³, R^4a/b/c variable positions of Formula (I)). The macrocyclic synthesis procedures described herein include Methods A, B, and C. The final synthesis 10 procedures described herein include Methods 1-7. 1. Macrocycle Synthesis Procedures a. Method A Generic Procedure for Method A: 127 PATENT Attorney Docket No.052687-508001WO Representative Procedure for Method A: 1) TFA/DCM 1) TFA/DCM O 2) O Cl O O Cl Cl Cl 2) Boc-Leu-OH _{O N O N} _{HO O} HN _{O N} HATU, DIPEA O B_ocN DMF OH O Br Step 1: tert-butyl ((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5- 5 chlorophenyl)-1-oxopropan-2-yl)(methyl)carbamate (500): [0316] To a so ut on o nt. 6 ( 5 g, .60 mmo , eq) an nt.7 ( 6. 7 g, 148.98 mmol, 1.3 eq, HCl) in DMF (1500 mL) was added HATU (61.00 g, 160.44 mmol, 1.4 eq) and DIEPA (44.43 g, 343.80 mmol, 59.88 mL, 3 eq) at 0 °C. The mixture was stirred at 15 10 °C for 2 hr. LC-MS showed the starting material was consumed. The reaction mixture was quenched by addition H2O (3000 mL) at 0 °C, and then extracted with EtOAc (3000 mL x 2). The combined organic layers were washed with brine (3000 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by FCC (0~20% EtOAc/pet. ether) to give 500 (59.0 g, 114.3 mmol, 99.0%) as a yellow oil. LCMS (ESI+): 15 m/z 415.2 (M-Boc+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 8.2 Hz, 1H), 7.34 (br s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.96 - 5.79 (m, 1H), 5.29 - 5.20 (m, 1H), 5.14 (qd, J = 1.6, 10.5 Hz, 1H), 5.06 (br s, 1H), 4.18 (br s, 1H), 4.01 - 3.86 (m, 2H), 3.56 - 3.16 (m, 4H), 3.07 – 3.08 (m, 2H), 2.75 - 2.69 (m, 3H), 1.96 - 1.74 (m, 4H), 1.33 - 1.11 (m, 9H) Step 2-3: tert-butyl ((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5- 20 chlorophenyl)-1-oxopropan-2-yl)(methyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (502): 128 PATENT Attorney Docket No.052687-508001WO [0317] added TFA (200 mL). The mixture was stirred at 15 °C until the starting material was consumedwas consumed (monitored by LCMS). The reaction mixture was concentrated under reduced 5 pressure. The resulting oil was redissolved in PhMe (500 mL) and concentrated to remove excess TFA. This process could be repeated as needed to give (S)-1-((R)-2- ((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5-chlorophenyl)-2-(methylamino)propan-1- one (501) (180 g, crude, TFA) as a yellow oil. The crude product was used directly in the next step. LCMS (ESI+): m/z 415.1(M+H⁺). 10 [0318] To a solution of 501 (170 g, 320.89 mmol, 1 eq, TFA) and Int.60 (74.22 g, 320.9 mmol, 1 eq) in DMF (3000 mL) was added HATU (158.62 g, 417.16 mmol, 1.3 eq) and DIEPA (165.89 g, 1.28 mol, 223.57 mL, 4 eq) at 0 °C. Additional DIPEA was added as needed to adjust the reaction to ~8 pH. The reaction was stirred at ambient temperature until the complete consumption of starting material (monitored by LCMS). The reaction mixture 15 was quenched by addition water (3000 mL) at 0°C, and then extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by FCC (0 to 25% EtOAc in pet. ether) to afford 502 (130 g, 206.67 mmol, 64.40%) as a yellow oil. LCMS (ESI+): m/z 628.1 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 7.54 (d, J = 8.4 Hz, 1H), 7.34 20 (s, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.38 - 6.13 (m, 1H), 5.96 - 5.71 (m, 1H), 5.58 - 5.42 (m, 1H), 5.22 (d, J = 17.4 Hz, 1H), 5.13 (d, J = 9.9 Hz, 1H), 4.36 (d, J = 2.7 Hz, 1H), 4.13 (s, 1H), 3.92 (s, 2H), 3.38 - 3.14 (m, 3H), 3.10 - 3.00 (m, 3H), 2.96 (s, 3H), 1.92 1.44 (m, 5H), 1.42 - 1.34 (m, 10H), 1.29 - 1.18 (m, 1H), 0.93 - 0.81 (m, 6H). Step 4-5: tert-butyl ((S)-1-(((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-25 bromo-5-chlorophenyl)-1-oxopropan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)-1- oxopent-4-en-2-yl)(methyl)carbamate (504): 129 PATENT Attorney Docket No.052687-508001WO [ A (100 mL). The mixture was stirred at ambient temperature for 1 hr. The LCMS trace showed that the starting material was consumed. The reaction mixture was concentrated under 5 reduced pressure. The resulting oil was redissolved in PhMe (500 mL) and concentrated to remove excess TFA. This process could be repeated as needed to give (S)-N-((S)-1-((R)-2- ((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5-chlorophenyl)-1-oxopropan-2-yl)-2-amino- N,4-dimethylpentanamide (503) (108 g, crude, TFA) as a yellow oil. The crude product was used in the next reaction without further purification. LCMS (ESI+): m/z 528.2 (M+H⁺). 10 [0320] To a solution of 503 (108 g, 126.0 mmol, 1 eq, TFA) and Int.61 (31.77 g, 138.58 mmol, 1.1 eq) in DMF (2000 mL) was added HATU (57.48 g, 151.18 mmol, 1.2 eq) and DIEPA (65.13 g, 503.94 mmol, 87.78 mL, 4 eq) at 0°C. Additional DIPEA was added as needed to adjust the reaction to ~8 pH. The reaction was stirred at ambient temperature until the complete consumption of starting material (monitored by LCMS). The reaction mixture 15 was quenched by the addition of water (2000 mL) at 0°C, then extracted with EtOAc (2000 mL x 2). The combined organic layers were washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.The resulting residue was purified by FCC (0~20% EtOAc/Pet. ether) give 504 (60 g, 81.06 mmol, 64.34%) as a yellow oil. LCMS (ESI+): m/z 739.4 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 7.53 (d, J = 7.9 Hz, 20 1H), 7.46 - 7.27 (m, 2H), 7.16 (d, J = 8.3 Hz, 1H), 5.96 - 5.62 (m, 2H), 5.59 - 5.45 (m, 1H), 5.23 (d, J = 16.9 Hz, 1H), 5.17 - 5.07 (m, 2H), 5.04 (d, J = 10.0 Hz, 1H), 4.71 (dt, J = 4.4, 9.0 Hz, 1H), 4.55 - 4.44 (m, 1H), 4.13 (s, 1H), 3.93 (s, 2H), 3.52 - 3.12 (m, 5H), 3.07 (s, 1H), 2.97 (s, 3H), 2.72 (s, 3H), 2.48 - 2.43 (m, 1H), 2.39 - 2.28 (m, 1H), 1.93 - 1.68 (m, 4H), 1.63 - 1.52 (m, 1H), 1.49 - 1.39 (m, 10H), 1.36 - 1.23 (m, 1H), 0.87 (d, J = 6.5 Hz, 6H) 25 Step 6-7: tert-butyl ((S)-2-(((S)-1-(((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)- 3-(2-bromo-5-chlorophenyl)-1-oxopropan-2-yl)amino)-4-methyl-1-oxopentan-2- 130 PATENT Attorney Docket No.052687-508001WO yl)amino)-1-oxopent-4-en-2-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (506): L) 5 was stirred at ambient temperature until the complete consumption of starting material was observed by LCMS. The reaction mixture was concentrated under reduced pressure. The resulting oil was redissolved in PhMe (500 mL) and concentrated to remove excess TFA. This process could be repeated as needed to give (S)-N-((S)-1-(((S)-1-((R)-2- ((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5-chlorophenyl)-1-oxopropan-2- 10 yl)(methyl)amino)-4-methyl-1-oxopentan-2-yl)-2-(methylamino)pent-4-enamide 505 (60 g, crude, TFA salt) as a yellow oil. LCMS (ESI+): m/z 639.3 (M+H⁺). [0322] To a solution of 505 (45 g, 59.68 mmol, 1 eq, TFA salt) and Int.62 (11.56 g, 53.71 mmol, 0.9 eq) in DMF (1000 mL) was added DIEPA (30.85 g, 238.70 mmol, 41.58 mL, 4 eq) and HATU (29.50 g, 77.58 mmol, 1.3 eq) at 0°C. The mixture was stirred at 15 °C until the 15 consumption of starting material (monitored by LCMS). The reaction was quenched by addition water (1000 mL), and extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (0~40% EtOAc in pet. ether) to afford 506 (40 g, 47.25 mmol, 79.18%) as a yellow oil. LCMS (ESI+): m/z 639.2 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): 20 δ 7.66 (br s, 1H), 7.45 (br s, 1H), 7.29 (br s, 1H), 6.61 - 6.31 (m, 1H), 6.13 - 5.60 (m, 3H), 5.44 - 4.98 (m, 4H), 4.83 (br s, 1H), 4.35 - 4.20 (m, 2H), 4.05 (br s, 2H), 3.65 - 3.26 (m, 5H), 3.23 - 2.91 (m, 8H), 2.67 - 2.61 (m, 3H), 2.04 - 1.81 (m, 4H), 1.67 (br s, 1H), 1.57 - 1.48 (m, 10H), 1.38 - 1.19 (m, 2H), 0.97 (d, J = 6.4 Hz, 6H), 0.60 - 0.43 (m, 4H). Step 8: tert-butyl ((S)-2-(((7S,10S,13S,18aR)-13-(2-bromo-5-chlorobenzyl)-10-isobutyl-25 12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro-1H- pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-1-cyclopropyl-2- oxoethyl)carbamate (507) 131 PATENT Attorney Docket No.052687-508001WO h Ar for 20 min. Then, [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2- isopropoxyphenyl)methylene]ruthenium (748.40 mg, 1.19 mmol, 0.1 eq) was added quickly 5 and the degassing was continued for an additional 10 min. The reaction was then stirred at 70 °C until the consumption of starting material was observed (monitored by LCMS, ~16 hr). The resulting mixture was concentrated under reduced pressure and the resulting residue residue was purified by RP flash chromatography (50-90% MeCN in water with 0.1% TFA). 507 (3.82 g, 4.7 mmol, 39.30%) as a brown solid after lyophilization. LCMS (ESI+): m/z 10 808.3 (M+H⁺).¹H NMR (400 MHz, DMSO-d6): δ 8.10 - 7.93 (m, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 1.9, 8.4 Hz, 1H), 6.51 - 6.28 (m, 1H), 5.58 (s, 2H), 5.38 - 5.01 (m, 1H), 4.83 (s, 1H), 4.41 - 4.08 (m, 3H), 3.97 (d, J = 13.5 Hz, 1H), 3.69 (d, J = 13.4 Hz, 2H), 3.46 - 3.30 (m, 2H), 3.21 (d, J = 8.9 Hz, 2H), 3.12 - 3.01 (m, 2H), 2.99 - 2.72 (m, 6H), 2.67 - 2.54 (m, 1H), 2.08 - 1.71 (m, 5H), 1.53 (s, 2H), 1.45 - 1.33 (m, 9H), 1.16 15 - 1.03 (m, 1H), 0.83 (d, J = 5.9 Hz, 3H), 0.75 - 0.66 (m, 3H), 0.49 - 0.25 (m, 4H). 132 PATENT Attorney Docket No.052687-508001WO b. Method B Generic Procedure for Method B: epese a ve oce ue o e o 5 133 PATENT Attorney Docket No.052687-508001WO Representative Experimental for Method B: Steps 1-3: 502: Steps 1-3 for Method B, the syn ed in Method A. 5 Step 4: tert-butyl (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-(((R)- 1-((S)-3-(2-bromo-5-chlorophenyl)-2-((S)-2-((tert-butoxycarbonyl)amino)-N,4- dimethylpentanamido)propanoyl)pyrrolidin-2-yl)methoxy)hex-4-enoate (508): [ 0324] 502 (2.33 g, 1 Eq, 3.71 mmo ) and Int.75 (4.9 g, 3.2 Eq, 12 mmo ) were d sso ved10 in DCE (25 mL). The solution was degassed with argon for 10 minutes. [2-(1-Methylethoxy- O)phenylmethyl-C](nitrato-O,O'){rel-(2R,5R,7S)-tricyclo[3.3.1.13,7]decane-2,1-diyl[3- (2,4,6-trimethylphenyl)-1-imidazolidinyl-2-ylidene]}ruthenium (236 mg, 0.1 Eq, 371 µmol) was added and the solution was heated to 60 °C. The reaction was stirred while being spared with Ar for 2 hours. The reaction was concentrated and purified by reverse-phase 15 chromatography (C18, 40 to 100% acetonitrile in water, 0.1% TFA) to 508 (2.0 g, 2.0 mmol, 53%). LCMS (ESI+): m/z 1009.4 (M+H⁺). Step 5: (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-(((R)-1-((S)-2- ((S)-2-amino-N,4-dimethylpentanamido)-3-(2-bromo-5- chlorophenyl)propanoyl)pyrrolidin-2-yl)methoxy)hex-4-enoic acid (509): 134 PATENT Attorney Docket No.052687-508001WO [032 olution was allowed to sit for 2 hours and concentrated by rotary evaporation. Excess TFA was removed by co-evaporation with Toluene. The crude product, 509, was used in the next step 5 without further purification. LCMS (ESI+): m/z 850.3 (M+H⁺). Step 6: (9H-fluoren-9-yl)methyl ((7S,10S,13S,18aR,Z)-13-(2-bromo-5-chlorobenzyl)-10- isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro- 1H-pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)(methyl)carbamate (510): 10 [0326] PyBOP (1.1 g, 1.1 Eq, 2.2 mmo ) was d sso ved n DCM (100 mL) and DIPEA (0.77 g, 1.0 mL, 3 Eq, 6.0 mmol) was added. Separately, 509, (1.7 g, 1 Eq, 2.0 mmol) was dissolved in DCM (100 mL) and DIPEA (0.77 g, 1.0 mL, 3 Eq, 6.0 mmol) was added. DIPEA was added to the solution of linear peptide (in ~1 Eq portions) until the solution was basic by pH paper. The peptide solution was added into PyBOP solution dropwise by a 15 syringe pump at a rate of 1 mL per hour while stirring overnight. On the next day, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to yield 510 (1.25 g, 1.5 mmol, 73%). LCMS (ESI+): m/z 834.2 (M+H⁺). 135 PATENT Attorney Docket No.052687-508001WO Step 7: (7S,10S,13S,18aR,Z)-13-(2-bromo-5-chlorobenzyl)-10-isobutyl-12-methyl-7- (methylamino)-6,7,9,10,12,13,16,17,18,18a-decahydro-1H-pyrrolo[2,1- c][1]oxa[4,7,10]triazacyclohexadecine-8,11,14(3H)-trione (511): 5 [0327] O₃ (621 mg, 3 Eq, 4.50 mmol) was added as solid. The heterogenous mixture was stirred for 3 hours. The solid was filtered off and the filtrate was concentrated by rotary evaporation. The crude product was purified by RP chromatography (C18, 10 to 60% MeCN in water, 0.1% TFA) to yield 511 (569 mg, 0.93 mmol, 62%). LCMS (ESI+): m/z 612.0 (M+H⁺). 10 Step 8: tert-butyl ((S)-2-(((7S,10S,13S,18aR,Z)-13-(2-bromo-5-chlorobenzyl)-10- isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro- 1H-pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (512): O BocHN O Cl Br 15 [0328] 511 (569 mg, 1 Eq, 930 µmol), Int.62 (400 mg, 2 Eq, 1.86 mmol), and HATU (707 mg, 2 Eq, 1.86 mmol) were dissolved in DMF (4.0 mL). DIPEA (601 mg, 810 µL, 5 Eq, 4.65 mmol) was added and pH was confirmed to be basic by indicator paper. The reaction was stirred overnight. The solution was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine, dried over MgSO4, filtered, 20 and concentrated by rotary evaporation. The crude product was purified by RP 136 PATENT Attorney Docket No.052687-508001WO chromatography (C18, 40 to 100% MeCN in water, 0.1% TFA) to yield 512 (230 mg, 0.284 mmol, 30%). LCMS (ESI+): m/z 809.2 (M+H⁺). c. Method C Generic Procedure for Method C 5 Representative Experimental for Method C: Steps 1-4: 503: 137 PATENT Attorney Docket No.052687-508001WO [0329] Steps 1-4 for Method C, s described in Method A. It was used in the next reaction as the TFA salt. Step 5: tert-butyl ((S)-2-(((1S,2R)-1-(((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1- 5 yl)-3-(2-bromo-5-chlorophenyl)-1-oxopropan-2-yl)(methyl)amino)-4-methyl-1- oxopentan-2-yl)carbamoyl)-2-vinylcyclopropyl)(methyl)amino)-1-cyclopropyl-2- oxoethyl)carbamate (513): [03 30] To a solution of 503 (1.5 g, 1 eq, TFA) and Int.70 (0.98 g, 1.3 Eq, 2.9 mmol) in 10 DMF (20 mL) was added HATU (1.1 g, 1.3 Eq, 2.9 mmol) and DIPEA (0.86 g, 1.2 mL, 3 Eq, 6.7 mmol) at 0°C. Additional DIPEA was added as needed to adjust the reaction to ~8 pH. The reaction was stirred at ambient temperature until the complete consumption of starting material (monitored by LCMS). The reaction mixture was quenched by the addition of water (20 mL) at 0°C, then extracted with EtOAc (20 mL x 2). The combined organic layers were 15 washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (SiO₂, 0~100% EtOAc/Hexane) give 513 (1.7 g, 2.0 mmol, 88 %) as a yellow oil. LCMS (ESI+): m/z 848.8 (M+H⁺). Step 6: tert-butyl ((S)-2-(((1aS,4S,7S,12aR,17aR)-7-(2-bromo-5-chlorobenzyl)-4-isobutyl- 6-methyl-2,5,8-trioxo-3,4,5,6,7,8,11,12,12a,13,15,17a-dodecahydro-1H,10H- 138 PATENT Attorney Docket No.052687-508001WO cyclopropa[l]pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-1a(2H)- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (514): , , , Ar 5 for 20 min. Then, [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2- isopropoxyphenyl)methylene]ruthenium (22.1 mg, 0.1 Eq, 35.3 μmol) was added quickly and the degassing was continued for an additional 10 min. The reaction was then stirred at 70 °C until the consumption of starting material was observed (monitored by LCMS, ~16 hr). The resulting mixture was concentrated under reduced pressure and the resulting residue was 10 purified by RP flash chromatography (C18, 50-90% MeCN in water with 0.1% TFA).514 (0.13 g, 0.16 mmol, 45 %) as a brown solid after lyophilization. LCMS (ESI+): m/z 820.3 (M+H⁺). 2. Final Synthesis Procedures to prepare Compounds of Formula (I) a. Method 1 15 Generic Procedure for Method 1 Representative Procedure for Method 1: (Example 48): 139 PATENT Attorney Docket No.052687-508001WO tert-butyl ((S)-2-(((7S,10S,13S,18aR)-13-((5-chloro-2-cyclobutoxypyridin-3-yl)methyl)- 10-isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a- 5 tetradecahydro-1H-pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (515): [0332] This starting ma ter a or et o , compoun , was synthesized using method A with with Int.6, Int.35, and Int.61 as starting materials. LCMS (ESI+): m/z 801.3 10 (M+H⁺). Steps 1-2: (2S,4R)-N-((S)-2-(((7S,10S,13S,18aR)-13-((5-chloro-2-cyclobutoxypyridin-3- yl)methyl)-10-isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a- tetradecahydro-1H-pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- 15 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 48): 140 PATENT Attorney Docket No.052687-508001WO t for 1 hour. The solution was concentrated, resuspended in toluene, and concentrated (x 2). (S)-2-amino-N-((7S,10S,13S,18aR)-13-((5-chloro-2-cyclobutoxypyridin-3-yl)methyl)-10- 5 isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro-1H- pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)-2-cyclopropyl-N-methylacetamide (516) (~100 mg, 125 µmol) was carried on without further purification. LCMS (ESI+): m/z 701.4 (M+H⁺). [0334] 516 (100 mg, 1 Eq, 125 µmol) along with (2S,4R)-1-(3,3-difluoro-1- 10 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid (79.7 mg, 2 Eq, 250 µmol), and HATU (94.9 mg, 2 Eq, 250 µmol) in DMF (1 mL). DIPEA (223 mg, 300 µL, 13.8 Eq, 1.72 mmol) was added and the reaction was stirred for 20 hours. The reaction was neutralized with 1M HCl, diluted with 1.5 mL acetonitrile, and purified by reverse-phase chromatography (40 to 100% acetonitrile in water, 0.1% formic acid) to yield Example 48 15 (60mg, 62.5 mmol, 50%). LCMS (ESI+): m/z 1002.47 (M+H⁺). b. Method 2 141 PATENT Attorney Docket No.052687-508001WO Generic Procedure for Method 2 5 Representative Experimental for Method 2: Example 54 Tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7,15-trimethyl- 5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadec-14-en-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (517): 142 PATENT Attorney Docket No.052687-508001WO [0335] The macrocycle as synthesized using Method A with Int.21, Int.26, and Int.61. It was used as a mixture of E/Z isomers (~9:1). LCMS (ESI+): 798.31 m/z (M+H⁺). 5 Step 1: Tert-butyl ((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzyl)- 9-isobutyl-4,7,15-trimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadec-14-en-12- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (518): [ 0336] 517 (120 mg, 1.0 Eq, 151 μmo ), Na2CO3 (47.9 mg, 3 Eq, 452 μmo ), Int.27 (62.6 10 mg, 2.0 Eq, 301 μmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (12.3 mg, 0.1 Eq, 15.1 μmol) were dissolved in 4:1 Dioxane/Water (4 mL). The reaction was degassed for 10 min with Ar and then heated to 80 °C until the complete consumption of starting material. The vial was then cooled and adjusted to pH ~7 with 1 N HCl. The homogeneous solution was directly purified by RP-HPLC (C18, 50% to 85% MeCN/H2O with 0.5% formic acid) to obtain 518 (100 mg, 15 44.0 μmol, 83.2 %) as a white solid after lyophilization. LCMS (ESI+): m/z 798.53 (M+H⁺). Step 2-3: (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(1-methyl-1H-pyrazol-4- yl)benzyl)-9-isobutyl-4,7,15-trimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadec-14- en-12-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 20 54): 143 PATENT Attorney Docket No.052687-508001WO ed until the deprotection was complete (monitored by LCMS). The volatile solvent was completely removed, and the resulting oil was redissolved in PhMe (2 mL) and 5 reconcentrated to afford a quantitative yield of 519 as a brown oil. LCMS (ESI+): m/z 698.22 (M+H⁺). [0338] The deprotected amine 519 and Int.50 (43.9 mg, 1.1 Eq, 138 μmol) were dissolved in DMF (1 mL). DIPEA (96.9 mg, 40.0 μL, 6 Eq, 750 μmol) and HATU (52.3 mg, 1.1 Eq, 138 μmol) were added sequentially and the reaction was continued until the consumption of 10 starting material (monitored by LCMS). The reaction mixture was neutralized to pH ~7 with 1N HCl and directly purified by RP-HPLC (C18, 45% to 75% MeCN/H₂O with 0.5% formic acid). Example 54 (59.0 mg, 24.3 μmol, 47 %) was obtained as a white solid after lyophilization. LCMS (ESI+): m/z 999.49 (M+H⁺). c. Method 3 15 Generic Procedure for Method 3 144 PATENT Attorney Docket No.052687-508001WO Representative Procedure for Method 3: Example 46 (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(2-methylthiazol-5-yl)benzyl)-9-isobutyl- 5 4,7-dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (520): [0339] The macrocycle starting material for method 4 (520), was synthesized using Method 10 A with Int.11, Int.26, and Int.61 as starting materials. It was used as a mixture of E/Z isomers (~9:1). LCMS (ESI+): 782.28 m/z (M+H⁺). Step 1: tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7- dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (521): 145 PATENT Attorney Docket No.052687-508001WO ent temperature. platinum(IV) oxide (2.78 mg, 0.08 eq, 12.3 μmol) was added to the stirring reaction mixture. The reaction was then placed under an atmosphere of hydrogen and stirred 5 vigorously until LCMS analysis showed complete consumption of starting material. The reaction mixture was filtered over a pad of Celite. The Filter was washed with EtOAc (2 x 5 mL). The organic solvent was concentrated to afford 521 (110 mg, 140 mmol, 91.4 %) as an off white solid. The reaction was used without further purification. LCMS: m/z 784.4 (M+H⁺). 10 Step 2: tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7- dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (522): [ 0341] 521 (110 mg, 1.0 Eq, 144.0 μmol), Na2CO3 (44.5 mg, 3 Eq, 420 μmol), Int.34 15 (63.0 mg, 2.0 Eq, 280 μmol) and PdCl2(dppf) •CH2Cl2 adduct (11.4 mg, 0.1 Eq, 14.0 μmol) were dissolved in 4:1 Dioxane/Water (4 mL). The reaction was degassed for 10 min with Ar and then heated to 80 °C until the complete consumption of starting material. The vial was then cooled and adjusted to pH ~7 with 1 N HCl. The solution was directly purified by RP- HPLC (C18, 50% to 85% MeCN/H2O with 0.5% formic acid) to obtain 522 (85 mg, 111 20 μmol, 79 %) as a white solid after lyophilization. LCMS (ESI+): m/z 803.4 (M+H⁺). Step 3-4: (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(2-methylthiazol-5-yl)benzyl)-9- isobutyl-4,7-dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12- 146 PATENT Attorney Docket No.052687-508001WO yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 46): 5 until the deprotection was complete (monitored by LCMS). The volatile solvent was completely removed, and the resulting oil was redissolved in PhMe (2 mL) and reconcentrated to afford a quantitative yield of tert-butyl ((S)-2-(((6S,9S,12S)-6-(5-chloro-2- (2-methylthiazol-5-yl)benzyl)-9-isobutyl-4,7-dimethyl-5,8,11-trioxo-1-oxa-4,7,10- 10 triazacyclohexadecan-12-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (523): LCMS (ESI+): m/z 703.34 (M+H⁺). [0343] 523 and Int.50 (42.4 mg, 1.1 Eq, 133 μmol) were dissolved in DMF (1 mL). DIPEA (93.7 mg, 120.0 μL, 6 Eq, 725 μmol) and HATU (50.5 mg, 1.1 Eq, 133 μmol) were added sequentially and the reaction was continued until the consumption of starting material 15 (monitored by LCMS). The reaction mixture was neutralized to pH ~7 with 1N HCl and directly purified by RP-HPLC (C18, 45% to 75% MeCN/H₂O with 0.5% formic acid). Example 46 (80.0 mg, 80.0 μmol, 66 %) was obtained as a white solid after lyophilization. LCMS (ESI+): m/z 1004.42 (M+H⁺). d. Method 4 147 PATENT Attorney Docket No.052687-508001WO Generic Procedure for Method 4 5 Representative Experimental for Method 4: Example 77 tert-butyl tert-butyl ((S)-2-(((1S,4S,7S,16R)-7-((5-chloro-2-cyclopropoxypyridin-3- yl)methyl)-4-isobutyl-6,9-dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadec-14- en-1-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (524): 148 PATENT Attorney Docket No.052687-508001WO [0344] The starting ma synthesized using Method C With Int.39 and Int.70 as starting materials. LCMS (ESI+): m/z 771.3 (M+H⁺). Step 1: tert-butyl ((S)-2-(((1S,4S,7S,16S)-7-((5-chloro-2-cyclopropoxypyridin-3- 5 yl)methyl)-4-isobutyl-6,9-dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadecan-1- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (525): [ ] ( mg, q, . mmo ) was sso ve n t c ( m ) an and platinum(IV) oxide (4.3 mg, 0.15 Eq, 19 μmol) was added. The reaction was vigorously 10 stirred under an atmosphere of hydrogen until the complete consumption of starting material (monitored by LCMS). Upon completion, the reaction mixture was filtered over a pad of Celite. The filter was washed with EtOAc (2 x 10 mL). The filtrate was concentrated to afford 525 (98 mg, 0.13 mmol) as a brown solid. The material was used directly in the next reaction with no further purification. LCMS (ESI+): m/z 773.7 (M+H⁺). 15 Step 2-3: ((2S,4R)-N-((S)-2-(((1S,4S ,7S,16S)-7-((5-chloro-2-cyclopropoxypyridin-3- yl)methyl)-4-isobutyl-6,9-dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadecan-1- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 77): 149 PATENT Attorney Docket No.052687-508001WO reaction was stirred at ambient temperature until the complete consumption of starting material (monitored by LCMS). Upon completion, the reaction was concentrated, PhMe was 5 added (3 mL), and the reaction was concentrated again to drive off excess TFA. (S)-2-amino- N-((1S,4S,7S,16R)-7-((5-chloro-2-cyclopropoxypyridin-3-yl)methyl)-4-isobutyl-6,9- dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadecan-1-yl)-2-cyclopropyl-N- methylacetamide (526) (100 mg, TFA) was isolated as a brown oil and used directly in the next reaction. LCMS (ESI+): m/z 673.3 (M+H⁺). 10 [0347] 526 (100 mg, 1 Eq, TFA), Int 50 (56 mg, 1.2 Eq, 0.17 mmol) and HATU (72 mg, 1.3 Eq, 0.19 mmol) were dissolved in DMF (4 mL) and DIPEA (56 mg, 76 μL, 3 Eq, 0.44 mmol) was added. Additional DIPEA was added if the pH was above ~8. The reaction was continued until the consumption of starting material (monitored by LCMS). Upon completion, the pH was adjusted to ~7 by the addition of 1N HCl and the reaction was 15 directly purified by RP flash chromatography (MeCN in Water with 0.1% TFA, 20 to 80%). Example 77 (64 mg, 65 μmol, 45 %) was isolated as a fluffy white solid after lyophilization. LCMS (ESI+): m/z 974.50 (M+H⁺). e. Method 5 150 PATENT Attorney Docket No.052687-508001WO Generic Procedure for Method 5 5 Rep resentative Experimental for Method 5: Example 96 151 PATENT Attorney Docket No.052687-508001WO [0348] The starting macrocycle for Method 5, 527 was synthesized using Method A with Int.14, and Int.26 as starting materials. LCMS (ESI+): m/z 794.2 (M+H⁺). Step 1: tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-7-methyl- 5,8,11-trioxo-17-oxa-4,7,10-triazaspiro[2.15]octadecan-12-yl)(methyl)amino)-1- 5 cyclopropyl-2-oxoethyl)carbamate (528): , , added PtO₂ (14.3 mg, 0.1 Eq, 62.9 µmol). The reaction was vigorously stirred under an atmosphere of hydrogen until the complete consumption of starting material (monitored by 10 LCMS). Upon completion, the reaction mixture was filtered over a pad of Celite. The filter was washed with EtOAc (2 x 10 mL). The filtrate was concentrated to afford 528 as a brown solid. The material was used directly in the next reaction with no further purification. LCMS (ESI+): m/z 796.3 (M+H⁺). Steps 2-3: (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-7-15 methyl-5,8,11-trioxo-17-oxa-4,7,10-triazaspiro[2.15]octadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (528): [0350] 528 (380 mg, 1 Eq, 417 μmol) was dissolved in 30% TFA in DCM (25 mL). The 20 reaction was continued until the complete consumption of starting materials (monitored by 152 PATENT Attorney Docket No.052687-508001WO LCMS). Upon completion, the reaction was concentrated. PhMe (10 mL) was added and the reaction was concentrated again to drive off excess TFA. (S)-2-amino-N-((6S,9S,12S)-6-(2- bromo-5-chlorobenzyl)-9-isobutyl-7-methyl-5,8,11-trioxo-17-oxa-4,7,10- triazaspiro[2.15]octadecan-12-yl)-2-cyclopropyl-N-methylacetamide (529) was isolated as a 5 brown oil and used directly in the next reaction. LCMS (ESI+): m/z 696.3 (M+H⁺). [0351] 529 (380 mg, 1 Eq, 417 μmol) Int.50 (133 mg, 1 Eq, 417 μmol) and HATU (159 mg, 1 Eq, 417 μmol) were dissolved in DMF (4 mL) and DIPEA (269 mg, 363 μL, 5 Eq, 2.09 mmol) was added. Additional DIPEA was added if the pH was above ~8. The reaction was continued until the consumption of starting material (monitored by LCMS). Upon 10 completion, the pH was adjusted to ~7 by the addition of 1N HCl and the reaction was directly purified by RP flash chromatography (MeCN in Water with 0.1% TFA, 20 to 80%). 530 (253 mg, 253 μmol, 60.8 %) was isolated as a fluffy white solid after lyophilization. LCMS (ESI+): m/z 997.0 (M+H⁺). Step 4: (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-((4-chloro-4'-(4-methylpiperazin-1-yl)-[1,1'-15 biphenyl]-2-yl)methyl)-9-isobutyl-7-methyl-5,8,11-trioxo-17-oxa-4,7,10- triazaspiro[2.15]octadecan-12-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3- difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 96): 20 [0352] 530 (125 mg, 1 Eq, 125 μmol), Int.43 (37.8 mg, 1 Eq, 125 μmol), PdCl2(dppf)•CH2Cl2 (10.2 mg, 0.1 Eq, 12.5 μmol) were dissolved in dioxane (2 mL). Na2CO3 (26.5 mg, 125 μL, 2.0 molar, 2 Eq, 250 μmol) was added and the reaction was degassed with Ar for 5 min. The vial was then capped, and the reaction was heated to 80°C until the complete consumption of starting material (monitored by LCMS). Upon completion, the 25 reaction was adjusted to a neutral pH with the addition of formic acid (5% in MeCN), was diluted with MeOH (2 mL), filtered, and directly purified by RP-HPLC. Example 96 (9.8 153 PATENT Attorney Docket No.052687-508001WO mg, 9.0 μmol, 7.2 %) was isolated as a white solid after lyophilization. LCMS (ESI+): m/z 1094.03 (M+H⁺). f. Method 6 Generic Procedure for Method 6: 5 Representative Experimental for Method 6: Example 67 tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10-isobutyl-10 12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro-1H- pyrrolo[2,1-c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2- oxoethyl)carbamate (531): 154 PATENT Attorney Docket No.052687-508001WO [0353] The macrocycle und 531, was synthesized using Method A with Int.12, Int.25, and Int.61. LCMS (ESI+): 780.6 m/z (M+H⁺). Step 1: tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- 5 isobutyl-12-methyl-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)carbamate (532): [ ] mg, q, µmo was sso ve n c . m y s rr ng a am ent temperature.10% Pd/C (31 mg) was added to the stirring reaction mixture. The reaction was 10 then placed under an atmosphere of hydrogen and stirred vigorously until LCMS analysis showed complete consumption of starting material. The reaction mixture was filtered over a pad of Celite. The filter was washed with EtOAc (2 x 5 mL). The organic solvent was concentrated to afford 532 (75 mg, 96 µmol, 100%) as an off white solid. The reaction was used without further purification. LCMS: m/z 782.8 (M+H⁺) 15 Step 2: tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2,2-dioxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)carbamate (533): 155 PATENT Attorney Docket No.052687-508001WO [ O, 6.1 uL, 1.0 Eq, 64 μmol) was added and let to react at 25 °C until the complete consumption of starting material (LCMS). The homogeneous solution was directly purified by RP-HPLC 5 (C18, MeCN /H2O with 0.1%TFA) to obtain 533 (26 mg, 32.0 μmol, 50.0 %) as a white solid after lyophilization. LCMS (ESI+): m/z 798.4 (M+H⁺). Step 3: (2S,4R)-N-((1S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2-oxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)-1-(3,3-difluoro-1- 10 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 67): [ 0356] 533 (26 mg, 1 Eq, 32.0 μmol) was dissolved in 6 mL DCM/TFA (3:1) and stirred until the deprotection was complete (monitored by LCMS). The volatile solvent was 15 completely removed, and the resulting oil was redissolved in PhMe (2 mL) and reconcentrated to afford a quantitative yield of 534 as a brown oil. LCMS (ESI+): m/z 698.5 (M+H⁺). [0357] 534 and Int.50 (17.0 mg, 1.5 Eq, 55.0 μmol) were dissolved in DMF (0.5 mL). DIPEA (28.0 mg, 38.0 μL, 6 Eq, 0.22 mmol) and HATU (21.0 mg, 1.5 Eq, 55.0 μmol) were 20 added sequentially and the reaction was continued until the consumption of starting material (monitored by LCMS). The reaction mixture was neutralized to pH ~7 with 1N HCl and 156 PATENT Attorney Docket No.052687-508001WO directly purified by RP-HPLC (C18, 45% to 75% MeCN/H₂O with 0.5% formic acid). Example 67 (11.5 mg, 96.55%) was obtained as a white solid after lyophilization. LCMS (ESI+): m/z 999.44 (M+H⁺). g. Method 7 5 Generic Procedure for Method 7: p p Representative Experimental for Method 7: Example 56 10 Step 1: (532): 157 PATENT Attorney Docket No.052687-508001WO [0358] Step 1 for Metho in Method 6. Step 2: tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2,2-dioxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- 5 c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)carbamate (535): [ g, . q, μ o was sso ve e . O, 1 mL, 160.0 Eq) and (NH4)6Mo7O24·4 H2O (2.1 mg, 0.02 Eq, 1.8 μmol) were added and set to react at 25 °C overnight. The homogeneous solution was directly purified by RP-HPLC (C18, 10 MeCN/H2O with 0.1%TFA) to obtain 535 (73 mg, 89.0 μmol, quant.) as a white solid after lyophilization. LCMS (ESI+): m/z 814.4 (M+H⁺). Step 3: (2S,4R)-N-((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2,2-dioxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)-1-(3,3-difluoro-1- 15 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 56): 158 PATENT Attorney Docket No.052687-508001WO until the deprotection was complete (monitored by LCMS). The volatile solvent was completely removed, and the resulting oil was redissolved in PhMe (2 mL) and 5 reconcentrated to afford a quantitative yield of tert-butyl ((S)-1-cyclopropyl-2- (((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10-isobutyl-12-methyl-2,2-dioxido-8,11,14- trioxohexadecahydro-1H-pyrrolo[2,1-c][1]thia[4,7,10]triazacyclohexadecin-7- yl)(methyl)amino)-2-oxoethyl)carbamate (536) as a brown oil. LCMS (ESI+): m/z 714.2 (M+H⁺). 10 [0361] 536 (73 mg, 1 Eq, 90 μmol), Int.50 (43 mg, 1.5 Eq, 0.13 mmol), HATU (0.20 g, 6 Eq, 0.54 mmol) were dissolved in DMF (1 mL). DIPEA (15 mg, 20 μL, 1.3 Eq, 0.12 mmol) was then added and the reaction was continued until the consumption of starting material (monitored by LCMS). The reaction mixture was neutralized to pH ~7 with 1N HCl and directly purified by RP-HPLC (C18, 45% to 75% MeCN/H₂O with 0.5% formic acid). 15 Example 56 (1.17 mg, 1.15 μmol, 1.3 %) was recovered as a white solid after lyophilization. LCMS (ESI+): m/z 1015.40 (M+H⁺). 3. Exemplary Compounds – Preparation Summary Tables [0362] Table 2, below, provides information on the methods used to prepare the exemplified compounds in the current application. This table includes a column listing the 20 Example Number, Macrocyclic Synthesis procedure, and Final Synthesis procedure. Chemical structures for the exemplified compounds are shown in Table 4, while analytical data for these compounds are shown in Table 3. Table 2: Summary Table Procedures for Compound Preparation 159 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 160 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 161 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 162 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 163 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 164 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis [0363] Table 3, below, provides the expected (Exact Mass) and observed molecular weight for each exemplary compound listed in Table 2. Table 3: Analytical Data for Exemplary Compounds of Table 2 E^{x. Number} _{Exact Mass Observed m/z} 1 9103 91144 165 PATENT Attorney Docket No.052687-508001WO E^{x. Number} _{Exact Mass Observed m/z} 24 1024.44 1025.51 166 PATENT Attorney Docket No.052687-508001WO E^{x. Number} _{Exact Mass Observed m/z} 60 964.35 965.42 167 PATENT Attorney Docket No.052687-508001WO E^{x. Number} _{Exact Mass Observed m/z} 96 1092.5 1093.89 [0364] Table 4, below, provides the full chemical structure for each exemplified compound in Table 2. Table 4: Chemical Structure for Exemplary 5 Compounds Described in Table 2 Ex. Chemical Structure Ex. Chemical Structure No. No. Cl Cl 168 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 169 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 170 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 171 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 172 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 173 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 174 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. OH 175 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. C. Biological Examples 1. Fluorescence Polarization Assay [0365] Binding affinity for the compounds of Formula (I) were determined by 5 Fluorescence Polarization (FP) competitive assay based on previously established protocols (Andrews et. al., Org Biomol Chem., 2004.2(19):2735-41.; Premnath et. al., J Med Chem., 2015.58(1):433-42.) with modifications as described below. Cyclin/CDK protein complexes were sourced as follows: CyclinA2/CDK2 (CRELUX Protein Services), CyclinB1/CDK1 (Eurofins, discovery. Cat. No.14-450) and CyclinE1/CDK2 (Eurofins, discovery. Cat. No. 10 14-475). 176 PATENT Attorney Docket No.052687-508001WO [0366] FP binding assays were performed in 25 mM HEPES pH 7.5, 100 mM NaCl, 1mM DTT, 0.01% NP-40 and 1 mg/mL BSA for all 3 protein complexes in black 96-well plates. After experimental plates are set, they were equilibrated by gentle mixing by placing them on an orbital shaker at 100 rpm for 2 hours at rt and then read on a SpectraMax i3X Multi-Mode 5 Microplate Detection platform. [0367] Affinity of the Cyclin/Cdk complexed for the fluorescent labeled probe was determined by adding increasing concentration of each protein complex in buffer containing a carboxyfluorescein labeled probe (FAM probe) at 2 nM (preparation of FAM probe is described below). The half maximal concentration of protein needed for the maximal FP 10 signal were 2 nM for Cyclin A2/Cdk2, 9 nM for Cyclin B1/Cdk1 and 3 nM for Cyclin E1/Cdk2. Methods to prepare the FAM probe are described in the heading below. [0368] The protein concentration used for the competitive FP assays were 8 nM for Cyclin A2/Cdk2 and 10 nM for Cyclin B1/Cdk1 and Cyclin E1/Cdk2 with 2 nM of FAM probe FAM probe. Under these conditions, the dynamic range was about 120 mP 100% binding of 15 FAM probe and complete inhibition of binding by excess of an unlabeled competitor compound, with all experiment showing a Z’ factor > 0.80. IC50 for test compounds were determined in eight-point serial dilution dose response curves. Reported IC₅₀ are the average of 2-3 independent experiments. Data from these assays are reported in Table 5. Table 5: Cyclin A, B, and E Activity Data of Exemplary Compounds Cyclin A Cyclin B Cyclin E Example 177 PATENT Attorney Docket No.052687-508001WO Cyclin A Cyclin B Cyclin E Example FP IC50 FP IC50 FP IC50 Number 178 PATENT Attorney Docket No.052687-508001WO Cyclin A Cyclin B Cyclin E Example FP IC50 FP IC50 FP IC50 Number 179 PATENT Attorney Docket No.052687-508001WO Cyclin A Cyclin B Cyclin E Example FP IC50 FP IC50 FP IC50 Number Preparation of Fluorescent Probe (FAM Probe) 180 PATENT Attorney Docket No.052687-508001WO [0369] The fluorescent probe was synthesized via solid phase peptide synthesis followed by cyclization, fluorescent labeling, and deprotection in solution. [0370] To load Fmoc-Glycine onto ~50 mg of CTC resin, Fmoc-Glycine (G), CAS#29022- 11-5, (4 equiv.) was dissolved in 1.0 mL of anhydrous NMP. Neat DIEA (8 equiv.) was 5 added to the Fmoc-amino acid solution. The solution was dispensed in a peptide reactor vessel containing 50 mg of 2-chlorotrityl chloride (CTC) resin and was agitated for 2 hours at rt. The amino acid solution was drained then the resin was washed with 1.0 mL DMF three times. Unreacted CTC resin was capped with 1.0 mL solution of methanol:DMF (50:50), and DIEA (8 equiv.) for 10 min at rt. The methanol solution was drained then the resin was 10 washed with 1.0 mL DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 10 to 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. [0371] A solution of Fmoc-L-2,5-dichlorophenylalanine-OH (25ClF), CAS#1260614-80-9, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was 15 prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 10 to 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. 20 [0372] To N-Methylate the amine of 25ClF, 2,6-lutidine (6 equiv.) dissolved in 0.5 mL of anhydrous DCE was added to the resin.2-nitrobenzenesulfonyl chloride (5 equiv.) dissolved in 0.5 mL anhydrous toluene was added to the resin and then was agitated at 40 to 45°C for 10 to 15 min. The mixture was drained, then the resin was washed with 1.0 mL of anhydrous toluene three times. The method was repeated twice. Triphenylphosphine (10 equiv.) 25 dissolved in 0.7 mL anhydrous toluene was added to the resin. Dry methanol (MeOH), (20 equiv.) was added to the resin. Azodicarboxylate (10 equiv.) was added to the resin and the mixture was agitated at 45^C for 30 min. The mixture was drained and the resin was washed with 1.0 mL of anhydrous DMF three times. Alkylation was repeated twice. The nosyl group was then deprotected. A solution of2-mercaptoethanol (5 equiv.) and 1,8- 30 Diazabicyclo[5.4.0]undec-7-ene (5 equiv.) in 1.0 mL NMP was added to the resin and the mixture was agitated at 45^C for 10 min. The mixture was drained and then the resin was washed with 1.0 mL of anhydrous DMF three times. Deprotection was repeated twice. 181 PATENT Attorney Docket No.052687-508001WO [0373] Fmoc-L-Leucine-OH (L), CAS# 35661-60-0 (12 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To 5 remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. [0374] Fmoc-L-Lysine(Mtt)-OH (KMtt), CAS#167393-62-6, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to 10 pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. 15 [0375] Fmoc-L-Arginine(Pbf)-OH (RPbf), CAS#154445-77-9, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin 20 and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. [0376] Fmoc-L-Lysine(Boc)-OH (KBoc), CAS#71989-26-9, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. 25 The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. [0377] Fmoc-L-Alanine-OH (A), CAS#35661-39-3, (4 equiv.), HATU (4 equiv.), and 30 DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To 182 PATENT Attorney Docket No.052687-508001WO remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times. [0378] Fmoc-L-Histidine(Trt)-OH (HTrt), CAS#109425-51-6, (4 equiv.), HATU (4 5 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was 10 washed with 1.0 mL DMF three times. [0379] Fmoc-6-aminohexanoic acid (Ahx), CAS#88574-06-5, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained and then the resin was washed with 1.0 mL of DMF three times. 15 [0380] To cleave peptide from CTC resin and simultaneously deprotect the Mtt protecting group, approximately 2 mL of a solution of 24% HFIP, 2% TIPS, in DCM was added to the polystyrene resin in a solid phase reaction vessel. The contents were shaken for 1 hour. The cleavage solution was filtered into a 50 mL conical vial. The cleaved resin was washed with an additional 2 mL of DCM and the wash was collected in the conical vial. The solution was 20 evaporated in a Genevac. The linear peptide was purified via reverse-phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid and the purified fractions were pooled and lyophilized to yield white powder of intermediate X (M/z observed = 1968.65 [M+H]⁺). 183 PATENT Attorney Docket No.052687-508001WO [0381] The linear intermediate X (~15 mg) was cyclized using a medium volume, T3P solution cyclization method. The deprotected and purified linear product was transferred to a 50 mL conical vial and dissolved in 1 mL NMP followed by the addition of DIEA (0.5 mL) and DCM (35 mL). T3P (3 eqv) was added to the solution and the reaction pH was adjusted 5 to pH 9 via dropwise addition of DIEA. The closed conical vial was agitated at rt for 2 hours at 150 rotations per minute. The solution was concentrated at 45°C under reduced pressure in a Genevac system. The Fmoc group was then removed with the addition of a 10% of KOH/Water solution (5 mL) heated at 70°C for 30 min. The resulting LCMS trace revealed that the trityl group had been unexpectedly removed during the cyclization and Fmoc- 10 deprotection steps. The cyclic peptide was then purified via reverse phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid. The purified fractions were pooled and lyophilized to yield intermediate Y (M/z observed = 1485.94 [M+Z]⁺). 15 [0382] The probe was fluorescently labeled via a peptide coupling in solution. A solution of 5-carboxyfluorescein (CAS#76823-03-5, FAM) (4 equiv.), EDC (4 equiv.), HOAt (3.9 equiv.) and DIEA (8 equiv.) in 1.0 mL of anhydrous DCM was prepared. The mixture was allowed to pre-activate at rt for 5 min. Intermediate Y was added to the coupling solution, and the reaction was agitated at rt until starting material was not observed by LCMS, resulting in 20 the formation of Intermediate Z (M/z observed = 1844.29 [M+Z]⁺). 184 PATENT Attorney Docket No.052687-508001WO [0383] The Boc and Pbf protecting groups were removed from the cyclic intermediate Z by dissolving the cyclic peptide in a 1 mL solution of 90% TFA, 5% TIPS, 5% DCM and 5 agitating for 1 hour. The reaction was monitored by LCMS for the disappearance of starting material. Upon completion, the reaction was concentrated. The crude material was co- evaporated with DCE (5 mL x 2), and then purified via reverse phase-HPLC to yield fluorescent probe (FAM probe) (M/z observed = 1492.14 [M+Z]⁺ , 0.7 mg, 99% purity by HPLC). 10 2. MTT Proliferation Assay [0384] MTT proliferation assay was used to determine the 50% growth inhibition (GI50) of disclosed compounds.5 x 10³ cells were seeded into 96 well plates.24 hours later, cells were dosed with compound in an 8- or 10-point 1:3 serial dilution starting at 10^M. Cells were exposed to compound for a sufficient time to allow 3-4 cell doublings (3 days (WI-38); 5 15 days (NCI-H1048 and OVCAR3)). Roscovitine and staurosporine were used as plate controls. At the end of the compound incubation, MTT reagent (TACS MTT Cell Proliferation Assay R&D Systems Catalog #4890-025-K) was added and assay carried out. Results are summarized in Table 6 Table 6: Cellular Activity Data of Exemplary Compounds Example H1048 GI50 OVCAR3 WI-38 GI50 185 PATENT Attorney Docket No.052687-508001WO Example H1048 GI50 OVCAR3 WI-38 GI50 Number (µM) GI50 (µM) (µM) 186 PATENT Attorney Docket No.052687-508001WO Example H1048 GI50 OVCAR3 WI-38 GI50 Number (µM) GI50 (µM) (µM) 187 PATENT Attorney Docket No.052687-508001WO Example H1048 GI50 OVCAR3 WI-38 GI50 Number (µM) GI50 (µM) (µM) [0385] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will 188 PATENT Attorney Docket No.052687-508001WO appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the 5 instant application shall dominate. 189

Claims

PATENT Attorney Docket No.052687-508001WO WHAT IS CLAIMED IS: 1. A compound of Formula (I) R^6d L^6b _N ^O B (I) wherein 3 R is (a) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R^3a, (b) C3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R^3b, or (c) heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 R^3c; (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 R^3g; each R^3a is independently –OH, C1-6 alkoxy, C1-6 haloalkoxy, –O–(CH2CH2O)1-4–C1-4 alkyl, –O–(CH₂CH₂O)_1-4–heterocycloalkyl, C_1-3 haloalkoxy, –NR^3a1R^3a2, –O–C(O)C1-6 alkyl, C3-6 cycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3b is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, C1-6 haloalkyl, cyano, –OH, C_1-6 alkoxy, C_1-6 haloalkoxy, –NR^3b1R^3b2, –N(R^3b3)C(O)R^3b4, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each R^3c is independently C1-6 alkyl, halo, C1-6 haloalkyl, cyano, oxo, or C3-6 cycloalkyl; each R^3g is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, or C_3-6 cycloalkyl; each R^3a1, R^3a2, R^3b1, R^3b2, and R^3b3 is independently H or C1-6 alkyl; 190 PATENT Attorney Docket No.052687-508001WO each R^3b4 is C_1-6 alkyl or C_1-6 haloalkyl; R^4a is H or C1-6 alkyl; R^4b and R^4c are each independently H, C_1-6 alkyl, –C_1-6 alkyl–OH, C_1-6 haloalkyl, –NR^4c1R^4c2, C1-6 alkyl–NR^4c1R^4c2, C3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, or 4 R^4a1; each R^4c1 and R^4c2 are independently C_1-6 alkyl or C_2-6 alkoxyalkyl; each R^4a1 is independently C1-6 alkyl, –OH, –C1-6 alkyl–OH, C1-6 alkoxy, halo, or –N(R^4a2)S(O)₂–C_1-4 alkyl; R^4a2 is H or C1-6 alkyl; alternatively, two R^4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0, 1, or 2 R^4a3; each R^4a3 is independently C_1-6 alkyl, –OH, –C_1-6 alkyl–OH, C_1-6 alkoxy, or halo; R^5a is H or C_1-6 alkyl; R^5b and R^5c are each independently H, C_1-6 alkyl, –C_1-6 alkyl–OH, C_2-6 alkoxyalkyl, C_1-6 haloalkyl, –C_1-6 alkyl–NR^5b1R^5b2, –C_1-6 alkyl–C(O)NR^5b1R^5b2, –C_1-6 alkyl–N(R^5b1)C(O)R^5b3, –C_1-6 alkyl–C(O)OR^5b1, C_3-6 cycloalkyl, –C_1-6 alkyl–C_3-6 cycloalkyl, heterocycloalkyl, –C_1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^5b5; each R^5b1 and R^5b2 are independently H, C_1-6 alkyl, or C_1-6 haloalkyl; alternatively, R^5b1 and R^5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^5b5; 191 PATENT Attorney Docket No.052687-508001WO each R^5b3 is C_1-6 alkyl, C_1-6 haloalkyl, or a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, substituted with 0, 1, 2, or 3 R^5b4; each R^5b4 is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, –NH₂, –N(C_1-6 alkyl)₂, or –NH(C1-6 alkyl); each R^5b5 is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, –NH₂, –N(C_1-4alkyl)₂, or –NH(C1-4 alkyl); R^6a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, –C1-6 alkyl–C3-6 cycloalkyl, heterocycloalkyl, –C1-6 alkyl–heterocycloalkyl, phenyl, –C_1-6 alkyl–phenyl, heteroaryl, or –C_1-6 alkyl–heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; R^6b is H or C_1-6 alkyl; R^6d is H, C1-6 alkyl, C1-6 deuteroalkyl, –OH, or C2-6 alkoxyalkyl; L^6a is C_1-5 alkylene or C_2-5 alkenylene, wherein C_1-5 alkylene and C_2-5 alkenylene is substituted with 0, 1, 2, or 3 R^L6a; L^6b is C_1-5 alkylene or C_2-5 alkenylene, wherein C_1-5 alkylene and C_2-5 alkenylene is substituted with 0, 1, 2, or 3 R^L6b; Y⁶ is a bond, O, NH, S, S(O), or S(O)₂, wherein when Y⁶ is a bond, then i) L^6a and L^6b combine to form C_8-10 alkylene or C_8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b; or ii) L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C_3-6 cycloalkyl; each R^L6a and R^L6b is independently C_1-4 alkyl, –OH, or halo; alternatively, an R^L6a and R^6b on adjacent atoms combine to form a C_3-6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 R^6e; alternatively, an R^L6a and R^6a on non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e; alternatively, two R^L6b moieties on the same atom or on adjacent atoms combine to form a C_3-6 cycloalkyl or a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the cycloalkyl and heterocycloalkyl is substituted with 0, 1, or 2 R^6e; 192 PATENT Attorney Docket No.052687-508001WO alternatively, an R^L6b and R^6d on adjacent or non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6e; each R^6e is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; R^7a is H or C1-6 alkyl; R^7b and R^7c are each independently H, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 haloalkyl, C1-6 alkyl–OH, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R^8a is H, C_1-6 alkyl, C_1-6 deuteroalkyl, C_2-6 alkoxyalkyl, C_3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl; R^8b, R^8d, and R^8e are each independently H or C_1-6 alkyl; alternatively R^8b and R^8d together with the carbons to which each is attached combine to form a C_3-6 cycloalkyl; ring B is C6-12 aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; the subscript m8 is 0, 1, 2, 3, 4, or 5; each R^8f is independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C1-6 deuteroalkoxy, C2-6 alkoxyalkyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, –X^8f–cyano, –NR^8f1R^8f2, –C(O)NR^8f1R^8f2, –N(R^8f1)C(O)R^8f2, C_3-12 cycloalkyl, –X^8f–C_3-6 cycloalkyl, heterocycloalkyl, –X^8f–heterocycloalkyl, C_6-12 aryl, –X^8f–C _6-12 aryl, heteroaryl, or –X^8f–heteroaryl, wherein each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; alternatively, two R^8f groups on adjacent ring vertices combine to form a C_3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the cycloalkyl or heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3; each X^8f is independently C_1-6 alkylene, C_2-6 alkenylene, –O–C_1-6 alkylene, C(O), O, or S; each R^8f1 and R^8f2 are independently H or C1-6 alkyl; each R^8f3 is independently C_1-6 alkyl, –Y⁸–C_1-6 alkyl, C_1-6 deuteroalkyl, –Y⁸–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y⁸–C1-6 alkyl–OH, –C_1-6 alkyl–Y⁸–C_1-6 alkyl, –(C_1-2 alkyl–O)_1-4–C_1-2 alkyl, C_1-6 alkoxy, halo, 193 PATENT Attorney Docket No.052687-508001WO C_1-6 haloalkyl, –Y⁸–C_1-6 haloalkyl, cyano, –C_1-6 alkyl–cyano, –C_1-6 alkyl–NR^8gR^8h, oxo, C3-6 cycloalkyl, –X^8f3–C3-6 cycloalkyl, heterocycloalkyl, –X^8f3– heterocycloalkyl, phenyl, –X^8f3–phenyl, heteroaryl, or –X^8f3–heteroaryl, wherein each heterocycloalkyl has 3 to 12 members and 1 to 4 heteroatoms, each independently N, O, S, or S(O)2, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, and wherein each heterocycloalkyl and heteroaryl are substituted with 0, 1, or 2 C_1-4 alkyl or halo; alternatively, two R^8f3 groups on the same or adjacent ring vertices combine to form a C_3-6 cycloalkyl or a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein nitrogen atom ring members in the heterocycloalkyl are substituted with 0 or 1 C_1-4 alkyl; each X^8f3 is independently C1-6 alkylene, O, C(O), or S(O)2; each Y⁸ is independently C(O), C(O)O, N(R^8f4)C(O), O, S, or S(O)₂; each R^8g and R^8h is independently H, C1-6 alkyl, or C1-6 haloalkyl; each R^8f4 is independently H or C_1-6 alkyl; and ring A comprises 13 to 21 ring atoms; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R³ is (a) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or C_1-6 haloalkyl substituted with 0, 1, 2, 3, 4, or 5 R^3a. 3. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R³ is (a) C_1-6 alkyl or C_1-6 haloalkyl substituted with 0, 1, or 2 R^3a. 4. The compound of any one of claims 1 to 3, or the pharmaceutically acceptable salt thereof, wherein each R^3a is –OH. 5. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R³ is (b) C3-7 cycloalkyl substituted with 0, 1, 2, or 3 R^3b. 6. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R³ is (b) C3-4 cycloalkyl substituted with 0, 1, or 2 R^3b. 7. The compound of claim 5 or claim 6, or the pharmaceutically acceptable salt thereof, wherein each R^3b is halo or C_1-4 haloalkyl. 194 PATENT Attorney Docket No.052687-508001WO 8. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein R³ is (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 R^3c. 9. The compound of claim 8, or the pharmaceutically acceptable salt thereof, wherein each R^3c is halo or C_1-4 haloalkyl. 10. The compound of claim 8, or the pharmaceutically acceptable salt thereof, wherein each R^3c is fluoro or trifluoromethyl. 11. The compound of any one of claims 1 to 10, or the pharmaceutically acceptable salt thereof, wherein R³ is , 12. The compound of any one of claims 1 to 11, or the pharmaceutically acceptable salt thereof, wherein R^4a, R^4b, and R^4c are each independently H or C_1-6 alkyl; alternatively, R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^4a1; and each R^4a1 is independently halo. 13. The compound of any one of claims 1 to 11, or the pharmaceutically acceptable salt thereof, wherein R^4a, R^4b, and R^4c are each independently H or C_1-6 alkyl. 14. The compound of any one of claims 1 to 11, or the pharmaceutically acceptable salt thereof, wherein 195 PATENT Attorney Docket No.052687-508001WO R^4b is H or C_1-6 alkyl; and R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^4a1. 15. The compound of any one of claims 1 to 14, or the pharmaceutically acceptable salt thereof, wherein R^4b is H; and R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0, 1, or 2 fluoro. 16. The compound of any one of claims 1 to 15, or the pharmaceutically acceptable salt thereof, wherein R^5a is H or C1-6 alkyl; R^5b and R^5c are each independently H, C_1-6 alkyl, –C_1-6 alkyl–OH, C_2-6 alkoxyalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or C1-4 alkyl–C3-6 cycloalkyl, wherein each cycloalkyl is substituted with 0, 1, 2, or 3 R^5b5; and each R^5b5 is independently C1-4 alkyl, halo, or C1-4 haloalkyl. 17. The compound of any one of claims 1 to 16, or the pharmaceutically acceptable salt thereof, wherein R^5a is H or C_1-6 alkyl; R^5b is H; and R^5c is C_3-6 cycloalkyl or C_1-4 alkyl–C_3-6 cycloalkyl. 18. The compound of any one of claims 1 to 17, or the pharmaceutically acceptable salt thereof, wherein R^5a and R^5b are each H; and R^5c is methyl . 19. The compound of any one of claims 1 to 18, or the pharmaceutically acceptable salt thereof, wherein R^6a is H, C_1-4 alkyl, or –C_1-4 alkyl–C_3-6 cycloalkyl; and 196 PATENT Attorney Docket No.052687-508001WO R^6b and R^6d are each independently H or C_1-6 alkyl. 20. The compound of any one of claims 1 to 19, or the pharmaceutically acceptable salt thereof, wherein R^6a is H, methyl, n-propyl, or ; R^6b is H; and 6^d R is H or methyl. 21. The compound of any one of claims 1 to 20, or the pharmaceutically acceptable salt thereof, wherein L^6a is C1-5 alkylene substituted with 0, 1, 2, or 3 R^L6a; L^6b is C1-5 alkylene substituted with 0, 1, 2, or 3 R^L6b, Y⁶ is a bond, O, S, S(O), or S(O)2, wherein Y⁶ is a bond, then i) L^6a and L^6b combine to form C8-10 alkylene or C8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b; or ii) L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C3-6 cycloalkyl. 22. The compound of any one of claims 1 to 20, or the pharmaceutically acceptable salt thereof, wherein L^6a is C_2-5 alkenylene substituted with 0, 1, 2, or 3 R^L6a; L^6b is C1-5 alkylene substituted with 0, 1, 2, or 3 R^L6b; Y⁶ is a bond, O, NH, S, S(O), or S(O)₂, wherein Y⁶ is a bond, then i) L^6a and L^6b combine to form C8-10 alkylene or C8-10 alkenylene substituted with 0, 1, 2, or 3 R^L6a and 0, 1, 2, or 3 R^L6b; or ii) L^6a is substituted with at least one R^L6a, and an R^L6a and R^6b on adjacent carbon atoms combine to form a C3-6 cycloalkyl. 23. The compound of any one of claims 1 to 22, or the pharmaceutically acceptable salt thereof, wherein the moiet is 197 PATENT Attorney Docket No.052687-508001WO 24. The compound of any one of claims 1 to 23, or the pharmaceutically acceptable salt thereof, wherein the moiet is 198 PATENT Attorney Docket No.052687-508001WO . 25. T , or the pharmaceutically acceptable salt thereof, wherein the moiet is , , 26. The compound of any one of claims 1 to 23, or the pharmaceutically acceptable salt thereof, wherein the moiet is 199 PATENT Attorney Docket No.052687-508001WO . 27 pharmaceutically acceptable salt thereof, wherein the moiet is . 28. The compound of any one of claims 1 to 27, or the pharmaceutically acceptable salt thereof, wherein R^7a and R^7b are each independently H or C1-6 alkyl; and R^7c is C1-6 alkyl. 29. The compound of any one of claims 1 to 27, or the pharmaceutically acceptable salt thereof, wherein R^7a and R^7b are each H; and R^7c is C_1-6 alkyl. 30. The compound of any one of claims 1 to 29, or the pharmaceutically acceptable salt thereof, wherein R^7a and R^7b are each H; and R^7c is isobutyl. 31. The compound of any one of claims 1 to 30, or the pharmaceutically acceptable salt thereof, wherein R^8a, R^8b, R^8d, and R^8e are each independently H or C_1-6 alkyl. 200 PATENT Attorney Docket No.052687-508001WO 32. The compound of any one of claims 1 to 30, or the pharmaceutically acceptable salt thereof, wherein R^8a is methyl; and R^8b, R^8d and R^8e are each H. 33. The compound of any one of claims 1 to 32, or the pharmaceutically acceptable salt thereof, wherein ring B is phenyl. 34. The compound of any one of claims 1 to 32, or the pharmaceutically acceptable salt thereof, wherein ring B is biphenyl. 35. The compound of any one of claims 1 to 32, or the pharmaceutically acceptable salt thereof, wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N. 36. The compound of any one of claims 1 to 32, or the pharmaceutically acceptable salt thereof, wherein ring B is pyridyl. 37. The compound of any one of claims 1 to 36, or the pharmaceutically acceptable salt thereof, wherein the subscript m8 is 1, 2, or 3. 38. The compound of any one of claims 1 to 36, or the pharmaceutically acceptable salt thereof, wherein the subscript m8 is 2. 39. The compound of any one of claims 1 to 38, or the pharmaceutically acceptable salt thereof, wherein at least one R^8f is halo. 40. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkoxy, C_1-6 deuteroalkoxy, halo, C1-6 haloalkyl, cyano, or –X^8f–cyano. 41. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently halo, C3-6 cycloalkyl, –X^8f–C3-6 cycloalkyl, –CH=CR^8f5R^8f6, heterocycloalkyl, –X^8f–heterocycloalkyl, phenyl, –X^8f–phenyl, heteroaryl, or – X^8f–heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 201 PATENT Attorney Docket No.052687-508001WO to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; each X^8f is independently C_1-6 alkylene, C_2-6 alkenylene, O, or S; and each R^8f5 and R^8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. 42. The compound of any one of claims 1 to 41, or the pharmaceutically acceptable salt thereof, wherein each X^8f is independently C_1-6 alkylene. 43. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently halo, C_3-6 cycloalkyl, –CH=CR^8f5R^8f6, heterocycloalkyl, phenyl, or heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3; each R^8f5 and R^8f6 are combined with the carbon to which they are attached to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently N, O or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R^8f3. 44. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 deuteroalkoxy, halo, C1-4 haloalkyl, cyano, or –C1-2 alkyl–cyano. 45. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently halo, C3-6 cycloalkyl, –O–C3-6 cycloalkyl, heterocycloalkyl, –C_2-4 alkenyl–heterocycloalkyl, –O–heterocycloalkyl, phenyl, –O–phenyl, 202 PATENT Attorney Docket No.052687-508001WO heteroaryl, or –O–heteroaryl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3. 46. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently halo, C3-6 cycloalkyl, –O–C3-6 cycloalkyl, heteroaryl, or –O–heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 R^8f3. 47. The compound of any one of claims 1 to 39, or the pharmaceutically acceptable salt thereof, wherein each R^8f is independently halo, heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, wherein each heterocycloalkyl and phenyl is substituted with 0, 1, 2, or 3 R^8f3. 48. The compound of any one of claims 1 to 47, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C_1-6 alkyl, –Y⁸–C_1-6 alkyl, C_1-6 deuteroalky, –Y⁸–C1-6 deuteroalkyl, –OH, –C1-6 alkyl–OH, –Y⁸–C1-6 alkyl–OH, –C_1-6 alkyl–Y⁸–C_1-6 alkyl, halo, C_1-6 haloalkyl, –Y⁸–C_1-6 haloalkyl, or oxo; each Y⁸ is independently C(O), C(O)O, N(R^8f4)C(O), O, S, or S(O)2; and each R^8f4 is independently H or C_1-6 alkyl. 49. The compound of any one of claims 1 to 47, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C1-6 alkyl, C1-6 deuteroalky, –OH, –C_1-6 alkyl–OH, halo, C_1-6 haloalkyl, or oxo. 50. The compound of any one of claims 1 to 47, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C1-6 alkyl or –Y⁸–C1-6 alkyl. 203 PATENT Attorney Docket No.052687-508001WO 51. The compound of any one of claims 1 to 50, or the pharmaceutically acceptable salt thereof, wherein each Y⁸ is independently a C(O) or C(O)O. 52. The compound of any one of claims 1 to 47, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C_3-6 cycloalkyl, –X^8f3–C_3-6 cycloalkyl, heterocycloalkyl, or –X^8f3–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)₂; and each X^8f3 is independently C1-6 alkylene, C(O), or S(O)2. 53. The compound of any one of claims 1 to 52, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or S(O)2. 54. The compound of any one of claims 1 to 52, or the pharmaceutically acceptable salt thereof, wherein each X^8f3 is independently C1-6 alkylene. 55. The compound of any one of claims 1 to 54, or the pharmaceutically acceptable salt thereof, wherein two R^8f3 groups on adjacent ring vertices combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O or S. 56. The compound of any one of claims 1 to 47, or the pharmaceutically acceptable salt thereof, wherein each R^8f3 is independently C1-4 alkyl, C1-4 alkoxy, C2-6 alkoxyalkyl, –S(O)2–C1-4 alkyl, –C_1-4 alkyl–S(O)₂–C_1-4 alkyl, halo, C_1-4 haloalkyl, oxo, –C(O)–C_1-4 alkyl, or –C(O)O–C1-4 alkyl. 57. The compound of any one of claims 1 to 56, or the pharmaceutically acceptable salt thereof, wherein m8 is 2; and 204 PATENT Attorney Docket No.052687-508001WO each R^8f is independently fluoro, chloro, bromo, , , 58. e compoun o cam , or te p armaceutca y accepta e salt thereof, wherein R³ is , R^4b is R^4c and R^4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0, 1, or 2 fluoro; R^5a is H; R^5b is H; R^5c is methyl ; 205 PATENT Attorney Docket No.052687-508001WO R^6a is H, methyl, n-propyl, or ; R^6b is H; R^6d is H or methyl; , , , 206 PATENT Attorney Docket No.052687-508001WO O , alternatively, the moiety is ; alternatively, the moiety is , 207 PATENT Attorney Docket No.052687-508001WO , alternatively, the moiet is ; 208 PATENT Attorney Docket No.052687-508001WO R^7a is H; R^7b is H; R^7c is isobutyl; R^8a is methyl; R^8b, R^8d and R^8e are each H; ring B is phenyl, biphenyl, or pyridyl; m8 is 2; and each R^8f is independently fluoro, chloro, bromo, , , 59. The compound of claim 1, or the pharmaceutically acceptable salt thereof, having the structure of any one of Examples 1-103. 60. A pharmaceutical composition comprising a compound of any one of claims 1 to 58 and a pharmaceutically acceptable excipient. 61. A method of treating a cancer mediated at least in part by cyclin A comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60, thereby treating the disorder or condition. 209 PATENT Attorney Docket No.052687-508001WO 62. A compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60 for use in a method for treating a cancer mediated at least in part by cyclin A. 63. Use of a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60 for the manufacture of a medicament for the treatment of a cancer mediated at least in part by cyclin A. 210