cyclin inhibitors

Abstract

Disclosed herein are compounds of formula (I) and methods for their preparation. Also disclosed are the use of such compounds, compositions, and intermediates useful in the preparation of these compounds for the treatment of diseases and disorders mediated, at least in part, by one or more cyclins, including cancer. JPEG2025535351000507.jpg55134

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 380,562, filed October 21, 2022, the entire contents of which are incorporated herein for all purposes. [Background technology]

[0002] background Cyclins are a family of proteins that play a central role in regulating the cell cycle. Specific cyclins, such as cyclins D, E, A, and B, are expressed during various stages of the cell cycle, during which they bind and activate corresponding cyclin-dependent kinases (CDKs) (e.g., CDK1, CDK2, CDK4, and CDK6) to form cyclin-CDK complexes. These complexes coordinate progression and transition through various stages of the cell cycle. Disruption of the normal regulatory function of cyclin-CDK complexes is a common cause of tumorigenesis and rapid proliferation of cancer cells. Due to the central role cyclins and CDKs play in the cell cycle, these proteins and their complexes have become attractive targets for the treatment of proliferative diseases and cancer. To date, most inhibitors of cyclin-CDK complexes target the kinase activity of CDKs ("CDK inhibitors") and include therapeutic agents currently in development and approved for clinical use. Alternative approaches involve inhibiting the binding of cyclins to CDKs or the interaction of specific cyclin-CDK complexes with their substrates or regulators.

[0003] Although CDK inhibitors have been developed and have demonstrated efficacy in certain cancers, they are currently limited by relatively low selectivity, a narrow therapeutic window, and ultimately the development of resistance. Therefore, there is a need for the development of drugs that offer an alternative approach to inhibiting the function of cyclin-CDK complexes as a means of regulating the cell cycle. Such drugs could represent a new tool in the treatment of proliferative diseases. The present disclosure addresses this need by providing compounds that inhibit substrate binding to various cyclins, thereby inhibiting the function of cyclin-CDK complexes. Summary of the Invention

[0004] Abstract In one embodiment, the present invention provides a compound of formula (I): [ka] (In the above formula, R 3 teeth (a)C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 haloalkyl, where each R is 0 to 5 3a has been replaced by (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH2CH2O) 1-4 -C 1-4 Alkyl, -O-(CH2CH2O) 1-4 -heterocycloalkyl, C 1-3 Haloalkoxy, -NR 3a1 R 3a2 , -OC(O)C 1-4Alkyl, 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 independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR 3b1 R 3b2 , -N(R 3b3 )C(O)R 3b4 phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3c independently, C 1-4 Alkyl, C 1-4 Haloalkyl, oxo or C 3-6 is cycloalkyl, Each R 3a1 , R 3a2 , R 3b1 , R 3b2 and R 3b3 are independently H or C 1-4 is alkyl, Each R 3b4 is C 1-4 Alkyl or C 1-4 is haloalkyl, R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, -NR 4c1 R 4c2 ,-C 1-4 Alkyl-NR 4c1 R 4c2 , C 3-6Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-4 Alkyl-heterocycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where 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; Alternatively, R 4c and R 4a each combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, said heterocycloalkyl containing 0 to 2 R 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 Alkyl or C 2-6 is an alkoxyalkyl; Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 Alkoxy, halo or -N(R 4a2 )S(O)2-C 1-4 is alkyl, R 4a2 is H or C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 alkoxy or halo; R 5a is H or C 1-4 is alkyl, R 5b and R5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, -C 1-4 Alkyl-NR 5b1 R 5b2 , -C 1-3 Alkyl-C(O)NR 5b1 R 5b2 , C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heteroaryl has 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S, and each cycloalkyl and heteroaryl has 0-3 R 5b5 is replaced by Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl or -C(O)C 1-4 is haloalkyl, Alternatively, R on the same carbon atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and the heterocycloalkyl is selected from 0 to 3 R 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and 0 to 3 R 5b5 is replaced by Each R 5b5 independently, C 1-4Alkyl, Halo, C 1-4 Haloalkyl, -NH2, -N(C 1-4 alkyl)2 or NH(C 1-4 alkyl), X 6 is C 2-5 is alkylene, R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl or C 1-4 alkyl-heterocycloalkyl, wherein the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; R 6b is H or C 1-6 having an alkyl group; R 6d is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, -OH or C 2-6 is an alkoxyalkyl; R 7a is H or C 1-4 is alkyl, R 7b and R 7c are each independently H, C 1-8 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H or C 1-4is alkyl, Alternatively, R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 forming a cycloalkyl, Ring B is phenyl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently being N, O, or S; The subscript m8 is an integer between 0 and 5, Each R 8f independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 , -C(O)NR 8f1 R 8f2 ,-N(R 8f1 )C(O)R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are independently H or C 1-4 is alkyl, Each R 8f3 independently, C 1-4Alkyl, -OH, C 1-4 Alkoxy, -SH, -SC 1-4 Alkyl, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S; X 9 is R 9b and R 9c C is replaced by 1-3 is alkylene, R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heteroaryl has 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S, and each cycloalkyl and heteroaryl independently has 0-3 R 9c1 is replaced by Alternatively, R 9b and R 9c Each is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9aeach taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 9c2 is replaced by Each R 9c1 and R 9c2 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl or C 1-4 is haloalkoxy, and Ring A contains 15 to 17 ring atoms or a pharmaceutically acceptable salt thereof.

[0005] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0006] In another embodiment, the present invention provides a method for treating a 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 invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, thereby treating the disorder or condition.

[0007] In another embodiment, the present invention provides a method for treating 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 invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, thereby treating the cancer.

[0008] In another embodiment, the present invention provides intermediates useful in the preparation of compounds of formula (I).

[0009] Other objects, features, and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description and drawings. [Brief explanation of the drawings]

[0010] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figures 1A and 1B show Western blots of H1048 cell lysates after treatment with Example 458 compared to its enantiomer, Example 680, demonstrating that only the active example displaces two substrates, E2F1 (1A) and CDC6 (1B), from their complexes with cyclin A2.

[0011] [Figure 2] Figures 2A and 2B show that intravenous administration of an exemplary compound in the present application (Example 456) causes tumor regression (tumor volume plot, 2A) in an in vivo SCLC model at tolerated dose levels (body weight change plot, 2B). DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description overview Provided herein are compounds and compositions that inhibit the typical cellular functions of cyclins. The invention also provides methods for treating or preventing, for example, diseases, disorders, or conditions mediated by cyclin activity, or symptoms thereof.

[0013] Cyclin-cyclin-dependent kinase (CDK) complexes phosphorylate a wide range of substrates, thereby regulating their activity. Many of these substrates are important for the cell cycle, and the cyclins and CDKs that regulate these substrates, including cyclins D, A, E, and B and CDKs 1, 2, 4, and 6, play important roles in cell cycle regulation. Without being bound by theory, certain substrates, such as 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. 1996. 16(12):6223-33), and then bind to a region of the cyclin called the RxL-binding domain or "hydrophobic patch" (Brown et al., Nat Cell Biol. 1999. 1(7):438-43). This region contains a highly conserved MRAIL motif. Compounds that inhibit the binding of substrates to cyclins have been proposed to have potential therapeutic utility, including inhibiting the growth of cancer cells (Chen et al., Proc Natl Acad Sci USA. 1999. 96(8):4325-9).

[0014] Without being bound by any particular theory, the compounds of the present disclosure are believed to inhibit substrate binding 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 potently to one or more cyclins.

[0015] definition As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, "about" refers to a range of up to ±10% of the specified value. In some embodiments, "about" refers to the specified value.

[0016] "Alkyl" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms.1-2 , 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 C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0017] "Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having the indicated number of carbon atoms and having at least two other groups attached thereto. The two moieties attached to the alkylene may be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is (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. The alkylene group can be substituted or unsubstituted.

[0018] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl includes, but is not limited to, C, C 2-3 , C 2-4 , C2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 and C6. Alkenyl groups can have any suitable number of double bonds, including, but not 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.

[0019] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl includes C, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6Alkynyl groups can contain any number of carbons, such as C, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C91, C91, C92, C93, C94, C95, C96, C97, C98, C99, C9

[0020] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. Like alkyl groups, alkoxy groups can be C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as , ...

[0021] "Alkoxyalkyl" refers to an alkyl group connected to an oxygen atom which is further connected to a second alkyl group, the second alkyl group being the point of attachment to the rest of the molecule: alkyl-O-alkyl. The alkyl portion is C 2-6 The alkoxy group can have any suitable number of carbon atoms, such as, for example, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. The alkoxy group can be substituted or unsubstituted.

[0022] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0023] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. Similar to alkyl groups, haloalkyl groups include C 1-6The alkyl group may have any suitable number of carbon atoms, such as 1,1,1-trifluoromethyl. For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some embodiments, the term "perfluoro" can be used to define a compound or group in which all hydrogen atoms have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0024] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms have been replaced with halogen atoms. Similar to alkyl groups, haloalkoxy groups can be C 1-6 The alkoxy group can have any suitable number of carbon atoms, such as . The alkoxy group can be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0025] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, spirocyclic, fused or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12Cycloalkyl groups can contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 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]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4-, and 1,5-isomers), norbornenyl, and norbornadienyl. When cycloalkyl is C 3-6 When cycloalkyl is monocyclic, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers). 5-10 When fused bicyclic cycloalkyl, exemplary groups include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[4.2.0]octanyl, and octahydro-1H-indenyl. 5-10 When the cycloalkyl is a 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. 5-10 When 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. The cycloalkyl group can be substituted or unsubstituted.

[0026] "Heterocycloalkyl" refers to a saturated or partially unsaturated, monocyclic, spirocyclic, fused, or bridged polycyclic ring assembly having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms can be oxidized, such as, but not limited to, -S(O)- and -S(O)-. A heterocycloalkyl group can contain any number of ring atoms, for example, 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. A heterocycloalkyl group can contain 1, 2, 3, or 4, or any suitable number of heteroatoms, such as 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, 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, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can be unsubstituted or substituted.

[0027] The heterocycloalkyl group can be attached 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-, 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.

[0028] When heterocycloalkyl is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, representative elements include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyl can be a monocyclic heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms, representative elements include, but are 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 and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms and 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 bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with methylene linking groups. Some aryl groups, such as phenyl, naphthyl, and biphenyl, have 6 to 12 ring members. Other aryl groups, such as phenyl or naphthyl, have 6 to 10 ring members. Some other aryl groups, such as phenyl, have 6 ring members. 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 1 to 6 of the ring atoms are heteroatoms such as N, O, or S. The heteroatoms may be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. A heteroaryl group can contain any number of ring atoms, for example, 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12, or 9 to 12 ring members. A heteroaryl group can contain 1, 2, 3, 4, 5, or 6 heteroatoms, or any suitable number of heteroatoms, such as 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 can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups 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, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused with aromatic ring systems, such as phenyl rings, to form elements such as, 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 heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0031] The heteroaryl group can be bonded through 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 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, and thiazole includes 2-, 4-, and 5-thiazoles are included; isothiazoles include 3-, 4-, and 5-isothiazoles; oxazoles include 2-, 4-, and 5-oxazoles; isoxazoles include 3-, 4-, and 5-isoxazoles; indoles include 1-, 2-, and 3-indole; isoindoles include 1- and 2-isoindole; quinolines include 2-, 3-, and 4-quinolines; isoquinolines include 1-, 3-, and 4-isoquinolines; quinazolines include 2- and 4-quinoazolines; cinnolines include 3- and 4-cinnolines; benzothiophenes include 2- and 3-benzothiophenes; and benzofurans include 2- and 3-benzofurans.

[0032] Some heteroaryl groups include groups having 5 to 10 ring members and 1 to 3 ring atoms, including N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, 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 groups having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, 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 groups having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include groups having 5 to 6 ring members and 1 to 2 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0033] "Oxo" refers to an oxygen atom attached to the point of attachment by a double bond (=O).

[0034] A "pharmaceutically acceptable excipient" refers to a substance that aids in the 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, coating agents, sweeteners, flavoring agents, coloring agents, etc. One of ordinary skill in the art will appreciate that other pharmaceutical excipients are also useful in the present disclosure.

[0035] "Subject" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In some embodiments, the subject is a human.

[0036] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intraspinal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0037] A "therapeutically effective amount" refers to a dosage that produces a therapeutic effect when administered. The exact dosage will vary depending on the therapeutic purpose and can be ascertained by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0038] "Treat," "treating," and "treatment" refer to any indication of success in treating or ameliorating an injury, condition, state, or symptom (e.g., pain), including objective or subjective parameters such as relief, remission, symptomatic relief, or making the symptom, injury, condition, or state more tolerable to the patient, or a reduction in the frequency or duration of the symptom or condition. Treatment or amelioration of symptoms can be based on objective or subjective parameters, such as the results of a physical examination.

[0039] III.Compound In some embodiments, the present invention provides a compound of formula (I): [ka] (In the above formula, R 3 teeth, (a) Each of 0 to 5 R 3a C is replaced by 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 haloalkyl, (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH2CH2O) 1-4 -C 1-4 Alkyl, -O-(CH2CH2O) 1-4 -heterocycloalkyl, C 1-3 Haloalkoxy, -NR 3a1 R 3a2 ,-OC(O)C 1-4 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 independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR 3b1 R 3b2 , -N(R 3b3 )C(O)R 3b4phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3c independently, C 1-4 Alkyl, C 1-4 Haloalkyl, oxo or C 3-6 is cycloalkyl, Each R 3a1 , R 3a2 , R 3b1 , R 3b2 and R 3b3 are independently H or C 1-4 is alkyl, Each R 3b4 is C 1-4 Alkyl or C 1-4 is haloalkyl, R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, -NR 4c1 R 4c2 ,-C 1-4 Alkyl-NR 4c1 R 4c2 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-4 Alkyl-heterocycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where 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; Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 Alkyl or C 2-6 is an alkoxyalkyl; Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 Alkoxy, halo, or -N(R 4a2 )S(O)2-C 1-4 is alkyl, R 4a2 is H or C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 alkoxy or halo; R 5a is H or C 1-4 is alkyl, R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, -C 1-4 Alkyl-NR 5b1 R 5b2 , -C 1-3 Alkyl-C(O)NR 5b1 R 5b2 , C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4alkyl-heteroaryl, where each heteroaryl has 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and each cycloalkyl and heteroaryl has 0-3 R 5b5 is replaced by Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl or -C(O)C 1-4 is haloalkyl, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and the heterocycloalkyl is 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and 0-3 R 5b5 is replaced by Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl, -NH2, -N(C 1-4 alkyl)2 or NH(C 1-4 alkyl), X 6 is C 2-5 is alkylene, R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl or C 1-4alkyl-heterocycloalkyl, wherein the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; R 6b is H or C 1-6 is alkyl, R 6d is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, -OH or C 2-6 is an alkoxyalkyl; R 7a is H or C 1-4 is alkyl, R 7b and R 7c are each independently H, C 1-8 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H or C 1-4 is alkyl, Alternatively, R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 forming a cycloalkyl, Ring B is phenyl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently being N, O, or S; The subscript m8 is an integer between 0 and 5, Each R 8f independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 , -C(O)NR 8f1 R 8f2 ,-N(R 8f1 )C(O)R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-phenyl, or heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are independently H or C 1-4 is alkyl, Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, -SH, -SC 1-4 Alkyl, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 cycloalkyl or heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S; X 9 is R 9b and R 9c C is replaced by1-3 is alkylene, R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heteroaryl has 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S, and each cycloalkyl and heteroaryl independently has 0-3 R 9c1 is replaced by Alternatively, R 9b and R 9c Each is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 9c2 is replaced by Each R 9c1 and R 9c2 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl or C 1-4 is haloalkoxy, and wherein ring A contains 15 to 17 ring atoms), or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein ring A contains 13 to 19 ring atoms. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein ring A contains 15 to 17 ring atoms. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein ring A contains 15 ring atoms. In some embodiments, ring A contains 16 ring atoms. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein ring A contains 17 ring atoms.

[0041] residue 3 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 3 teeth, (a) Each of 0 to 5 R 3a C is replaced by 1-6 Alkyl, C 2-6 Alkynyl or C 1-6 haloalkyl, (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH2CH2O) 1-3 -C 1-4 Alkyl, -O-(CH2CH2O) 1-2 -heterocycloalkyl, C 1-3 Haloalkoxy, -NR 3a1 R 3a2 , -OC(O)C 1-4 Alkyl, C 3-6cycloalkyl, phenyl, or heteroaryl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -N(R 3b3 )C(O)R 3b4 phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3c independently, C 1-4 Alkyl, C 1-4 Haloalkyl, oxo or C 3-6 is cycloalkyl, Each R 3a1 , R 3a2 and R 3b3 are independently H or C 1-4 is alkyl, and Each R 3b4 is C 1-4 It is alkyl.

[0042] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 3 teeth, (a) Each of 0 to 5 R 3a C is replaced by 1-6 Alkyl, C 2-6 Alkynyl or C 1-6 haloalkyl, (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3chas been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH2CH2O) 1-3 -C 1-4 Alkyl, -O-(CH2CH2O) 1-2 -heterocycloalkyl, C 1-3 Haloalkoxy, -NH2, -OC(O)C 1-4 Alkyl, C 3-6 cycloalkyl or phenyl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, or -NHC(O)C 1-4 is alkyl, and Each R 3c independently, C 1-4 Alkyl, C 1-4 It is haloalkyl or oxo.

[0043] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 (a)C 1-6 Alkyl, C 2-6 Alkynyl or C 1-6 haloalkyl, each of which is 0 to 5 R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3a C substituted with a group 1-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R3a C substituted with a group 2-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3a C substituted with a group 1-6 haloalkyl. R 3 These embodiments of R 3a can be combined with any of the embodiments described herein.

[0044] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 There are 0 R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is one R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is two R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is three R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 4 R 3a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R3 is 5 R 3a It is substituted with an R group. 3 These embodiments of R 3a can be combined with any of the embodiments described herein.

[0045] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3a are independently -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NH2, -OC(O)C 1-4 Alkyl, C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3a are independently -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NH2, -OC(O)C 1-4 Alkyl or C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3a are independently -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NH2 or -OC(O)C 1-4 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3a are independently -OH, C 1-3 Alkoxy or C 1-3 haloalkoxy. 3a These embodiments of R 3 can be combined with any of the embodiments described herein.

[0046] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3a At least one of the is -O-(CH2CH2O) 1-2 -heterocycloalkyl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S. R 3a These embodiments of R 3 can be combined with any of the embodiments described herein.

[0047] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 (b) 0 to 5 R 3b C is replaced by 3-12 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3b C is replaced by 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3b C is replaced by 5-10 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3b C is replaced by 5-10In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 0 to 5 R 3b C is replaced by 5-10 Spirocycloalkyl. R 3 These embodiments of R 3b can be combined with any of the embodiments described herein.

[0048] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 There are 0 R 3b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is one R 3b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is two R 3b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is three R 3b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 4 R 3b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 5 R 3bIt is substituted with an R group. 3 These embodiments of R 3b can be combined with any of the embodiments described herein.

[0049] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3b independently, C 1-4 Alkyl, C 2-4 Alkynyl, Halo, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3b independently, C 1-4 Alkyl, halo or C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3b is C 1-4 haloalkyl. R 3b These embodiments of R 3 can be combined with any of the embodiments described herein.

[0050] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and the heterocycloalkyl is 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is a monocyclic heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms, each independently O or S, wherein the heterocycloalkyl is 3c It is replaced by R 3 These embodiments of R 3c can be combined with any of the embodiments described herein.

[0051] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 There are 0 R 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is one R 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is two R 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is three R 3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 4 R3c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 3 is 5 R 3c It is substituted with an R group. 3 These embodiments of R 3c can be combined with any of the embodiments described herein.

[0052] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3c independently, C 1-4 Alkyl, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 3c independently, C 1-4 Alkyl or C 1-4 haloalkyl. R 3c These embodiments of R 3 can be combined with any of the embodiments described herein.

[0053] R 3a The embodiments described herein for R 3 and wherein R 3 is (a)C 1-8 Alkyl, C 2-8 Alkynyl or C 1-8 haloalkyl, each of which is 0 to 5 R 3a It is replaced by R 3b The embodiments described herein for R 3 and wherein R 3 (b) 0 to 5 R 3bC is replaced by 3-12 is cycloalkyl. R 3c The embodiments described herein for R 3 and wherein R 3 (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c is replaced by .

[0054] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 3 teeth, [ka] is.

[0055] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 3 teeth, [ka] is.

[0056] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 3 teeth, [ka] is.

[0057] 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, 8, and 9. For example, any of the R 3 Any of the embodiments of R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c It can be combined with any of the embodiments.

[0058] residue 4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 1-4 Alkyl-NR 4c1 R 4c2 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, C 1-4 Alkyl-heterocycloalkyl or C 1-4alkyl-heteroaryl, where 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; Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 Alkyl or C 2-6 is an alkoxyalkyl; Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, halo or -N(H)S(O)2-C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 are independently -OH, C 1-4 Alkyl-OH or C 1-4 It is an alkoxy.

[0059] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 3-6 Cycloalkyl, C 1-4 Alkyl-C3-6 Cycloalkyl, C 1-4 Alkyl-heterocycloalkyl or C 1-4 alkyl-heteroaryl, where 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; Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, halo or -N(H)S(O)2-C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 are independently -OH, C 1-4 Alkyl-OH or C 1-4 It is an alkoxy.

[0060] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl or C 1-4 Alkyl-NR 4c1 R 4c2 and Alternatively, R 4c and R 4aeach taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 is alkyl, Each R 4a1 are independently —OH or halo; Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 is -OH.

[0061] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H or C 1-8 is alkyl, Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 is alkyl, Each R 4a1 are independently —OH or halo; Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3forming a phenyl ring substituted with Each R 4a3 is -OH.

[0062] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 4a is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a is ethyl. R 4a These embodiments of R 4b and R 4c can be combined with any of the embodiments described herein.

[0063] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 4b is H, C 1-8 Alkyl or C 1-4 Alkyl-NR 4c1 R 4c2In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein R 4b is C 1-8 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 4b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 4b is H. R 4b These embodiments of R 4a and R 4c can be combined with any of the embodiments described herein.

[0064] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is C 1-8 Alkyl, -C 1-4 Alkyl-NR 4c1 R 4c2 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4c1 and R 4c2 independently, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is C 1-8 Alkyl or C 3-6In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is C 1-8 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 4c These embodiments of R 4a and R 4b can be combined with any of the embodiments described herein.

[0065] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c and R4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl selected from pyrrolidinyl, azetidinyl, and piperidinyl, said heterocycloalkyl comprising 0 to 2 R 4a1 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c and R 4a are combined with the carbon and nitrogen to which each is attached to form a pyrrolidinyl, and the pyrrolidinyl is selected from 0 to 2 R 4a1 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c and R 4a are combined together with the carbon and nitrogen to which each is attached to form an azetidinyl, and the azetidinyl is 4a1 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4c and R 4a are combined together with the carbon and nitrogen to which each is attached to form a piperidinyl, which is 4a1 It is replaced by R 4a and R 4c These embodiments of R 4b can be combined with any of the embodiments described herein.

[0066] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a / R 4c Heterocycloalkyl containing 0 R 4a1In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a / R 4c Heterocycloalkyl containing one R 4a1 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 4a / R 4c Heterocycloalkyl containing two R 4a1 It is replaced by R 4a and R 4c These embodiments of R 4b can be combined with any of the embodiments described herein.

[0067] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, halo or -N(H)S(O)2-C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4a1 independently, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4a1are independently —OH or halo. 4a1 These embodiments of R 4b and combined R 4a and R 4c can be combined with any of the embodiments described herein.

[0068] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein the phenyl ring is substituted with zero R 4a3 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein the phenyl ring is substituted with one R 4a3 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein the phenyl ring is substituted with two R 4a3 It is replaced by R 4a1 These embodiments of R 4b and combined R 4a and R 4c can be combined with any of the embodiments described herein.

[0069] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 4a3 are independently -OH, C 1-4 Alkyl-OH or C 1-4is an alkoxy. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), where each R 4a3 is independently -OH. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), where each R 4a3 is independently C 1-4 alkyl-OH. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), where each R 4a3 is independently C 1-4 is an alkoxy. These embodiments of R 4a3 can be combined with any of the embodiments described herein for two combined R 4a1 groups, combined R 4c and R 4a , and R 4b .

[0070] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), where R 4c and R s 4a are combined together with the carbon and nitrogen to which each is attached to form a pyrrolidinyl substituted with two R 4a1 groups, where the two R 4a1 groups are on adjacent ring atoms and combine to form a phenyl ring substituted with 0-2 R 4a3 . In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), where R 4c and R 4a are combined together with the carbon and nitrogen to which each is attached to form an azetidinyl substituted with two R 4a1 groups, and the two R 4a1The groups are on adjacent ring atoms and, in combination, can be 0 to 2 R 4a3 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 4c and R 4a are combined with the carbon and nitrogen to which they are attached to form two R 4a1 forming a piperidinyl substituted with two R 4a1 The groups are on adjacent ring atoms and, in combination, can be 0 to 2 R 4a3 The combined R 4c and R 4a , and the combination of the two R 4a1 These embodiments of the group R 4b and R 4a3 can be combined with any of the embodiments described herein.

[0071] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl or tert-butyl, [ka] and Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, said heterocycloalkyl being 4a1 is replaced by, and Each R 4a1 are independently methyl, —OH, methoxy, fluoro, or —N(H)S(O)CH; Alternatively, two R on adjacent ring atoms 4a1 The groups combine to form a phenyl ring substituted with 0-2 -OH.

[0072] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 4a , R 4b and R 4c is as follows: R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, [ka] or R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being selected from 0 to 2 R 4a1 is replaced by, and Each R 4a1 are independently —OH or fluoro; Alternatively, two R on adjacent ring atoms 4a1 The groups combine to form a phenyl ring substituted with 0-1 -OH.

[0073] R 4a , R 4b and R 4c The embodiments described herein for residue 4 can be present in any combination. Additionally, the embodiments described herein for residue 4 can be combined with any of the embodiments described herein for residues 3, 5, 6, 7, 8, and 9. For example, R as described herein can be combined with any of the embodiments described herein for residues 3, 5, 6, 7, 8, and 9. 4a , R 4b and R 4c The embodiment of R3 , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0074] Ring 5 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5a is H, R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, -C 1-4 Alkyl-NR 5b1 R 5b2 , -C 1-3 Alkyl-C(O)NR 5b1 R 5b2 , -C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 , C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 cycloalkyl, each cycloalkyl having 0 to 3 R 5b5 is replaced by Each R 5b1 and R 5b2 are independently H, C1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, or -C(O)C 1-4 haloalkyl, where R 5b1 and R 5b2 at most one of is H, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0-1 additional oxygen ring members, said heterocycloalkyl comprising 0-2 R 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and 0-1 R 5b5 is replaced by, and Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 It is haloalkyl or NH(CH3).

[0075] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 cycloalkyl, each cycloalkyl having 0 to 3 R 5b5 is replaced by Each R 5b5 independently, C 1-4 Alkyl, halo or C 1-4 It is haloalkyl.

[0076] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5b and R 5c are each independently H, C 1-4 Alkyl-NR 5b1 R 5b2 , C 1-3 Alkyl-C(O)NR 5b1 R 5b2 or -C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 and Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 haloalkyl, where R 5b1 and R 5b2 at most one of is H, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0-1 additional oxygen ring members, said heterocycloalkyl comprising 0-2 R 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and 0-1 R 5b5 is replaced by, and Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 It is haloalkyl or NH(CH3).

[0077] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5a is H. R 5a These embodiments of R 5b and R 5c can be combined with any of the embodiments described herein.

[0078] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b is H. R 5b These embodiments of R 5a and R 5c can be combined with any of the embodiments described herein.

[0079] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5c is C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, C1-4 Alkyl-C 3-6 cycloalkyl, each cycloalkyl having 0 to 3 R 5b5 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl or C 1-8 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is C 1-8 Alkyl, C 1-8 Alkyl-OH or C 1-8 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is C 3-4 Cycloalkyl or C 1-4 Alkyl-C 3-4 and each cycloalkyl is substituted with 0 to 2 halo. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c R is cyclopropyl, cyclobutyl, cyclopropylmethyl, or cyclobutylmethyl substituted with 0 to 2 halo. 5c These embodiments of R 5a and R5b can be combined with any of the embodiments described herein.

[0080] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is C 1-4 Alkyl-NR 5b1 R 5b2 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b1 and R 5b2 are each independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b1 and R 5b2 is other than H. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 5b1 and R 5b2 is H. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0-1 additional oxygen ring members, said heterocycloalkyl comprising 0-2 R 5b5 It is replaced by R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0081] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c Ha-C 1-3 Alkyl-C(O)NR 5b1 R 5b2 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b1 and R 5b2 are each independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b1 and R 5b2 is other than H. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 5b1 and R 5b2 is H. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0-1 additional oxygen ring members, said heterocycloalkyl comprising 0-2 R 5b5 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b1 and R 5b2are combined to form piperidine or morpholine, each of which is selected from 0 to 2 R 5b5 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 5b5 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 5b5 is fluoro. R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0082] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c Ha-C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b3 is H or C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b3 is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 5b3 is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b4is heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and 0-1 R 5b5 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b4 is pyridine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, or isoxazole, each of which is 0 to 1 R 5b5 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5b5 is methyl. R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0083] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, [ka] R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0084] In some embodiments, R5c is H, methyl, ethyl, [ka] R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0085] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5c teeth, [ka] R 5c These embodiments of R 5a and R 5b can be combined with any of the embodiments described herein.

[0086] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5a is H, R 5b is H, and R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, [ka] is.

[0087] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 5a is H, R 5b is H, and R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, [ka] is.

[0088] R 5a , R 5b and R 5c The embodiments described herein for residue 5 can be present in any combination. Additionally, 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, 8, and 9. For example, the embodiments described herein for R as described herein can be present in combination with any of the embodiments described herein for residues 3, 4, 6, 7, 8, and 9. 5a , R 5b and R 5c The embodiment of R 3 , R 4a , R 4b , R 4c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0089] residue 6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6a is H, C 1-4Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl or C 1-4 alkyl-heterocycloalkyl, wherein the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; R 6b is H, and R 6d is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, -OH or C 2-6 R is an alkoxyalkyl. 6a , R 6b and R 6d These embodiments of X 6 can be combined with any of the embodiments described herein.

[0090] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 is cycloalkyl, R 6b is H, and R 6d is H, C 1-4 Alkyl or C 1-4 It is a deuteroalkyl. R 6a , R 6b and R 6d These embodiments of X 6 can be combined with any of the embodiments described herein.

[0091] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6a is C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6a is H or C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6a is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 6a is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6a is methyl. 6a These embodiments of R 6b , R 6d and X 6can be combined with any of the embodiments described herein.

[0092] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6b is H. R 6b These embodiments of R 6a , R 6d and X 6 can be combined with any of the embodiments described herein.

[0093] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6d is H, C 1-4 Alkyl or C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6d is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 6d is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl.6d These embodiments of R 6a , R 6b and X 6 can be combined with any of the embodiments described herein.

[0094] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CD3, [ka] and R 6b is H, and R 6d is H, methyl, ethyl, n-propyl, isopropyl, -CD3, or [ka] R 6a , R 6b and R 6d These embodiments of X 6 can be combined with any of the embodiments described herein.

[0095] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 6a is H, methyl, ethyl, n-propyl, isobutyl, -CD3 or [ka] and R 6b is H, and R 6d is H, methyl, isopropyl or -CD3. 6a , R 6b and R 6dThese embodiments of X 6 can be combined with any of the embodiments described herein.

[0096] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] X 6 These embodiments of R 6a , R 6b , R 6d and X 9 can be combined with any of the embodiments described herein.

[0097] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] X 6 These embodiments of R 6a , R 6b , R 6d and X 9 can be combined with any of the embodiments described herein.

[0098] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] X 6 These embodiments of R 6a , R 6b , R 6d and X 9can be combined with any of the embodiments described herein.

[0099] X 6 , R 6a , R 6b and R 6d The embodiments described herein for residue 6 can be present in any combination. Additionally, 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, 8, and 9. For example, X as described herein can be present in any combination. 6 , R 6a , R 6b and R 6d The embodiment of R 3 , 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 , X 9 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0100] residue 7 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein: R 7a is H, and R 7b and R 7c are each independently H, C 1-8 Alkyl or C 1-4 Alkyl-C 3-6 It is cycloalkyl.

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein: R 7a is H, R 7b is H, and R 7c is isobutyl, [ka] is.

[0102] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein: R 7a is H, R 7b is H, and R 7c is isobutyl.

[0103] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein: R 7a is H, R 7b is H, and R 7c is isobutyl, [ka] is.

[0104] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein: R 7ais methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), or (Ib), wherein R 7a is H. R 7a These embodiments of R 7b and R 7c can be combined with any of the embodiments described herein.

[0105] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 7b is H. R 7b These embodiments of R 7a and R 7c can be combined with any of the embodiments described herein.

[0106] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 7c In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein R 7c teeth [ka] R 7c These embodiments of R 7a and R 7b can be combined with any of the embodiments described herein.

[0107] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 7c teeth, [ka] R 7c These embodiments of R 7a and R 7b can be combined with any of the embodiments described herein.

[0108] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein R 7c teeth, [ka] R 7c These embodiments of R 7a and R 7b can be combined with any of the embodiments described herein.

[0109] R 7a , R 7b and R 7c The embodiments described herein for residue 7 can be present in any combination. Additionally, the embodiments described for residue 7 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, 8, and 9. For example, R 7a , R 7b and R 7c The embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9ccan be combined with any of the embodiments described herein.

[0110] residue 8 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I) wherein Ring B is phenyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I) having the structure of Formula (Ia): [ka]

[0111] In the above formula, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c can each independently be as defined for embodiments of formula (Ia) as described herein.

[0112] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) having the structure of Formula (Ia1): [ka]

[0113] In the above formula, R 3 , R 4a , R 4b , R4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c can each independently be as defined for embodiments of formula (Ia1) as described herein.

[0114] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein Ring B is a heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each heteroatom being N. These embodiments of Ring B include R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of the embodiments described herein.

[0115] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein Ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S. These embodiments of Ring B include R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of the embodiments described herein.

[0116] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) wherein Ring B is a heteroaryl having 5-6 ring members and 1-3 heteroatoms, each heteroatom being N. These embodiments of Ring B include R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of the embodiments described herein.

[0117] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I) wherein Ring B is pyridyl or thiophenyl. These embodiments of Ring B include R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of the embodiments described herein.

[0118] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), wherein Ring B is: [ka] These embodiments of ring B are R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of the embodiments described herein.

[0119] The embodiments described herein for ring B include R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 Positions may occur in combination with any of the embodiments described herein. Thus, for the embodiments of ring B described herein, R3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , m8, R 8f , X 9 , R 9a , R 9b and R 9c can each independently be as defined for an embodiment of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), as described herein.

[0120] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8a is C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H; Alternatively, R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 forming a cycloalkyl, The subscript m8 is an integer between 0 and 5, Each R 8f independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 ,-C(O)NR 8f1 R 8f2 , -N(R 8f1 )C(O)R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-4 alkyl-heterocycloalkyl, phenyl, -O-phenyl, or heteroaryl, where 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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from the group consisting of 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are independently H or C 1-4 is alkyl, and Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 alkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S. R 8a , R 8b , R 8d , R 8e , m8 and R 8f These embodiments of can be combined with any of the embodiments described herein for ring B.

[0121] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 8a is C 1-4 Alkyl, C 1-4 Deuteroalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H; The subscript m8 is an integer between 0 and 5, Each R 8f independently, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are C 1-4 is alkyl, and Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S. R 8a , R 8b , R 8d , R 8e , m8 and R 8f These embodiments of can be combined with any of the embodiments described herein for ring B.

[0122] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 8a is methyl, ethyl, n-propyl, n-butyl, -CD3, [ka] and R 8b , R 8d and R 8e are H, Alternatively, R 8b and R 8d are combined with the carbon to which each is attached to form a cyclopropyl. R 8a , R 8b , R 8d and R 8e These embodiments of m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0123] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 8ais methyl, ethyl, n-propyl, n-butyl, -CD3 or [ka] and R 8b , R 8d and R 8e are each H. R 8a , R 8b , R 8d and R 8e These embodiments of m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0124] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo, [ka] is. m8 and R 8f These embodiments of R 8a , R 8b , R 8d , R 8e and may be combined with any of the embodiments described herein for Ring B.

[0125] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, [ka] is. m8 and R 8f These embodiments of R 8a , R 8b , R 8d , R 8e and may be combined with any of the embodiments described herein for Ring B.

[0126] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, [ka] is. m8 and R 8f These embodiments of R 8a , R 8b , R 8d , R 8e and may be combined with any of the embodiments described herein for Ring B.

[0127] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 8a is C 1-4 Alkyl, C 1-4 Deuteroalkyl or C 1-4 Alkyl-C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8a is C 1-4In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8a is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8a is C 1-4 Alkyl-C 3-6 is cycloalkyl. R 8a These embodiments of R 8b , R 8d , R 8e , m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0128] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8b is H. R 8b These embodiments of R 8a , R 8d , R 8e , m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0129] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8d is H. R 8d These embodiments of R 8a , R 8b , R 8e , m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0130] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8e is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 8e is H. R 8e These embodiments of R 8a , R 8b , R 8d , m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0131] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ib), wherein R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 Forms a cycloalkyl. R 8b and R 8dThese embodiments of R 8a , R 8e , m8, R 8f and may be combined with any of the embodiments described herein for Ring B.

[0132] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 0. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 1. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 3. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where subscript m8 is 4. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein the subscript m8 is 5. These embodiments of m8 include R 8a , R 8b , R 8d , R 8e , R 8f and may be combined with any of the embodiments described herein for Ring B.

[0133] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein at least one R 8f is C 1-4 Alkyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, cyano or -NR 8f1 R 8f2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein at least one R 8f is C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl or C 1-4 alkyl-heterocycloalkyl, where each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and each cycloalkyl and heterocycloalkyl has 0 to 3 R 8f3 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein at least one R 8f is phenyl, -O-phenyl, or heteroaryl, each heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each phenyl and heteroaryl is selected from 0 to 3 R 8f3 It is replaced by R 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8 and ring B may be combined with any of the embodiments described herein.

[0134] In some embodiments, at least one R 8f is C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 In some embodiments, at least one R 8f is 0 to 3 R 8f3 C is replaced by 3-6 In some embodiments, at least one R 8f is 0 to 3 R 8f3 -OC is substituted with 3-6 In some embodiments, at least one R 8f is 0 to 3 R 8f3 C is replaced by 1-4 Alkyl-C 3-6 In some embodiments, at least one R 8f is 0 to 3 R 8f3 -OC is substituted with 1-4 Alkyl-C 3-6 In some embodiments, at least one R 8f is heterocycloalkyl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heterocycloalkyl having 0 to 3 R 8f3 In some embodiments, at least one R 8f is C 1-4alkyl-heterocycloalkyl, where each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each heterocycloalkyl has 0 to 3 R 8f3 In some embodiments, at least one R 8f is 0 to 3 R 8f3 In some embodiments, at least one R 8f is 0 to 3 R 8f3 In some embodiments, at least one R 8f is heteroaryl, each heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; and each heterocycloalkyl has 0-3 R 8f3 It is replaced by R 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8 and ring B may be combined with any of the embodiments described herein.

[0135] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 8f3 is C 1-4 Alkyl, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy or -OC 1-4 Alkyl-C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 8f3 is C 1-4 Alkyl, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl or C 1-4In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 8f3 is C 1-4 Alkyl, Halo, C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 8f3 is methyl, chloro or trifluoromethyl. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , R f , m8 and ring B may be combined with any of the embodiments described herein.

[0136] R 8a , R 8b , R 8d , R 8e , m8 and R 8f The embodiments described herein for residue 8 can be present in any combination. Additionally, the embodiments described herein for residue 8 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 9. For example, the embodiments described herein for residue 8 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 9. 8a , R 8b , R 8d , R 8e , m8 and R 8f An embodiment of the invention is 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , X9 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0137] residue 9 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein the moiety —C(O)—X 9 -NR 9a -teeth, [ka] is. Part-C(O)-X 9 -NR 9a These embodiments of X 6 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0138] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein the moiety —C(O)—X 9 -NR 9a -teeth, [ka] is. Part-C(O)-X 9 -NR 9a These embodiments of X 6 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0139] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein the moiety —C(O)—X 9 -NR 9a -teeth, [ka] is. Part-C(O)-X 9 -NR 9a These embodiments of X 6 , R 9a , R 9b and R 9c can be combined with any of the embodiments described herein.

[0140] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 1-6 Alkyl-OH, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl or C 1-4 alkyl-heteroaryl, each heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently N, O, or S; Alternatively, R 9b and R 9c Each is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 9c2 is replaced by Each R 9c1are independently haloes, and Each R 9c2 is independently —OH or halo. R 9a , R 9b and R 9c These embodiments of X 9 can be combined with any of the embodiments described herein.

[0141] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl or C 3-6 is cycloalkyl, Alternatively, R 9b and R 9c Each is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is selected from the group consisting of 0 or 2 R 9c2 is replaced by, and Each R 9c2 is independently —OH or halo. R 9a , R 9b and R 9c These embodiments of X 9 can be combined with any of the embodiments described herein.

[0142] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9a is H or C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9a is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 9a is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9a In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9a is ethyl. R 9a These embodiments of R 9b , R 9c and X 9 can be combined with any of the embodiments described herein.

[0143] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b is H or C 1-4In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 9b is C 1-4 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b is ethyl. R 9b These embodiments of R 9a , R 9c and X 9 can be combined with any of the embodiments described herein.

[0144] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c is H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl or C 1-4and alkyl-heteroaryl, where each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), where R 9c is H. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein R 9c is C 1-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c is C 2-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c is C 3-6 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c is C 1-4 alkyl-heteroaryl. R 9c These embodiments of R 9a , R 9b and X 9 can be combined with any of the embodiments described herein.

[0145] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9b and R 9c Each is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein cycloalkyl is a group consisting of zero R 9c2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein cycloalkyl is substituted with one R 9c2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein cycloalkyl is substituted with two R 9c2 It is replaced by R 9b and R 9c These embodiments of R 9a and X 9 can be combined with any of the embodiments described herein.

[0146] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 9c2 is independently halo or —OH. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 9c2 is independently halo. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 9c2are independently —OH. 9c2 These embodiments of R 9a , combined R 9b and R 9c and X 9 can be combined with any of the embodiments described herein.

[0147] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein R 9c and R 9a each combines with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein the heterocycloalkyl is selected from 0 or 2 R 9c2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein heterocycloalkyl is substituted with zero R 9c2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein heterocycloalkyl is substituted with one R 9c2 In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein heterocycloalkyl is substituted with two R 9c2 It is replaced by R 9c and R 9a These embodiments of R 9b and X 9 can be combined with any of the embodiments described herein.

[0148] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), wherein each R 9c2 is independently halo or —OH. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 9c2 is independently halo. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein each R 9c2 are independently —OH. 9c2 These embodiments of R 9b , combined R 9c and R 9a and X 9 can be combined with any of the embodiments described herein.

[0149] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 9a is H or methyl, R 9b is H, methyl or ethyl, and R 9c is H, methyl, ethyl, n-propyl, sec-butyl, [ka] and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form a C substituted with 0-2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9aeach combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or —OH group. R 9a , R 9b and R 9c These embodiments of X 9 can be combined with any of the embodiments described herein.

[0150] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein: R 9a is H or methyl, R 9b is H or methyl, and R 9c is H, methyl, ethyl, n-propyl, [ka] and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0-2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a each combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or —OH group. R 9a , R 9b and R 9c These embodiments of X 9 can be combined with any of the embodiments described herein.

[0151] X 9 , R 9a, R 9b and R 9c The embodiments described herein for residue 9 can be present in any combination. Additionally, the embodiments described herein for residue 9 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, 7, and 8. For example, X as described herein can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 6, 7, and 8. 9 , R 9a , R 9b and R 9c The embodiment of R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8 and R 8f can be combined with any of the embodiments described herein.

[0152] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] and Part-C(O)-X 9 -NR 9a -teeth, [ka] is.

[0153] For the above embodiment, R 3 , R 4a , R4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0154] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] and Part-C(O)-X 9 -NR 9a -teeth, [ka] is.

[0155] For the above embodiment, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R8d , R 8e , ring B, m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0156] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) having the structure of Formula (Ib). [ka]

[0157] R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (Ib) as described herein.

[0158] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) having the structure of Formula (Ib1): [ka]

[0159] R 3 , R 4a , R4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (Ib1) as described herein.

[0160] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] and Part-C(O)-X 9 -NR 9a -teeth, [ka] is.

[0161] In the above embodiment, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R8e , ring B, m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0162] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia) or (Ia1), wherein: X 6 teeth, [ka] and Part-C(O)-X 9 -NR 9a -teeth, [ka] is.

[0163] In the above embodiment, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0164] residues 3-9 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), and (Ic1), wherein: R 3 teeth [ka] [ka] and R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, tert-butyl, [ka] and Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, said heterocycloalkyl being 4a1 is replaced by Each R 4a1 are independently methyl, —OH, methoxy, fluoro, or —N(H)S(O)CH; Alternatively, two R on adjacent ring atoms 4a1 the groups combine to form a phenyl ring substituted with 0 to 2 -OH; R 5a is H, R 5b is H, R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, [ka] and X 6 teeth, [ka] and R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CD3, [ka] and R 6b is H, R 6d is H, methyl, ethyl, n-propyl, isopropyl, -CD3 or [ka] and R 7a is H, R 7b is H, R 7c is isobutyl, [ka] and R 8a is methyl, ethyl, n-propyl, n-butyl, -CD3, [ka] and R 8b , R 8d and R 8e are H, Alternatively, R 8b and R 8d are combined with the carbon to which each is attached to form a cyclopropyl; m8 is 0, 1, 2 or 3, Each R 8f are independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo, [ka] and X 9 teeth, [ka] and R 9a is H or methyl, R 9b is H, methyl or ethyl, and R 9c is H, methyl, ethyl, n-propyl, sec-butyl, [ka] and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0-2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a each combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or —OH group.

[0165] In the above embodiment, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , R 9a , R 9b and R 9ccan be as defined in any of the embodiments of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) as described herein.

[0166] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), and (Ic1), wherein: R 3 teeth [ka] and R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, [ka] or R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being selected from 0 to 2 R 4a1 is replaced by Each R 4a1 are independently —OH or fluoro; Alternatively, two R on adjacent ring atoms 4a1 the groups combine to form a phenyl ring substituted with 0 to 1 -OH; R 5a is H, R 5b is H, R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, [ka] and X 6 teeth [ka] and R 6a is H, methyl, ethyl, n-propyl, isobutyl, -CD3, or [ka] and R 6b is H, R 6d is H, methyl, isopropyl or -CD3, [ka] and R 7a is H, R 7b is H, R 7c is isobutyl, [ka] and R 8a is methyl, ethyl, n-propyl, n-butyl, -CD3, or [ka] and R 8b , R 8d and R 8e are H, m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, [ka] and X 9 teeth, [ka] and R 9a is H or methyl, R 9b is H or methyl, and R 9c is H, methyl, ethyl, n-propyl, [ka] and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0-2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a each combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or —OH group.

[0167] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), and (Ic1), wherein: R 3 teeth, [ka] and R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, [ka] or R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being selected from 0 to 2 R 4a1is replaced by Each R 4a1 are independently —OH or fluoro; Alternatively, two R on adjacent ring atoms 4a1 the groups combine to form a phenyl ring substituted with 0 to 1 -OH; R 5a is H, R 5b is H, R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, [ka] and X 6 teeth [ka] and R 6a is H, methyl, ethyl, n-propyl, isobutyl, -CD3, or [ka] and R 6b is H, R 6d is H, methyl, isopropyl or -CD3, [ka] and R 7a is H, R 7b is H, R 7c is isobutyl, [ka] and R 8a is methyl, ethyl, n-propyl, n-butyl, -CD3, or [ka] and R 8b , R 8d and R 8e are H, m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, [ka] and X 9 teeth, [ka] and R 9a is H or methyl, R 9b is H or methyl, and R 9c is H, methyl, ethyl, n-propyl, [ka] and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0-2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a each combines together with the carbon and nitrogen to which it is attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or —OH group.

[0168] For the above embodiment, R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any of the embodiments of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) as described herein.

[0169] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) having the structure of Formula (Ic): [ka]

[0170] R 3 , R 4a , R 4c , R 5c , R 6a , R 6d , R 8a , m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any of the embodiments of formula (Ic) as described herein.

[0171] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) having the structure of Formula (Ic1): [ka]

[0172] R 3 , R 4a , R 4c, R 5c , R 6a , R 6d , R 8a , m8, R 8f , R 9a , R 9b and R 9c can each independently be as defined in any of the embodiments of formula (Ic1) as described herein.

[0173] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 1-693. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 1-50. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 51-100. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 101-150. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 151-200. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 201-250. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 251-300. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 301-350. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 351-400. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 401-450.In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 451-500. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 501-550. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 551-600. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 601-650. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) having the structure of any one of Examples 651-693.

[0174] The present disclosure includes all tautomers and stereoisomers of the compounds described herein, in mixtures or in pure or substantially pure form. Compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) can have asymmetric centers at one or more carbon atoms, and therefore compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) can exist in diastereomeric or enantiomeric forms, or mixtures thereof. All conformational isomers (e.g., cis- and trans-isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of these isomers, as well as solvates, hydrates, and tautomers, are within the scope of the present disclosure. Compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) can be prepared using diastereomeric, enantiomeric, or racemic mixtures as starting materials. Further, diastereomeric and enantiomeric products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art.

[0175] The compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) can also be in the form of a salt, such as an acid or base salt of the compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1). Specific examples of pharmaceutically acceptable salts are mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citric acid), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0176] Pharmaceutically acceptable salts of acidic compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) are salts formed with bases, i.e., cationic salts such as alkali metal salts and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, etc., and ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)methylammonium salts.

[0177] Similarly, acid addition salts with mineral acids, organic carboxylic acids and organic sulfonic acids (eg, hydrochloric acid, methanesulfonic acid, maleic acid) are also possible as long as a basic group such as pyridyl forms part of the structure.

[0178] 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 may differ 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 compound for the purposes of this disclosure.

[0179] The present disclosure also includes isotopically labeled compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), in which one or more atoms have been replaced with one or more atoms having a specified atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 18 F, 35 S and 36Isotopically labeled compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may be useful in tissue distribution assays of the compounds and their prodrugs and metabolites, preferred isotopes for such assays include, but are not limited to, 3 H and 14 C. In addition, under certain circumstances, deuterium ( 2 Substitution with heavier isotopes, such as H, may provide therapeutic advantages such as increased metabolic stability, increased in vivo half-life, or reduced dosage. Isotopically labeled compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) may generally be prepared according to methods known in the art.

[0180] IV. Composition Compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein are useful for preparing pharmaceutical compositions or medicaments for modulating one or more cyclins (e.g., cyclin A, cyclin B, cyclin E). In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient thereof. In some embodiments, pharmaceutical compositions or medicaments comprising one or more compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) can be administered to a subject for the treatment of cancer.

[0181] Pharmaceutical compositions or medicaments used in the present disclosure can be formulated using one or more physiologically acceptable carriers or excipients by standard techniques or methods well known in the art of pharmacy. Suitable pharmaceutical carriers are described herein and, for example, in "Remington's Pharmaceutical Sciences" by E.W. Martin. Compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), as well as physiologically acceptable salts and solvates thereof, can be formulated for administration by any suitable route, including, but not limited to, oral, topical, nasal, rectal, pulmonary, parenteral (e.g., intravenous, subcutaneous, intramuscular, etc.), and combinations thereof. In some embodiments, compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) are dissolved in a liquid, such as water. The most appropriate route of administration of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) in any given case will depend in part on the nature, severity and, optionally, stage of the cancer.

[0182] Pharmaceutical compositions or medicaments of the present disclosure can comprise as an active ingredient a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) and a pharmaceutically acceptable carrier and / or excipient or diluent. Any carrier and / or excipient suitable for the formulation desired for administration is contemplated for use with the compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) disclosed herein.

[0183] 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 from the digestive tract) or parenteral administration (e.g., injection, infusion, or implantation). In some embodiments, the pharmaceutical compositions or medicaments can be administered via syringe or intravenously. In a preferred embodiment, the pharmaceutical compositions or medicaments are injected subcutaneously.

[0184] For oral administration, the pharmaceutical composition or medicament may take the form of, for example, a tablet or capsule prepared by conventional means with pharmaceutically acceptable excipients. Preferably, the active ingredient is combined with (a) a diluent or filler, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylate, and / or calcium hydrogen phosphate, calcium sulfate, (b) a lubricant, such as silica, anhydrous colloidal silica, talc, stearic acid, its magnesium or calcium salts (e.g., magnesium stearate or calcium stearate), metal stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate, and / or polyethylene glycol. and gelatin capsules containing the composition together with polyethylene glycol, and in the case of tablets, (c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or hydroxypropyl methylcellulose, optionally together with (d) a disintegrant, such as starch (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or an effervescent mixture, (e) a wetting agent, such as sodium lauryl sulfate, and / or (f) an absorbent, colorant, flavoring, and sweetener. In some embodiments, the tablet contains a mixture of hydroxypropyl methylcellulose, polyethylene glycol 6000, and titanium dioxide. The tablet can be film-coated or enteric-coated according to methods known in the art.

[0185] Liquid preparations for oral administration can be in the form of, for example, a solution, syrup, or suspension, or can be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives, such as suspending agents such as sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils, emulsifying agents such as lecithin or acacia, non-aqueous vehicles such as almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils, and preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, or sorbic acid. These preparations can also contain buffer salts, flavoring agents, coloring agents, and / or sweeteners as needed. If desired, preparations for oral administration can be suitably formulated to provide controlled release of the active compound.

[0186] Typical formulations for topical administration include creams, ointments, sprays, lotions, and patches. However, the pharmaceutical compositions can be formulated for any administration mode, such as intradermal, subcutaneous, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary, or intratumoral injection using a syringe or other device. Formulations for administration by inhalation (e.g., aerosol), or oral, rectal, or vaginal administration are also contemplated.

[0187] Pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of a powder of the compound or salt thereof described herein and a powder of a suitable carrier and / or lubricant. Compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler known to those skilled in the art. In certain cases, the compositions can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as 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 dispense a metered amount. Capsules and cartridges, made, for example, of gelatin, for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base (e.g., lactose or starch).

[0188] The compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0189] The compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein can be formulated for parenteral administration by injection, such as bolus injection. Injectable preparations can be provided in unit dosage form, e.g., ampoules or 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 auxiliary substances such as preservatives, stabilizers, wetting agents, emulsifiers, solubility enhancers, salts for adjusting osmotic pressure, and / or buffers. Alternatively, the compounds can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Additionally, the compositions may contain other therapeutically valuable substances. The compositions are prepared according to conventional blending, granulating, or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the compounds.

[0190] In some embodiments, the compositions described herein are prepared using polysaccharides such as chitosan or its derivatives (e.g., chitosan succinate, chitosan phthalate, etc.), pectin and its derivatives (e.g., amidated pectin, calcium pectate, etc.), chondroitin and its derivatives (e.g., chondroitin sulfate), and alginate.

[0191] In some embodiments, the compositions described herein further comprise a pharmaceutical surfactant. In other embodiments, the compositions further comprise a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HPI3CD), glycerol, maltose, mannitol, sucrose, and mixtures thereof.

[0192] method The present disclosure contemplates the use of compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein for the treatment or prevention of a disease or disorder regulated, at least in part, by one or more cyclins. In some embodiments, the cyclin-mediated disease is a proliferative disease or disorder, including cancer. In some embodiments, the invention provides a method of treating cancer 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 invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, thereby treating cancer.

[0193] In some embodiments, provided herein are compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for use in therapy.

[0194] The present disclosure contemplates the use of a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is modulated, at least in part, by cyclin A. In some embodiments, the cyclin A-mediated disease is a proliferative disease or disorder, including cancer. In some embodiments, the present invention provides a method of treating cancer that is 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 invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, thereby treating the cancer.

[0195] In some embodiments, provided are methods for treating a proliferative disease or disorder mediated at least in part by cyclin A, comprising administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein.

[0196] In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for use in a method for treating a proliferative disease or disorder mediated at least in part by cyclin A.

[0197] In some embodiments, provided herein is the use of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for the manufacture of a medicament for treating a proliferative disease or disorder mediated at least in part by cyclin A.

[0198] The present disclosure contemplates the use of compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is modulated, at least in part, by cyclin B. In some embodiments, the disease mediated by cyclin B is a proliferative disease or disorder, including cancer. In some embodiments, the invention provides a method of treating cancer that is mediated, at least in part, by cyclin B, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, thereby treating the cancer.

[0199] In some embodiments, provided are methods for treating a proliferative disease or disorder mediated at least in part by cyclin B, comprising administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein.

[0200] In some embodiments, provided herein is a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for use in a method for treating a proliferative disease or disorder mediated at least in part by cyclin B.

[0201] In some embodiments, provided herein is the use of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for the manufacture of a medicament for treating a proliferative disease or disorder mediated at least in part by cyclin B.

[0202] The present disclosure contemplates the use of compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is modulated, at least in part, by cyclin E. In some embodiments, the disease mediated by cyclin E is a proliferative disease or disorder, including cancer. In some embodiments, the invention provides a method of treating cancer that is mediated, at least in part, by cyclin E, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, thereby treating cancer.

[0203] In some embodiments, provided are methods for treating a proliferative disease or disorder mediated at least in part by cyclin E, comprising administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein.

[0204] In some embodiments, there is provided a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for use in a method of treating a proliferative disease or disorder mediated at least in part by cyclin E.

[0205] In some embodiments, there is provided a use of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for the manufacture of a medicament for treating a proliferative disease or disorder mediated at least in part by cyclin E.

[0206] In some embodiments, a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein can be used to treat or prevent a proliferative disease or disorder such as cancer, for example, uterine cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, stomach cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer), kidney cancer, renal cell cancer, bladder cancer, bone cancer, bone marrow cancer, skin cancer, head or neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), pancreatic cancer, salivary gland cancer, adrenal gland cancer, thyroid cancer, brain cancer, ganglionic cancer, central nervous system (CNS) and peripheral nervous system (PNS) cancer, and cancer of the hematopoietic and immune systems (e.g., spleen or thymus).

[0207] The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders, or conditions, including, for example, virally-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically-induced cancer, metastasis, and angiogenesis.

[0208] In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioma, or leukemia.

[0209] In some embodiments, the tumor or cancer is small cell lung cancer (SCLC).

[0210] The use of the term cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are directly or indirectly associated with cancer, and includes, for example, pre-cancerous conditions such as angiogenesis and dysplasia.

[0211] In some embodiments, the cancer is a hematological cancer (e.g., leukemia, lymphoma, multiple myeloma).

[0212] In some embodiments, the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, or hairy cell leukemia.

[0213] In some embodiments, the lymphoma is non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma.

[0214] In some embodiments, the cancer is an Rb-mutated cancer. In some embodiments, the cancer has a mutation in the Rb / E2F pathway.

[0215] VI. Administration The present disclosure contemplates administering compounds (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) and compositions thereof by any suitable method, including oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal), and intracerebroventricular), nasal, vaginal, sublingual, ocular, rectal, topical (e.g., transdermal), buccal, and inhalation.

[0216] The pharmaceutical compositions comprising Compound (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) are preferably in unit dosage form. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, or powder in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0217] Compound (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) or a pharmaceutical composition or medicament thereof can be administered to a subject diagnosed with or suspected of having a disease or disorder mediated at least in part by cyclin A in an amount sufficient to elicit an effective therapeutic response in the subject.

[0218] The dosage of the compound administered depends on various factors, including the subject's weight, age, individual condition, and / or administration form. The size of the dosage is also determined by the existence, nature, and extent of side effects associated with the administration of a particular compound in a particular subject. Typically, the dosage of the active compound is a dosage sufficient to achieve the desired effect. The optimal administration schedule can be calculated by measuring the accumulation of the compound in the subject's body. Generally, the dosage can be administered once a day, once a week, once a month, or more than once a month. Those skilled in the art can easily determine the optimal dosage, administration method, and repetition rate.

[0219] In some embodiments, a unit dosage for oral administration of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein to a subject (e.g., a human) weighing about 50 to about 70 kg can include about 1 to about 5,000 mg, about 1 to about 3,000 mg, about 1 to about 2,000 mg, or about 1 to about 1,000 mg of the compound.

[0220] In some embodiments, a unit dose of a compound of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein for subcutaneous administration to a subject (e.g., a human) weighing about 50 to about 70 kg can include about 0.1 to about 500 mg, about 0.5 to about 300 mg, about 0.5 to about 200 mg, about 0.5 to about 100 mg, or about 0.5 to about 50 mg.

[0221] Doses can be administered once daily or divided into subdoses to be administered multiple times, e.g., two, three, or four times daily, however, as will be appreciated by those skilled in the art, different amounts can be administered at different times depending on the route of administration.

[0222] In some embodiments, the compound is administered for about 1-31 days, or for about 1-12 months. In some embodiments, the compound is administered for one week or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 weeks or more. In some embodiments, the compound is administered for one month or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more.

[0223] Optimal dosage, toxicity, and therapeutic efficacy of such compounds will vary depending on the relative potency of the individual compounds and may be determined by standard pharmacological procedures in experimental animals, e.g., LD 50 (a dose lethal to 50% of the population) and ED 50 The LD (the dose that is therapeutically effective in 50% of the population) can be determined by measuring the dose ratio between toxic and therapeutic effects. 50 / ED 50 The therapeutic index can be expressed as a ratio of . Compounds that exhibit large therapeutic indices are preferred. Compounds that exhibit toxic side effects can also be used, but care must be taken to design a delivery system that targets such compounds to the affected area in order to minimize potential damage to normal cells, thereby reducing side effects.

[0224] The dosage of the pharmaceutical composition or medicament of the present disclosure can be monitored and adjusted throughout treatment depending on the severity of symptoms, frequency of recurrence, and / or physiological response to the treatment regimen. Such adjustments of the treatment regimen are commonly performed by those skilled in the art.

[0225] The pharmaceutical composition or medicament can be administered once or multiple times, depending on the dosage and frequency of administration, according to the patient's needs and tolerance.In any case, the composition or medicament must provide a sufficient amount of the compound of the present disclosure to effectively treat the patient.Generally, when treating cancer, the dosage is sufficient to stop tumor growth or cause tumor regression without causing unacceptable toxicity or side effects to the patient.

[0226] VII. Intermediates In some embodiments, the present disclosure provides intermediates useful for preparing compounds of Formula (I). Particular intermediates useful for preparing compounds of Formula (I) can be found, for example, in the Examples section of this disclosure.

[0227] In some embodiments, intermediates useful in the preparation of compounds of formula (I) are represented by formula (II): [ka] (In the above formula, R 3 is 0 to 5 R 3b C is replaced by 3-6 is cycloalkyl, Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -OH, C 1-3 Alkoxy, C 1-3 haloalkoxy, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; The subscript m4 is an integer between 0 and 2, and Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, intermediates useful in the preparation of compounds of formula (I) are represented by formula (IIa): [ka] (In the above formula, The subscript m3 is an integer between 0 and 5, Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -OH, C 1-3 Alkoxy, C 1-3 haloalkoxy, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; The subscript m4 is an integer between 0 and 2, and Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 1 to 5. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 2 to 5. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 2 to 4. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 2 to 3. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 3 to 4. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (IIa), where subscript m3 is an integer from 3 to 4. In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of Formula (IIa), wherein subscript m3 is 3.

[0230] In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 3b independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C 1-4In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 3b independently, C 1-4 Alkyl, halo or C 1-4 In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 3b are independently halo or C 1-4 In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 3b is independently fluoro or trifluoromethyl.

[0231] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (II) or (IIa), where subscript m4 is an integer from 1 to 2. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (II) or (IIa), where subscript m4 is 0. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (II) or (IIa), where subscript m4 is 1. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of Formula (II) or (IIa), where subscript m4 is 2.

[0232] In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 4a1 independently, C 1-4In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 4a1 is independently halo. In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (II) or (IIa), wherein each R 4a1 is independently fluoro.

[0233] In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (IIa), wherein: the subscript m3 is an integer from 1 to 5; Each R 3b independently, C 1-4 Alkyl, halo or C 1-4 is haloalkyl, The subscript m4 is an integer between 0 and 2, and Each R 4a1 independently, C 1-4 It is alkyl or halo.

[0234] In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (IIa), wherein: the subscript m3 is an integer from 1 to 5; Each R 3b are independently halo or C 1-4 is haloalkyl, The subscript m4 is an integer between 0 and 2, and Each R 4a1 are, independently, halos.

[0235] In some embodiments, the intermediate, or a pharmaceutically acceptable salt thereof, is an intermediate of formula (IIa), wherein: The subscript m3 is an integer between 2 and 3, Each R 3b are independently halo or C 1-4 is haloalkyl, The subscript m4 is an integer between 0 and 2, and Each R 4a1 are, independently, halos.

[0236] The embodiments described herein for intermediates of formula (II) or (IIa) can be combined with any of the embodiments described in this section. For example, R 3 , m3, R 3b , m4, R 4a1 Any of the above embodiments can be combined.

[0237] In some embodiments, the intermediate is a building block described herein. In some embodiments, the intermediate is any of building blocks 1-69. In some embodiments, the intermediate is building block 4. In some embodiments, the intermediate is building block 7. In some embodiments, the intermediate is building block 43. In some embodiments, the intermediate is building block 47. In some embodiments, the intermediate is building block 69.

[0238] In some embodiments, the intermediate is a combination of one or more covalently linked building blocks.

[0239] VIII. Kit The present disclosure contemplates kits comprising compounds of Formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein, and pharmaceutical compositions thereof. The kits are generally in the form of physical structures housing the various components described below, and can be utilized, for example, in practicing the methods described above.

[0240] The kits can include one or more compounds disclosed herein (e.g., contained in a sterile container) and can be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a ready-to-use form (e.g., tablet, capsule, syringe) or in a form that requires, for example, reconstitution or dilution before administration (e.g., powder). When the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit can also include a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged with or separately from the compounds described herein. Each component of the kit can be enclosed in a separate container, or all of the various containers can be contained in a single package. The kits of the present disclosure can be designed for conditions (e.g., refrigeration or freezing) necessary to properly maintain the contained components.

[0241] The kit may include a label or package insert containing identification and instructions for use of the components included in the kit (e.g., administration parameters, clinical pharmacology of the active ingredients (including mechanism of action, pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.)). The label or package insert may include manufacturer information such as lot number and expiration date. The label or package insert may, for example, be integral to the physical structure that contains the component, may be contained separately within the physical structure, or may be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0242] The label or insert may further include or incorporate a computer readable medium such as a disk (e.g., hard disk, card, memory disk), electronic storage medium such as CD-ROM / RAM, DVD-ROM / RAM, DVD, optical disk such as MP3, magnetic tape, RAM and ROM, or hybrids thereof such as magnetic / optical storage media, flash media, memory type cards, etc. In some embodiments, the kit is free of actual instructions, but means are provided for obtaining the instructions from a remote source, such as via the internet. [Example]

[0243] IX. Working Example The following examples illustrate methods for preparing various building blocks and exemplary compounds of Formula I. The following examples are offered to illustrate the present invention and are not intended to limit the disclosure as set forth in the claims.

[0244] A. Building Blocks The compounds of Formula I described herein are prepared by covalently linking the building blocks described in this section. The building blocks of this disclosure are identified in Table 1 below by abbreviation, reagent name, and CAS number, if known. For those without CAS numbers, experimental results are provided herein. Capitalization and lowercase letters in abbreviation names are relevant when they can indicate stereochemistry (i.e., 25ClF refers to Fmoc-L-2,5-dichlorophenylalanine, while 25Clf refers to Fmoc-D-2,5-dichlorophenylalanine). The sequence and details associated with covalently linking these building blocks are described in separate sections. [Table 1]

[0245] [Table 2]

[0246] [Table 3]

[0247] [Table 4]

[0248] [Table 5]

[0249] [Table 6]

[0250] [Table 7]

[0251] [Table 8]

[0252] [Table 9]

[0253] Building Block 1: Preparation of (S)-4,4-Difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0254] 1-(Trifluoromethyl)cyclohexane-1-carboxylic acid (500 mg, 2.55 mmol) was dissolved in thionyl chloride (3.6 mL, 51 mmol) and heated to reflux for 3 hours. The mixture was allowed to cool, and the thionyl chloride was removed by azeotropy with toluene. The crude material was carried on to the next step without further purification.

[0255] Methyl (S)-4,4-difluoropyrrolidine-2-carboxylate was dissolved in 5 ml of DCM. Pyridine (615 μl, 7.65 mmol) and the mixture was cooled to 0° C. A solution of dissolved 1-(trifluoromethyl)cyclohexane-1-carbonyl chloride was added dropwise to the reaction. The reaction was allowed to warm to room temperature and left for 12 hours. The reaction was quenched with NaHCO3 and the mixture was extracted three times with DCM. The combined extracts were dried over MgSO4, filtered and concentrated to provide methyl (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylate (743 mg, 85%). ESI MS m / z 343.1

[0256] Methyl (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylate (500 mg, 1.36 mmol) was dissolved in 10 ml of dioxane. A solution of dissolved LiOH (112 mg, 2.73 mmol) in 5 ml of water was added to the reaction and allowed to stand for 2 hours. The reaction was quenched with 1N HCl and extracted three times with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (80% EtOAc / hexane) to provide (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylic acid (450 mg, 93%) as a white powder. ESI MS m / z 329.1

[0257] Building Block 2: Preparation of (1-(trifluoromethyl)cyclohexane-1-carbonyl)-L-pyrroline [ka]

[0258] This compound was prepared according to the general synthetic procedure described for the preparation of building block 1, using methyl L-pyrroline instead of methyl (S)-4,4-difluoropyrrolidine-2-carboxylate. ESI MS m / z 293.12

[0259] Building Block 3: Preparation of (2S,4R)-4-Fluoro-1-(2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0260] This compound was prepared according to the general synthetic procedure described for the preparation of building block 1 using 2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate. ESI MS m / z 323.12

[0261] Building Block 4: Preparation of (2S,4R)-4-Fluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0262] This compound was prepared according to the general synthetic procedure described for the preparation of building block 1 using 1-(trifluoromethyl)cyclohexane-1-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate. ESI MS m / z 311.10

[0263] Building Block 5: Preparation of (2S,4R)-4-Fluoro-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0264] This compound was prepared according to the general synthetic procedure described for the preparation of building block 1 using 1-(trifluoromethyl)cyclopropane-1-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate. ESI MS m / z 269.07

[0265] Building Block 6: Preparation of (2S,4R)-4-Fluoro-1-[2-(trifluoromethyl)oxane-2-carbonyl]pyrrolidine-2-carboxylic acid [ka]

[0266] A mixture of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (3.6 g, 19.572 mmol, 1 equiv, 80%), 2-(trifluoromethyl)oxane-2-carboxylic acid (3.88 g, 19.572 mmol, 1.00 equiv), TCFH (8.22 g, 29.35 mmol, 1.5 equiv), and NMI (8.03 g, 97.860 mmol, 5 equiv) in ACN (50 mL) was stirred for 16 h at 25 °C under a nitrogen atmosphere. This mixture was directly purified by reverse flash chromatography along with EB2128270-100. This gave methyl (2S,4R)-4-fluoro-1-[2-(trifluoromethyl)oxane-2-carbonyl]pyrrolidine-2-carboxylate (3.5 g, 54.64%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 328

[0267] A mixture of methyl (2S,4R)-4-fluoro-1-[2-(trifluoromethyl)oxane-2-carbonyl]pyrrolidine-2-carboxylate (4.5 g, 13.750 mmol, 1 equiv.) and NaOH (2.75 g, 68.750 mmol, 5 equiv.) in MeOH (50 mL) / water (50 mL) was stirred for 16 h at 20 °C. Methanol was evaporated in vacuo. The aqueous phase was acidified by the addition of HCl (1N) and extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. This afforded (2S,4R)-4-fluoro-1-[2-(trifluoromethyl)oxane-2-carbonyl]pyrrolidine-2-carboxylic acid (4.0020 g, 92.03%) as a pale yellow solid. LCMS: (ESI, m / z): [M+H] + =314.0

[0268] Building Block 7: Preparation of (2S,4R)-4-Fluoro-1-((R)-3,3,3-trifluoro2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl)pyrrolidine-2-carboxylic acid [ka]

[0269] To a solution of (R)-3,3,3-2-hydroxy-2-methylpropanoic acid (6.7 g, 42.38 mmol, 1 equiv.) in DMF (200 mL) was added K2CO3 (11.72 g, 84.77 mmol, 2 equiv.) and bromomethylbenzene (8.70 g, 50.86 mmol, 6.04 mL, 1.2 equiv.). The mixture was stirred at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) showed that (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid was completely consumed and one new spot was formed. The reaction mixture was poured into 100 mL of ammonium chloride and then extracted with 200 mL of ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 200:1 to 5:1) to give benzyl (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (7.2 g, crude) as a white oil.

[0270] To a solution of benzyl (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (3.6 g, 14.50 mmol, 1 equiv.) and 1-(2-bromoethoxy)-2-methoxyethane (5.31 g, 29.01 mmol, 2 equiv.) in DMF (150 mL) was added NaH (638.14 mg, 15.96 mmol, 60% purity, 1.1 equiv.) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 5:1) showed the completion of the reaction. The reaction mixture was added to 100 mL of ammonia chloride solution and then extracted with 180 mL of ethyl acetate (90 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether: ethyl acetate = 200:1 to 5:1) to give benzyl (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoate (6.7 g, crude) as a yellow oil.

[0271] A mixture of benzyl (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoate (4.3 g, 12.27 mmol, 1 equiv.) in MeOH (150 mL) was added to Pd / C (3 g, 10% purity) at 20 °C. The mixture was then degassed and purged with H three times. The mixture was then stirred at 50 °C for 2 h under an H atmosphere (15 psi). TLC (petroleum ether:ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction was filtered, and the filtrate was concentrated under reduced pressure to provide (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (6.2 g, crude) as a yellow oil.

[0272] To a solution of (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (5.6 g, 21.52 mmol, 1 equiv.) in DCM (90 mL) was added oxalyl dichloride (8.19 g, 64.56 mmol, 5.65 mL, 3 equiv.) and DMF (157.31 mg, 2.15 mmol, 165.59 μL, 0.1 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl chloride (6 g, crude) as a colorless oil.

[0273] To a solution of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (3.76 g, 20.48 mmol, 1 equiv., HCl) in DCM (50 mL) was added TEA (6.22 g, 61.44 mmol, 8.55 mL, 3 equiv.) at 0 °C. Then, a solution of (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl chloride (5.99 g, 21.50 mmol, 1.05 equiv.) in DCM (50 mL) was added to the above mixture at 0 °C. The mixture was stirred at 20 °C for 12 hours. LCMS showed that the reaction was complete and the desired material was detected. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, petroleum ether: ethyl acetate = 10:1 to 0:1) to give methyl (2S,4R)-4-fluoro-1-((R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl)pyrrolidine-2-carboxylate (7.3 g, 18.75 mmol, 91.56% yield) as a yellow oil.

[0274] To a solution of methyl (2S,4R)-4-fluoro-1-((R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl)pyrrolidine-2-carboxylate (7.74 g, 19.88 mmol, 1 equiv.) in THF (60 mL) and MeOH (60 mL) was added LiOH.HO (1.67 g, 39.76 mmol, 2 equiv.) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed that compound 6 was completely consumed and the desired material was detected. The reaction mixture was adjusted to pH 5 with a saturated solution of citric acid to separate some solids, then filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO, DCM:Methanol = 100:1 to 5:1) to give (2S,4R)-4-fluoro-1-((R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl)pyrrolidine-2-carboxylic acid (3.12 g, 7.95 mmol, 40.01% yield, 95.668% yield) as a white solid. LCMS (ESI+): m / z 376.0 (M+H)

[0275] Building Block 8: Preparation of (2S,4R)-1-[6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carbonyl]-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0276] To a stirred solution of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate (10 g, 52.579 mmol, 1 equiv.) in THF (150 mL) was added LDA (52.58 mL, 105.158 mmol, 2.00 equiv.) dropwise to give -78 o The resulting mixture was stirred at −78° C. for 45 min under an argon atmosphere. oC under argon atmosphere, and 1-(trifluoromethyl)-1λ3,2-benziodaoxol-3-one (33.23 g, 105.158 mmol, 2 equiv.) was added to -78 o The resulting mixture was stirred at −78° C. for 4 hours. o The mixture was stirred at 0°C to room temperature under an argon atmosphere. The desired product could be detected by GCMS. Then, LiOH (6.30 g, 262.895 mmol, 5 equiv.) and H2O (200 mL) were added dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (200 mL). The organic layer was washed with 4x100 mL of 1N NaOH. The mixture was diluted with concentrated HCl to 0°C. o The mixture was acidified to pH 5 with HCl. The aqueous layer was extracted with EtOAc (2x500 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with MeCN (2x200 mL). The filtrate was concentrated under reduced pressure. The crude product (20 g) was purified by MS-guided preparative HPLC under the following conditions: (C column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 41% B to 54% B, 54% B in 7 min; wavelength: 254; 220 nm; RT1 (min): 6.140; run number: 0) to give 6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid (900 mg, 6.31%) as a pale yellow solid. LCMS: (ESI, m / z): [M+H] - =243

[0277] To a stirred solution of 6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid (500 mg, 2.048 mmol, 1.00 equiv) and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (10.85 mg, 0.074 mmol, 1.8 equiv) in MeCN (5 mL) was added TCFH (861.87 mg, 3.072 mmol, 1.5 equiv) and NMI (1261.01 mg, 15.360 mmol, 7.5 equiv) dropwise to afford 0.05% methyl 2,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid (500 mg, 2.048 mmol, 1.00 equiv) and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (10.85 mg, 0.074 mmol, 1.8 equiv) in MeCN (5 mL). o The resulting mixture was stirred overnight at 50°C under an argon atmosphere. o The mixture was stirred at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water (0.1% FA), 40% to 100% gradient in 15 min; detector, UV 210 nm). This provided methyl (2S,4R)-1-[6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carbonyl]-4-fluoropyrrolidine-2-carboxylate (350 mg, 42.12%) as a pale yellow solid. LCMS: (ESI, m / z): [M+H] + =374

[0278] To a stirred solution of methyl (2S,4R)-1-[6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carbonyl]-4-fluoropyrrolidine-2-carboxylate (380 mg, 1.018 mmol, 1.00 equiv.) in THF (3 mL) / HO (3 mL) was added LiOH (44.91 mg, 1.876 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. The desired product could be detected by LCMS. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (10 mL). The mixture / residue was acidified to pH 4 with HCl (aq.). The aqueous layer was extracted with EtOAc (10 mL). The resulting mixture was concentrated under reduced pressure. This gave (2S,4R)-1-[6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (319.6 mg, 92.51%) as a white solid. LCMS: (ESI, m / z): [M+H] - =358

[0279] Building Block 9: Preparation of (2S,4R)-1-[3,3-Difluoro-1-(trifluoromethyl)cyclopentanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0280] This compound was prepared according to the general synthetic procedure described for the preparation of building block 8, using methyl 3,3-difluorocyclopentane-1-carboxylate instead of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate. ESI MS m / z 332

[0281] Building Block 10: Preparation of (2S,4R)-1-[4,4-Difluoro-1-(trifluoromethyl)cyclohexanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0282] This compound was prepared according to the general synthetic procedure described for the preparation of building block 8, using ethyl 4,4-difluorocyclohexane-1-carboxylate instead of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate. ESI MS m / z 348

[0283] Building Block 11: Preparation of (2S,4R)-1-(1-(difluoromethyl)-3,3-difluorocyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0284] To a stirred solution of 1,1-diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (10 g, 34.681 mmol, 1 equiv.) in DCM (100 mL) was added DIBAl-H (69.36 mL, 69.362 mmol, 2 equiv., 1 M in DCM) dropwise at −78°C under an argon atmosphere. The resulting mixture was stirred for 4 h at −78°C under an argon atmosphere. The desired product could be detected by GCMS. The reaction was quenched with 2 N HCl (aq.) at 0°C. The aqueous layer was extracted with CHCl (2×50 mL). The combined organics were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (2.1 g, 24.98%) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =230

[0285] A mixture of isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (2.1 g, 9.120 mmol, 1 equiv.) in 6N HCl (25 mL) was stirred overnight at room temperature. The desired product could be detected by GCMS. The aqueous layer was extracted with CHCl (50 mL). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. This gave isopropyl 1-formyl-3-oxocyclobutane-1-carboxylate (1 g, 53.58%) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =184

[0286] To a stirred solution of isopropyl 1-formyl-3-oxocyclobutane-1-carboxylate (1 g, 5.429 mmol, 1 equiv.) in DCM (20 mL) was added DAST (4.81 g, 29.860 mmol, 5.5 equiv.) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred overnight at room temperature under an argon atmosphere. The desired product could be detected by GCMS. The reaction was quenched by the addition of saturated NaHCO3 (aq.) (100 mL) at 0 °C. The residue was purified by silica gel column chromatography, eluting with CHCl2, to give isopropyl 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylate (1 g, 72.65%) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =228

[0287] To a stirred solution of isopropyl 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylate (1.5 g, 6.574 mmol, 1 equiv.) in THF (20 mL) was added dropwise 0.1 mL of NaOH (0.79 g, 19.722 mmol, 3 equiv.) in HO (20 mL). oC. The resulting mixture was stirred overnight at room temperature. The desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and acidified to pH=5 with HCl (aq.). The aqueous layer was extracted with EtOAc (2x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. This gave 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylic acid (730 mg, 56.69%) as a colorless oil. LCMS: (ESI, m / z): [M+H] - =185

[0288] To a solution of 1-(difluoromethyl)-3,3-difluorocyclobutane-1-carboxylic acid (1 g, 5.373 mmol, 1 equiv.), TCFH (2.26 g, 8.059 mmol, 1.5 equiv.), and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (0.87 g, 5.910 mmol, 1.1 equiv.) in ACN (20 mL) was added NMI (3.31 g, 40.297 mmol, 7.5 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred for 16 h at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 40 min; detector, UV 220 nm. This gave methyl (2S,4R)-1-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (300 mg, 15.94%) as a brown solid. LCMS: (ESI, m / z): [M+H] + = 315.24

[0289] To a solution of methyl (2S,4R)-1-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (600 mg, 1.903 mmol, 1 equiv.) in THF (10 mL) was added LiOH (136.75 mg, 5.709 mmol, 3 equiv.) in HO (10 mL) at 0 °C under a nitrogen atmosphere. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo to remove THF. The aqueous layer was acidified to pH = 5 with 1 N HCl. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated in vacuo. This gave (2S,4R)-1-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid (0.4957 g, 84.80%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 301.21

[0290] Building Block 12: Preparation of (2R)-2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoropropanoic acid [ka]

[0291] To a stirred solution of trifluoro-D-alanine (700 mg, 4.893 mmol, 1 equiv.) and TEA (4.08 mL, 29.358 mmol, 6.0 equiv.) in THF (14.00 mL) was added BocO (1.57 mL, 7.339 mmol, 1.5 equiv.) in small portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (15 mL). The organic layer was washed with dilute HCl (aq.) (1×15 mL) and water (1×15 mL), dried, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to provide (2R)-2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoropropanoic acid (0.4712 g, 37.62%) as a white solid. LCMS: (ESI, m / z): [M−H] - =242.2

[0292] Building Block 13: Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoropropanoic acid [ka]

[0293] This compound was prepared according to the general synthetic procedure described herein for the preparation of building block 12 using trifluoro-L-alanine. ESI MS m / z 242.2

[0294] Building Block 14: Preparation of (R)-2-(Difluoromethoxy)-3,3,3-trifluoro-2-methylpropanoic Acid [ka]

[0295] (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7.0 g, 44.3 mmol) was dissolved in DMF (70 ml), K2CO3 (6.7 g, 48.7 mmol) was added, and the mixture was stirred for 10 minutes. Benzyl bromide (8.34 g, 48.7 mmol) was added, and the reaction mixture was stirred at room temperature for another 4 hours. The mixture was quenched with water (150 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (70 mL x 3), dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1) to give benzyl (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (7.7 g, 73%) as an anhydrous liquid. ESI MS m / z: 248.07

[0296] Aqueous KOH (20 wt%, 41 mL, 176.4 mmol) was added to a mixture of benzyl (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (7.3 g, 29.4 mmol) and DCM (150 mL) at 0 °C with vigorous stirring. Then, a solution of TMSCFBr (9.0 g, 44.0 mmol) in DCM (30 mL) was added to the mixture at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding water (100 mL) and extracted with CHCl (50 mL × 3). The organic layers were combined and dried over anhydrous MgSO. The solvent was removed in vacuo and purified by preparative HPLC (water (0.01 mol / L NH4HCO3):ACN = 100% to 75%) to obtain the product benzyl (R)-2-(difluoromethoxy)-3,3,3-trifluoro-2-methylpropanoate (2.2 g, 25%) as a colorless liquid. ESI MS m / z: 298.06

[0297] A mixture of benzyl (R)-2-(difluoromethoxy)-3,3,3-trifluoro-2-methylpropanoate (2.2 g, 7.38 mmol) and 10% Pd / C (600 mg) in MeOH (100 mL) was stirred at room temperature for 1 hour under a H atmosphere. The Pd / C was then removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (DCM:MeOH = 100:0 to 50:1) to afford the desired product (850 mg, 55%) as a light brown liquid. ESI MS m / z: 208.06.

[0298] Building block 15: N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine Preparation of [ka]

[0299] To a solution of methyl ((benzyloxy)carbonyl)-L-lysinate (5g, 16.99 mmol) in THF (84 ml) was added cesium carbonate (16.57g, 50.99 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.58 ml, 17.84 mmol). The reaction was allowed to proceed at 60°C for 4 hours. Upon completion, the reaction was cooled, quenched with water, and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and reduced. The crude product was carried forward without further purification. ESI MS m / z 464.1

[0300] Methyl N2-((benzyloxy)carbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysinate (6.0 g, 12.93 mmol) was added to dioxane (64 ml), and to this was added a solution of NaHCO3 (3.25 g, 38.79 mmol) dissolved in water (20 ml). Boc2O (5.5 g, 25.39 mmol) was added, and the reaction was carried out at room temperature for 12 hours. Upon completion of the reaction, water was added, and the organic matter was extracted three times with EtOAc. The combined organic matter was dried over MgSO4, filtered, and reduced. The crude material was purified by column chromatography (60% EtOAc / Hex) to provide the desired product (5.7 g, 93%). ESI MS m / z 476.3

[0301] Methyl N2-((benzyloxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysinate (5.2g, 10.92mmol) was dissolved in dioxane (120ml). To this was added a solution of lithium hydroxide (895mg, 21.82mmol) and the reaction was carried out at room temperature for 2 hours. After that, a saturated solution of citric acid was added to the reaction and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and reduced to give the crude product, which was carried on to the next step without further purification. ESI MS m / z 462.20

[0302] N2-((benzyloxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine was suspended in MeOH (150 ml). Palladium (10% on carbon, 1.09 mmol, 116 mg) was added, and the mixture was stirred under 1 atm of hydrogen for 30 h. The resulting suspension was filtered and reduced. The crude product was dissolved in dioxane (110 ml), and to this was added a solution of NaHCO3 (4.5 g, 53.5 mmol) in (80 ml), and FMOCOSu (3.8 g, 11.27 mmol) was added. The mixture was stirred for 12 h. Upon completion, a saturated solution of citric acid was added, and the organics were extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and reduced. The crude product was purified by column chromatography (80% EtOAc) to give N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine as a white powder after lyophilization (5.7 g, 95%). ESI MS m / z 550.18

[0303] Building Block 16: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-fluorophenyl)propanoic acid [ka]

[0304] Step 1: Synthesis of (2-chloro-5-fluorophenyl)methanol [ka]

[0305] 2-Chloro-5-fluorobenzaldehyde (1 g, 6.32 mmol) was dissolved in MeOH (30 mL) and cooled to 0 °C. NaBH (257 mg, 6.96 mmol) was added in two batches, then the mixture was warmed to room temperature and stirred for 1 h. The reaction was then quenched with 1 N HCl and extracted three times with EtOAc. The combined organics were dried over MgSO, filtered, and the solvent was reduced. The crude product was carried forward without further purification.

[0306] Step 2: Synthesis of 2-(bromomethyl)-1-chloro-4-fluorobenzene [ka]

[0307] (2-Chloro-5-fluorophenyl)methanol was dissolved in DCM (80 ml) and cooled to 0° C. To this was added phosphorus tribromide (610 μl, 6.32 mmol) dropwise. After the addition, the reaction was carried out at room temperature for 4 hours. Upon completion, the reaction was cooled in an ice bath. Saturated sodium bicarbonate was added until the mixture reached pH 7. The organics were then extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude product was carried on to the next reaction without further purification.

[0308] Step 3: Synthesis of 2-(2-chloro-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine [ka]

[0309] A three-necked round-bottom flask equipped with a thermometer, septum, and argon inlet was charged with (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (693 mg, 3.76 mmol). Dry THF (37 mL) was added, and the reaction was cooled to −78°C. To this was added 2.5 M nBuLi (1.8 mL) dropwise. The reaction was carried out at −78°C for 30 minutes. A solution of 2-(bromomethyl)-1-chloro-4-fluorobenzene (1.0 g, 4.52 mmol) in THF (20 mL) was then added. The reaction was carried out at −78°C for 2 hours. The reaction was then quenched with saturated ammonium chloride and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude material was purified by column chromatography (15% EtOAc / Hex) to provide the desired product (2S,5R)-2-(5-chloro-2-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.5 g, 73%) as a clear oil. ESI MS m / z 231.05

[0310] Step 4: Synthesis of methyl 2-amino-3-(2-chloro-5-fluorophenyl)propanoate [ka]

[0311] 2-(2-Chloro-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.5 g, 4.60 mmol) was dissolved in THF (50 mL) and cooled to 0 °C in an ice bath. 2N HCl (65 mL) was added dropwise. The reaction was then warmed to room temperature and reacted for 2 h. Upon completion, the reaction was cooled in an ice bath, and NH4OH was added until a pH of 8–9 was reached. The reaction was then extracted three times with EtOAc, and the combined organics were dried over MgSO4, filtered, and reduced in solvent. The crude product was purified by column chromatography (60% EtOAc / Hex) to provide the desired product, methyl 2-amino-3-(2-chloro-5-fluorophenyl)propanoate (800 mg, 75%), as a clear oil.

[0312] Step 5: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-fluorophenyl)propanoic acid [ka]

[0313] Methyl 2-amino-3-(2-chloro-5-fluorophenyl)propanoate (800 mg, 3.46 mmol) was dissolved in dioxane (12 ml), and a solution of LiOH (290 mg, 6.92 mmol) in water (23 ml) was added to the solution. The reaction was carried out for 1 hour. The mixture was then cooled in an ice bath, and 2N HCl was added until the pH reached 4-5. A solution of NaHCO3 (1.4 g, 16.6 mmol) in water (20 ml) was added, followed by a solution of FmocOSu (1.2 g, 3.56 mmol) in dioxane (30 ml). The reaction was carried out at room temperature for 12 hours. The reaction was quenched with 1N HCl and then extracted three times with EtOAc. The combined organic layer was dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography (50% EtOAc) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-fluorophenyl)propanoic acid (1.3 gr, 85%) as a white solid. ESI MS m / z 439.10

[0314] Building Block 17: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,6-dichloro-2-fluorophenyl)propanoic acid [ka]

[0315] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 3,6-dichloro-2-fluorobenzaldehyde as the starting material. ESI MS m / z 473.0

[0316] Building Block 18: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2,5-difluorophenyl)propanoic acid [ka]

[0317] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 2,5-difluorobenzaldehyde as the starting material. ESI MS m / z 423.13

[0318] Building Block 19: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chloro-5-fluorophenyl)propanoic acid [ka]

[0319] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 2-chloro-5-fluorobenzaldehyde as the starting material. ESI MS m / z 439.10

[0320] Building Block 20: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-methylphenyl)propanoic acid [ka]

[0321] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-chloro-2-methylbenzaldehyde as the starting material. ESI MS m / z 435.12

[0322] Building Block 21: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(trifluoromethoxy)phenyl)propanoic acid [ka]

[0323] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-chloro-2-(trifluoromethoxy)benzaldehyde as the starting material. ESI MS m / z 505.09

[0324] Building Block 22: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-methoxyphenyl)propanoic acid [ka]

[0325] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-chloro-2-methoxybenzaldehyde as the starting material. ESI MS m / z 451.12

[0326] Building Block 23: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-bromo-2-chlorophenyl)propanoic acid [ka]

[0327] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-bromo-2-chlorobenzaldehyde as the starting material. ESI MS m / z 499.02

[0328] Building Block 24: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-bromo-5-chlorophenyl)propanoic acid [ka]

[0329] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 2-bromo-5-chlorobenzaldehyde as the starting material. ESI MS m / z 499.02

[0330] Building Block 25: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-iodophenyl)propanoic acid [ka]

[0331] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-chloro-2-iodobenzaldehyde as the starting material. ESI MS m / z 547.00

[0332] Building Block 26: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(difluoromethoxy)phenyl)propanoic acid [ka]

[0333] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, using 5-chloro-2-(difluoromethoxy)benzaldehyde as the starting material. ESI MS m / z 487.10

[0334] Building Block 27: Preparation of (2S)-3-(3,3-Difluorocyclobutyl)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic Acid [ka]

[0335] This compound was prepared according to the general synthetic procedure described for the preparation of building block 16, steps 3-5, using 3-(bromomethyl)-1,1-difluorocyclobutane instead of 2-(bromomethyl)-1-chloro-4-fluorobenzene. ESI MS m / z 402.3

[0336] Building Block 28: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoic acid [ka]

[0337] Step 1: Synthesis of 5-chloro-2-(cyclopropylmethoxy)benzaldehyde [ka]

[0338] To a solution of 5-chloro-2-hydroxybenzaldehyde (1.5g, 9.61mmol) in DMF (20ml) was added K2CO3 (2.0g, 14.4mmol). This was allowed to react for 10 minutes, and then bromomethylcyclopropane (2.5g, 15.3mmol) was added. This was allowed to react overnight at room temperature. Upon completion, the mixture was quenched with water, and the organics were extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography (15% EtOAc / hexane) to give 5-chloro-2-(cyclopropylmethoxy)benzaldehyde (1.8g, 90%) as a clear oil. ESI MS m / z 210.04

[0339] Step 2: Synthesis of 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene [ka]

[0340] 5-Chloro-2-(cyclopropylmethoxy)benzaldehyde (2.1 g, 10.0 mmol) was dissolved in EtOH (0.5 M) and the mixture was cooled to 0° C. in an ice bath. Sodium borohydride (407 mg, 11 mmol) was added in three portions. The mixture was then warmed to room temperature and allowed to react for 1 hour. Upon completion, the solvent was reduced and redissolved in DCM. 1 M HCl was added and the organics were extracted three times with DCM. The combined organics were dried over MgSO4, filtered and the solvent reduced to provide crude (5-chloro-2-(cyclopropylmethoxy)phenyl)methanol, which was carried on to the next reaction without further purification.

[0341] (5-Chloro-2-(cyclopropylmethoxy)phenyl)methanol (2.1 g, 9.9 mmol) was dissolved in DCM (40 ml) and cooled to 0° C. in an ice bath. Phosphorus tribromide (2.7 g, 9.9 mmol) was added dropwise and the mixture was allowed to warm to room temperature. The reaction was carried out for 4 hours. Upon completion, the reaction was cooled in an ice bath and a cold solution of saturated NaHCO3 was added until pH 7. The mixture was extracted three times with DCM and the combined organics were dried over MgSO4 and the solvent was reduced. The crude product, 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene, was carried on to the next reaction without further purification.

[0342] Step 3: Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoate [ka]

[0343] To a 100 ml round-bottom flask were added O-allyl-N-(9-anthracenylmethyl)cinchodinium bromide (487 mg, 0.805 mmol) and N-(diphenylmethylene)glycine tert-butyl ester (2.2 g, 8.05 mmol). This was dissolved in DCM, and the mixture was cooled to -20 °C. To this was added 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene (2.5 g, 9.15 mmol), followed by 45% aqueous KOH (4.35 ml). The reaction was carried out for 16 hours at -20 °C. Water was then added, and the organics were extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and reduced. The crude material was then redissolved in dioxane. 2 N HCl (20 ml) was added dropwise, and the reaction was stirred at room temperature for 1 hour. Upon completion, the mixture was cooled in an ice bath, and saturated NaHCO was added until the pH reached 7-9. Then, a dissolved solution of FmocOSu (2.8 g, 8.30 mmol) was added, and the mixture was allowed to react for 12 hours. The solution was quenched with water, and the organics were extracted three times with EtOAc. The combined organics were dried over MgSO, filtered, and the solvent was reduced. The crude was purified by column chromatography (25-50% EtOAc / hexanes) to provide the desired product tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoate (3.5 g, 85%) as a clear oil. ESI MS m / z 547.2

[0344] Step 4: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoic acid [ka]

[0345] The starting material tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoate (3.5 gr, 6.39 mmol) was dissolved in DCM (20 ml), and to this was added 50% TFA in DCM (30 ml), and the reaction was carried out to completion at room temperature. Then, the solvent was reduced, and the crude was purified on column chromatography (80% EtOAc / hexane) to give the desired product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoic acid (3.1 gr, 100%) as a white solid. ESI MS m / z 491.1

[0346] Building Block 29: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-phenoxyphenyl)propanoic acid [ka]

[0347] To a solution of 5-chloro-2-fluorobenzaldehyde (1.0 g, 6.32 mmol) in DMF (20 ml) was added K2CO3 (3.93 g, 28.4 mmol). This was allowed to react for 10 minutes, and then phenol (0.89 g, 9.48 mmol) was added. This was allowed to react overnight at 110°C. Upon completion, the mixture was quenched with water, and the organics were extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography (15% EtOAc / hexane) to provide 5-chloro-2-phenoxybenzaldehyde (1.0 g, 68%) as a clear oil. ESI MS m / z 232.03

[0348] Building block 29 was prepared from 5-chloro-2-phenoxybenzaldehyde according to the general synthetic procedure described for the preparation of building block 28, steps 2-4. ESI MS m / z 513.13

[0349] Building Block 30: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopentylmethoxy)phenyl)propanoic acid [ka]

[0350] This compound was prepared according to the general synthetic procedure described herein for the preparation of building block 28, using (bromomethyl)cyclopentane instead of bromomethylcyclopropane. ESI MS m / z 519.18

[0351] Building Block 31: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopentyloxy)phenyl)propanoic acid [ka]

[0352] This compound was prepared according to the general synthetic procedure described for the preparation of building block 28, using bromocyclopentane instead of bromomethylcyclopropane. ESI MS m / z 505.17

[0353] Building Block 32: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclohexyloxy)phenyl)propanoic acid [ka]

[0354] This compound was prepared according to the general synthetic procedure described for the preparation of building block 28, using bromocyclohexane instead of bromomethylcyclopropane. ESI MS m / z 519.17

[0355] Building Block 33: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)propanoic acid [ka]

[0356] This compound was prepared according to the general synthetic procedure described for the preparation of building block 28, except that 2,2,2-trifluoroethyl trifluoromethanesulfonate was used instead of bromomethylcyclopropane. ESI MS m / z 519.11

[0357] Building Block 34: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclobutylmethoxy)phenyl)propanoic acid [ka]

[0358] A mixture of 4-chloro-2-iodophenol (6 g, 23.580 mmol, 1 equiv.) and K2CO3 (9.85 g, 70.740 mmol, 3 equiv.) in DMF (50 mL) was treated with (bromomethyl)cyclobutane (4.22 g, 28.296 mmol, 1.2 equiv.) and stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was diluted with water and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20 / 1-5 / 1) to give 4-chloro-1-(cyclobutylmethoxy)-2-iodobenzene (7.3 g, 95.97%) as a white solid. No MS signal was observed by LCMS.

[0359] To a stirred solution of 4-chloro-1-(cyclobutylmethoxy)-2-iodobenzene (4 g, 12.400 mmol, 1 equiv.), CuI (0.05 g, 0.248 mmol, 0.02 equiv.), and Pd(dppf)ClCHCl (0.10 g, 0.124 mmol, 0.01 equiv.) in DMA (30 mL) was added methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(iodozincio)propanoate (24.80 mL, 24.800 mmol, 2.0 equiv.) dropwise at 20 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere. The reaction was directly purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 60% gradient in 10 min; detector, UV 210 nm. This gave methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propanoate (3.1 g, 62.83%) as a dark brown oil. LCMS: (ESI, m / z): [M+Na] + = 420

[0360] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxyphenyl)propanoate (2.9 g, 7.555 mmol, 1 equiv.) in THF (30 mL) was added aqueous sodium hydroxide (1.51 g, 37.775 mmol, 5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 12 h. The reaction was acidified to pH = 5 with HCl (1 N). The resulting mixture was extracted with EtOAc (2 * 50 mL). The combined organic layers were washed with brine (1 * 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxyphenyl)propanoic acid (2.3129 g, 82.78%) as a white solid. LCMS: (ESI, m / z): [M+Na] + =406.20

[0361] A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propanoic acid (2.2 g, 5.731 mmol, 1 equiv.) in HCl (4 M in EtOAc) was stirred for 12 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give (2S)-2-amino-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propanoic acid (2.0688 g, 127.22%) as a white solid. LCMS: (ESI, m / z): [M+H] + =283.90

[0362] To a stirred mixture of (2S)-2-amino-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propanoic acid (1.6 g, 5.639 mmol, 1 equiv.) and NaHCO3 (2.37 g, 28.195 mmol, 5 equiv.) in 1,4-dioxane:HO (3:1, 50 mL) was added 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (2.28 g, 6.767 mmol, 1.2 equiv.) in small portions at 0 °C. The resulting mixture was stirred for an additional 12 h at room temperature. The reaction was acidified to pH = 5 with HCl (aq. 1N). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 40 min; detector, UV 254 nm. This gave (2S)-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (1.3205 g, 46.28%) as a white solid. LCMS: (ESI, m / z): [M+H] + =506.15

[0363] Building Block 35: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-cyclobutoxyphenyl)propanoic acid [ka]

[0364] This compound was prepared according to the general synthetic procedure described for the preparation of building block 34, using bromocyclobutane instead of (bromomethyl)cyclobutane. ESI MS m / z 492.1

[0365] Building Block 36: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid [ka]

[0366] To a stirred mixture of methyl 5-chloro-2-hydroxybenzoate (10 g, 53.593 mmol, 1 equiv.) and K2CO3 (14.81 g, 107.186 mmol, 2 equiv.) in DMF was added 2-chloroethyl p-tosylate (13.84 g, 58.952 mmol, 1.1 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed successively with NH4Cl (3 × 150 mL), NH4HCO3 (1 × 150 mL), and brine (1 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give methyl 5-chloro-2-(2-chloroethoxy)benzoate (13 g, 97.38%) as an off-white solid. LCMS: (ESI, m / z): [M+H] + = 249.00

[0367] To a stirred solution of methyl 5-chloro-2-(2-chloroethoxy)benzoate (13 g, 52.190 mmol, 1 equiv.) in THF was added t-BuOK (65.24 mL, 65.240 mmol, 1.25 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction was diluted with water (200 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to provide methyl 5-chloro-2-(ethenyloxy)benzoate (6.9 g, 51.61%) as a colorless oil.

[0368] The aqueous layer was acidified to pH 3 with HCl and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was collected and reacted with CHI to give another batch of product.

[0369] A solution of methyl 5-chloro-2-(ethenyloxy)benzoate (6.9 g, 32.451 mmol, 1 equiv.) in CHCl was treated with chloro(iodo)methane (17.17 g, 97.353 mmol, 3 equiv.) for 20 min at 0 °C under a nitrogen atmosphere, and then diethylzinc (48.68 mL, 48.677 mmol, 1.5 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The reaction was quenched with NHCl (100 mL) and NH.H0 (10 mL) at 0 °C. The resulting mixture was diluted with water (100 mL) and extracted with CHCl (2 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (7:1) to give methyl 5-chloro-2-cyclopropoxybenzoate (6.25 g, 84.97%) as a pale green oil.

[0370] To a stirred solution of methyl 5-chloro-2-cyclopropoxybenzoate (6.25 g, 27.574 mmol, 1 equiv.) in toluene (130 mL) was added DIBAl-H (46.08 mL, 227.124 mmol) dropwise at −78°C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature, then quenched with NH4Cl at 0°C and diluted with water (200 mL). The mixture was then acidified to pH 5 with dilute HCl (1N) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give (5-chloro-2-cyclopropoxyphenyl)methanol (4.9 g, 89.45%) as a light brown solid.

[0371] To a stirred solution of (5-chloro-2-cyclopropoxyphenyl)methanol (3.73 g, 18.777 mmol, 1 equiv.) in DCM (37 mL) was added PBr (7.62 g, 28.166 mmol, 1.5 equiv.) dropwise at 0 °C under a N atmosphere. The mixture was stirred for 2 h at 0 °C and then neutralized to pH = 7 with NaHCO. The resulting mixture was extracted with EtOAc (4 × 200 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc (80:1) to give 2-(bromomethyl)-4-chloro-1-cyclopropoxybenzene (3.35 g, 68.22%) as a white oil.

[0372] A solution of (3R)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine (2.60 g, 14.090 mmol, 1.1 equiv.) in THF (33 mL) was treated with n-BuLi (7.8 mL, 82.797 mmol, 6.46 equiv.) for 0.5 h at −78°C under a nitrogen atmosphere, and the resulting solution was heated at −78°C for 1 h. o The mixture was stirred at -78°C. To the above solution, 2-(bromomethyl)-4-chloro-1-cyclopropoxybenzene (3.35 g, 12.809 mmol, 1 equiv.) was added dropwise at -78°C. The mixture was stirred for 2 h at -78°C and then quenched with NH4Cl at -78°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: EtOAc (80:1) to give (2S,5R)-2-[(5-chloro-2-cyclopropoxyphenyl)methyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.06 g, 65.48%) as a white oil. LCMS: (ESI, m / z): [M+H] + = 365.40

[0373] To a stirred solution of (2S,5R)-2-[(5-chloro-2-cyclopropoxyphenyl)methyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.1 g, 8.496 mmol, 1 equiv.) in THF (30 mL, 370.283 mmol, 43.58 equiv.) was added HCl (2 M) (8.5 mL) at room temperature. The mixture was stirred for 2 h at room temperature and neutralized to pH = 7 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water in ACN, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave methyl (2S)-2-amino-3-(5-chloro-2-cyclopropoxyphenyl)propanoate (1.9 g, 82.91%) as a white oil. LCMS: (ESI, m / z): [M+H] + = 270.10

[0374] To a stirred solution of methyl (2S)-2-amino-3-(5-chloro-2-cyclopropoxyphenyl)propanoate (920 mg, 3.411 mmol, 1 equiv.) in MeOH (5 mL) was added NaOH (682.11 mg, 17.055 mmol, 5 equiv.) in HO (5 mL) dropwise at room temperature. The mixture was stirred at room temperature for 1 h and then acidified to pH=2 with dilute HCl (1N). The resulting mixture was concentrated under reduced pressure to provide the crude product, which was used in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 256.20

[0375] To a stirred solution of (2S)-2-amino-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid (850 mg, 3.324 mmol, 1 equiv.) in 1,4-dioxane (30 mL) / water (10 mL), 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (1143.77 mg, 3.390 mmol, 1.02 equiv.) and NaHCO3 (1396.27 mg, 16.620 mmol, 5 equiv.) were added in small portions at room temperature. The mixture was stirred for 2 h at room temperature and then acidified to pH = 2 with dilute HCl (1 N). The resulting mixture was extracted with EtOAc (5 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, HO in ACN, 0% to 100% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give (2R)-3-(5-chloro-2-cyclopropoxyphenyl)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (1.1361 g, 71.51%) as a white solid. LCMS: (ESI, m / z): [M+Na] + = 500.10

[0376] Building Block 37: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl)propanoic acid [ka]

[0377] To a stirred solution of 5-chloro-3-iodopyridin-2-ol (3.2 g, 12.527 mmol, 1 equiv.) and AgCO (4.15 g, 15.032 mmol, 1.2 equiv.) in toluene was added (bromomethyl)cyclopropane (3.38 g, 25.054 mmol, 2 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 3–4 h. The reaction was cooled to room temperature and quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × mL). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to provide 5-chloro-2-(cyclopropylmethoxy)-3-iodopyridine (3.6 g, 92.84%) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =310

[0378] A solution of 5-chloro-2-(cyclopropylmethoxy)-3-iodopyridine (5 g, 16.154 mmol, 1 equiv.) in DMA was treated with copper(I) iodide (0.62 g, 3.231 mmol, 0.2 equiv.) and Pd(dppf)Cl2 (2.36 g, 3.231 mmol, 0.2 equiv.) for 2 min under a nitrogen atmosphere, followed by the dropwise addition of methyl 2-[(tert-butoxycarbonyl)amino]-3-zinciopropanoate (3 mL, 9.692 mmol, 1.5 equiv., prepared from iodide and Zn powder) at room temperature. The resulting mixture was stirred at 80 °C for an additional 2–3 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (5 × mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoate (6.4 g, 102.95%) as a crude white solid. LCMS: (ESI, m / z): [M+Na] + = 385

[0379] To a stirring solution / mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoate (6.4 g, 16.629 mmol, 1 equiv.) in 20 mL of THF was added aqueous sodium hydroxide (NaOH (3.33 g, 83.145 mmol, 5 equiv.) in 20 mL of water) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 1-2 h at room temperature. The reaction was acidified to pH = 4 with dilute HCl. The resulting mixture was extracted with EtOAc (50 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, HO in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoic acid (4.8 g, 77.84%) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 371

[0380] To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoic acid (3.3 g, 8.899 mmol, 1 equiv.) and 2,6-lutidine (1.8 g, 18 mmol, 2 equiv.) in 30 mL of DCM was added trimethylsilyl triflate (2.78 g, 13.5 mmol, 1.5 equiv.) dropwise to give 0.05% methylsilyl triflate. oC over 5 minutes. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water in ACN, gradient from 0% to 100% in 40 minutes; detector, UV 254 nm. This gave (2S)-2-amino-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoic acid (1.6 g, 66.42%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 271

[0381] To a stirred solution of 1,4-dioxane:HO (40 mL, v / v=3 / 1), (2S)-2-amino-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoic acid (1.5 g, 5.541 mmol, 1 equiv.) and 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (1.87 g, 5.541 mmol, 1 equiv.) and NaCO (2.33 g, 27.705 mmol, 5 equiv.) were added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 1–2 h at room temperature. The residue was acidified to pH=5, then extracted with EtOAc (50 mL×3), and the organic layer was washed with brine, dried in vacuo, and concentrated. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, HO in ACN, 0% to 100% gradient in 60 min; detector, UV 254 nm to provide (2S)-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (691.5 mg, 25.32%) as a white solid. LCMS: (ESI, m / z): [M-tert-butyl] + =493

[0382] Building Block 38: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyridin-2-yl)phenyl)propanoic acid [ka]

[0383] Step 1: Synthesis of (2-bromo-5-chlorophenyl)methanol [ka]

[0384] To a solution of methyl 2-bromo-5-chlorobenzoate (10 g, 40.082 mmol, 1 equiv.) in THF was added lithium aluminum hydride (1.0 M in THF) (4.56 g, 120.246 mmol, 3 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. TLC showed OK (PE:EA=1:1). The reaction was quenched with saturated NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give (2-bromo-5-chlorophenyl)methanol (8 g, 90.12%) as a light brown oil. TLC: Rf=0.5 (PE / EA=1:1).

[0385] Step 2: Synthesis of 1-bromo-2-(bromomethyl)-4-chlorobenzene [ka]

[0386] To a solution of (2-bromo-5-chlorophenyl)methanol (8.0 g, 36.121 mmol, 1 equiv.) in CHCl was added PBr (19.55 g, 72.242 mmol, 2 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. TLC (PE / EA = 1:1) showed the reaction was complete. The reaction was quenched by the addition of saturated NHCl (aq.) (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 1-bromo-2-(bromomethyl)-4-chlorobenzene (5.89 g, 57.34%) as a brown oil. TLC: Rf =0.5 (PE / EA=3:1)

[0387] Step 3: Synthesis of tert-butyl (2S)-3-(2-bromo-5-chlorophenyl)-2-[(diphenylmethylidene)amino]propanoate [ka]

[0388] A solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (5.89 g, 20.712 mmol, 1 equiv.) in CHCl (100 mL) was treated with tert-butyl 2-[(diphenylmethylidene)amino]acetate (6.12 g, 20.712 mmol, 1 equiv.) and (2R,4R,5S)-1-(anthracen-9-ylmethyl)-5-ethenyl-2-[(S)-(prop-2-en-1-yloxy)(quinolin-4-yl)methyl]-1-azabicyclo[2.2.2]octan-1-ium bromide (0.63 g, 1.036 mmol, 0.05 equiv.) for 30 min at 0 °C under a nitrogen atmosphere, followed by KOH (11.62 g, To the resulting mixture was added dropwise 207.120 mmol, 10 equiv. at 0°C. The resulting mixture was stirred for another 2 h at 0°C. TLC detected the product (PE / EA=4:1). The reaction was quenched by the addition of water (30 mL) at room temperature and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give tert-butyl (2S)-3-(2-bromo-5-chlorophenyl)-2-[(diphenylmethylidene)amino]propanoate (1.5 g, 14.52%) as a light brown oil. LCMS: (ESI, m / z): [M+H] + = 497.60

[0389] Step 4: Synthesis of tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylidene)amino]propanoate [ka]

[0390] To a stirred solution of tert-butyl (2S)-3-(2-bromo-5-chlorophenyl)-2-[(diphenylmethylidene)amino]propanoate (2.1 g, 4.210 mmol, 1 equiv.) and 2-(tributylstannyl)pyridine (6.20 g, 16.840 mmol, 4 equiv.) in 1,4-dioxane, Pd(PPh3)4 (1.46 g, 1.263 mmol, 0.3 equiv.) and CuI (0.80 g, 4.210 mmol, 1 equiv.) were added in small portions at room temperature under a nitrogen atmosphere. The mixture was stirred overnight at 80 °C. The desired product was detected by LCMS. Water (50 mL) was added to the resulting mixture, which was then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This afforded tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylidene)amino]propanoate (1.5 g, 71.69%) as a pale yellow oil. LCMS: (ESI, m / z): [M+H] + = 497.20

[0391] Step 5: Synthesis of (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid [ka]

[0392] A solution of tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylidene)amino]propanoate (1.5 g, 3.018 mmol, 1 equiv.) in 1,4-dioxane (30 mL) was treated with HCl (6 M) (20 mL, 658.256 mmol, 218.12 equiv.) for 2 hours at 50°C under a nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was basified to pH 6 with NaOH (1 M). The resulting mixture was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 277.15

[0393] To a solution of (2S)-2-amino-3-[5-chloro-2-(pyridin-2-yl)phenyl]propanoic acid (1.2 g, 4.337 mmol, 1 equiv.) and NaHCO3 (0.52 g, 21.685 mmol, 5 equiv.) in 1,4-dioxane (50 mL) / water (15 mL) was added 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (1.61 g, 4.771 mmol, 1.1 equiv.) in small portions at room temperature under a nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was neutralized to pH = 6 with CH3COOH. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 100% gradient in 30 min; detector, UV 254 nm. This gave (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (0.2511 g, 11.60%) as an off-white solid. LCMS: (ESI, m / z): [M+H] + = 499.1

[0394] Building Block 39: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0395] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 516.1

[0396] Building Block 40: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(5-fluoropyridin-3-yl)phenyl)propanoic acid [ka]

[0397] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using (5-fluoropyridin-3-yl)boronic acid in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 517.05

[0398] Building Block 41: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0399] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 538.1

[0400] Building Block 42: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0401] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 578.0

[0402] Building Block 43: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0403] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 516.1

[0404] Building Block 44: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl)propanoic acid [ka]

[0405] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 516.1

[0406] Building Block 45: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyrimidin-5-yl)phenyl)propanoic acid [ka]

[0407] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38 using pyrimidin-5-ylboronic acid 4. LCMS: (ESI, m / z): [M+H] + = 500.1

[0408] Building Block 46: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(morpholinomethyl)phenyl)propanoic acid [ka]

[0409] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using potassium trifluoro(morpholinomethyl)borate in steps 4-5. LCMS: (ESI, m / z): [M+H] + = 521.09

[0410] Building Block 47: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoic acid [ka]

[0411] Step 1: Synthesis of 5-chloro-2-(thiazol-5-yl)benzaldehyde [ka]

[0412] To a 100 mL round-bottom flask was added 4-chloro-2-formylphenylboronic acid (4.0 g, 21.73 mmol), 5-bromothiazole (3.0 g, 18.51 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.5 g, 1.83 mmol) complexed with dichloromethane. This was dissolved in dioxane (90 mL) and 2 M K2CO3 (22 mL). Nitrogen was bubbled through the mixture, and the reaction was heated to 60 °C for 3 hours. Upon completion, the reaction was cooled and quenched with water. The crude product was extracted three times with EtOAc, and the combined organics were dried over MgSO4, filtered, and the solvent reduced. The crude material was purified by column chromatography (15%) to give 5-chloro-2-(thiazol-5-yl)benzaldehyde (4.0 g, 98%) as a white solid. ESI MS m / z 222.1

[0413] Step 2: Synthesis of (5-chloro-2-(thiazol-5-yl)phenyl)methanol [ka]

[0414] Ethanol was added to 5-chloro-2-(thiazol-5-yl)benzaldehyde (4.04 g, 18.01 mmol), and the solution was cooled to 0° C. in an ice bath. Sodium borohydride (740 mg, 20 mmol) was added in three portions, and the mixture was warmed to room temperature and reacted for 1 hour. The solvent was reduced, and 1N HCl was added. The crude product was then extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography to provide the desired product (5-chloro-2-(thiazol-5-yl)phenyl)methanol (4.0 g, 98%) as a clear oil. ESI MS m / z 225.0

[0415] Step 3: Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoate [ka]

[0416] The starting material (5-chloro-2-(thiazol-5-yl)phenyl)methanol (4.0 g, 17.77 mmol) was dissolved in DCM (30 ml) and cooled to 0° C. in an ice bath. PBr (1.7 ml, 17.77 mmol) was added dropwise, and the mixture was allowed to warm to room temperature. This allowed the reaction to proceed for 5 hours. Upon completion, the mixture was poured into a cold saturated solution of NaHCO. The crude product was extracted three times with DCM, and the combined organics were dried over MgSO, filtered, and the solvent was reduced. The crude product was carried on to the next step without further purification.

[0417] To a 100 ml round-bottom flask was added O-allyl-N-(9-anthracenylmethyl)cinchodinium bromide (574 g, 0.94 mmol) and N-(diphenylmethylene)glycine tert-butyl ester (2.83 g, 9.4 mmol). This was dissolved in DCM (60 ml) and the mixture was cooled to -20 °C. To this was added 5-(2-(bromomethyl)-4-chlorophenyl)thiazole (3.3 g, 11.53 mmol), followed by 45% aqueous KOH (5.3 ml). The reaction was carried out for 16 hours at -20 °C. Water was then added, and the organics were extracted three times with DCM. The combined organics were dried over MgSO, filtered, and reduced. The crude material was then redissolved in dioxane (100 ml). 2N HCl (20 ml) was added dropwise, and the reaction was stirred at room temperature for 1 hour. Upon completion, the mixture was cooled in an ice bath, and saturated NaHCO3 was added until the pH reached 7-9. A solution of dissolved FmocOSu (3.4 g, 10.08 mmol) was then added, and the mixture was allowed to react for 12 hours. The solution was quenched with water, and the organics were extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude material was purified by column chromatography (20% EtOAc / hexane) to provide the desired product, tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoate, as a clear oil (6.1 g, 94%). ESI MS m / z 560.1

[0418] Step 4: Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoate [ka]

[0419] The starting material was dissolved in DCM (30 ml), and to this was added 50% TFA in DCM (30 ml), and the reaction was carried out at room temperature until completion. Then, the solvent was reduced, and the crude was purified by column chromatography (80% EtOAc / hexane) to give the desired product tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoate (5.0 g, 91%) as a white solid. ESI MS m / z 504.9

[0420] Building Block 48: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-2-yl)phenyl)propanoic acid [ka]

[0421] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 2-bromothiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 504.09

[0422] Building Block 49: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)propanoic acid [ka]

[0423] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 3-bromopyrazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 501.15

[0424] Building Block 50: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0425] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 4-bromopyrazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 501.15

[0426] Building Block 51: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid [ka]

[0427] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 4-fluoro-2-formylphenylboronic acid and 3-bromopyrazole in steps 1-4. ESI MS m / z 485.18

[0428] Building Block 52: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-4-yl)phenyl)propanoic acid [ka]

[0429] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 4-bromothiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 504.09

[0430] Building Block 53: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(4-methylthiazol-5-yl)phenyl)propanoic acid [ka]

[0431] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 5-bromo-4-methylthiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 518.11

[0432] Building Block 54: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2,4-dimethylthiazol-5-yl)phenyl)propanoic acid [ka]

[0433] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 5-bromo-2-methylthiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 532.12

[0434] Building Block 55: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3,4-thiadiazol-2-yl)phenyl)propanoic acid [ka]

[0435] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 2-bromo-1,3,4-thiadiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 505.09

[0436] Building Block 56: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)propanoic acid [ka]

[0437] This compound was prepared according to the general synthetic procedure described for the preparation of block 47, using 4-bromo-2-methyl-2H-1,2,3-triazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 502.14

[0438] Building Block 57: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2-methylthiazol-5-yl)phenyl)propanoic acid [ka]

[0439] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47. ESI MS m / z 518.11

[0440] Building Block 58: Preparation of (S)-2((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-2-(thiazol-5-yl)phenylpropanoic acid [ka]

[0441] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 5-bromothiazole and (4-fluoro-2-formylphenyl)boronic acid instead of 5-bromothiazole and (4-chloro-2-formylphenyl)boronic acid in steps 1-4. ESI MS m / z 488.12.

[0442] Building Block 59: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)propanoic acid [ka]

[0443] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 2-bromo-5-methyl-1,3,4-thiadiazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 519.10

[0444] Building Block 60: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)propanoic acid [ka]

[0445] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 5-bromo-1-methyl-1H-pyrazole instead of 5-bromothiazole in steps 1-4. ESI MS m / z 501.15

[0446] Building Block 61: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyridin-3-yl)phenyl)propanoic acid [ka]

[0447] This compound was prepared according to the general synthetic procedure described for the preparation of building block 47, using 3-bromopyridine instead of 5-bromothiazole in steps 1-4. ESI MS m / z 498.1

[0448] Building Block 62: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chloro-[1,1'-biphenyl]-2-yl)propanoic acid [ka]

[0449] This compound was prepared according to the general synthetic procedure described for the preparation of building block 38, using bromobenzene instead of 5-bromothiazole in steps 1-4. LCMS: (ESI, m / z): [M+H] + = 497.14

[0450] Building Block 63: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)propanoic acid [ka]

[0451] 5-Chloro-2-fluorobenzaldehyde (2.0 g, 12.7 mmol) and sodium azide (852 mg, 13.10 mmol) were dissolved in DMF (6 ml). The mixture was heated to 60° C. and reacted for 8 hours, then cooled to room temperature. The reaction mixture was diluted with water and DCM, then acidified with 1N HCl to pH 4. The organics were extracted three times with DCM, dried over MgSO4, and the solvent was reduced. The crude mixture was purified by column chromatography (15% EtOAc / Hex) to provide the desired product (1.0 g, 86%). ESI MS m / z: 181.0

[0452] In a round-bottom flask, 2-azido-5-chlorobenzaldehyde (1 g, 5.52 mmol), trimethylsilylacetylene (852 μl, 5.79 mmol), CuSO (137 mg, 0.55 mmol), and sodium ascorbate (220 mg, 1.11 mmol) were combined. This was dissolved in a 4:1 mixture of t-butanol (20 mL) and water (5 mL). The reaction was allowed to react at 50° C. for 12 hours and then cooled to room temperature. The mixture was washed with water, and the organics were extracted three times with DCM. The combined organics were dried over MgSO, filtered, and reduced. The crude product was purified by column chromatography (25% EtOAc / hexanes) to provide the desired product (600 mg, 54%). ESI MS m / z: 207.02

[0453] 5-Chloro-2-(1H-1,2,3-triazol-1-yl)benzaldehyde (600 mg, 2.89 mmol) was dissolved in methanol and cooled to 0° C. in an ice bath. Sodium borohydride (130 mg, 3.51 mmol) was added in two small portions. The mixture was warmed to room temperature and reacted for 1 hour. The solvent was reduced, and 1N HCl was added. The crude product was extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography to provide the desired product (5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)methanol (600 mg, 99%) as a clear oil. ESI MS m / z: 225.0

[0454] (5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)methanol (600 mg, 2.89 mmol) was dissolved in DCM (20 ml) and cooled to 0° C. in an ice bath. Phosphorus tribromide (390 μl, 2.89 mmol) was added dropwise, and the mixture was warmed to room temperature and reacted for 12 hours. The reaction was then transferred to an ice-cold solution of saturated NaHCO3 until basic. The organics were then extracted three times with DCM. The combined organics were dried over MgSO4, filtered, and reduced. The crude material was carried on to the next reaction without further purification.

[0455] To a 100 ml round-bottom flask was added O-allyl-N-(9-anthracenylmethyl)cinchodinium bromide (40 mg, 0.06 mmol) and N-(diphenylmethylene)glycine tert-butyl ester (180 mg, 0.61 mmol). This was dissolved in DCM (15 ml) and the mixture was cooled to -20 °C. To this was added 1-(2-(bromomethyl)-4-chlorophenyl)-1H-1,2,3-triazole (200 mg, 0.074 mmol), followed by 45% aqueous KOH (340 μl). The reaction was carried out for 16 hours at -20 °C. Water was then added, and the organics were extracted three times with DCM. The combined organics were dried over MgSO, filtered, and reduced. The crude material was then redissolved in dioxane. 2N HCl (3 ml) was added dropwise, and the reaction was stirred at room temperature for 1 hour. Upon completion, the mixture was cooled in an ice bath, and saturated NaHCO3 was added until the pH reached 7-9. A solution of FmocOSu (215 mg, 6.37 mmol) was then added, and the mixture was allowed to react for 12 hours. The solution was quenched with water, and the organics were extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and the solvent was reduced. The crude was purified by column chromatography to provide the desired product, tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)propanoate (350 mg, 86%), as a clear oil. ESI MS m / z 544.19

[0456] The starting material was dissolved in DCM (10 ml), and to this was added 50% TFA in DCM (10 ml), and the reaction was carried out at room temperature until completion. Then, the solvent was reduced, and the crude was purified by column chromatography (60% EtOAc / hexane) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)propanoic acid (300 mg, 95%) as a white solid. ESI MS m / z 488.13

[0457] Building Block 64: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(dimethylamino)phenyl)propanoic acid [ka]

[0458] A 250 ml round-bottom flask was charged with 4-chloro-2-iodoaniline (5 g, 19.726 mmol, 1 equiv.) in DMF (20 ml), and NaH (2.37 g, 98.630 mmol, 5.00 equiv.) was added to the flask. o The mixture was added under a nitrogen atmosphere at 0 o C for 30 min. CHCl (14.00 g, 98.630 mmol, 5 equiv.) was added dropwise and the mixture was stirred at 0°C for 10 min. o C. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice water (500 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were combined and washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0-50%). This afforded 4-chloro-2-iodo-N,N-dimethylaniline (4 g, 72.03%) as a yellow solid. LCMS: (ESI, m / z): [M+H] + = 281.85

[0459] To a mixture of Zn (1.6 g, 24.14 mmol, 1.7 equiv.) in DMA (10 mL) was added ethylene dibromide (374 mg, 2 mmol, 0.14 equiv.) in one portion under N2. Then, TMSCl (153.4 mg, 1.42 mmol, 0.1 equiv.) was added slowly, and the mixture was stirred for 30 min at 25°C. oThe mixture was stirred at RT. A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (7 g, 21.3 mmol, 1.5 equiv.) in DMA (10 mL) was slowly added dropwise (30 min), and the resulting mixture was stirred at RT. o The resulting mixture was stirred at room temperature for 2 hours, maintaining a temperature below 80°C, and then added via cannula to a solution of 4-chloro-2-iodo-N,N-dimethylaniline (4 g, 14.2 mmol, 1 equiv.), Pd(dppf)Cl.CHCl (2.31 g, 2.842 mmol, 0.2 equiv.), and CuI (0.54 g, 2.842 mmol, 0.2 equiv.) in DMA (20 ml) under N. The mixture turned brown in color, and then the mixture was heated and cooled to 80°C. o The mixture was stirred at RT for 2 h under N2. The mixture was quenched with ice water (200 ml) and extracted with EtOAc (3 x 50 ml). The organic layers were combined and washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified.

[0460] A 100 ml round-bottom flask was charged with methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propanoate (1.88 g, 5.268 mmol, 1 equiv.) in THF (20 mL). NaOH (1.05 g, 26.340 mmol, 5 equiv.) in HO (4 mL) was added to the flask. oC under air atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified with 2N HCl (aq.) to pH=6. The resulting mixture was extracted with EtOAc (2 x 200 mL). The organic layers were combined and washed with brine, then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0-50%) to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propanoic acid (1.8 g, 99.66%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 343.05

[0461] A 100 ml round-bottom flask was charged with (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propanoic acid (1.8 g, 5.251 mmol, 1 equiv.) in DCM, and TFA (20 mL, 269.261 mmol, 51.28 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was used in the next step without further purification. LCMS: (ESI, m / z): [M+H] + =243.05

[0462] A 100 ml round-bottom flask was charged with (2S)-2-amino-3-[5-chloro-2-(dimethylamino)phenyl]propanoic acid (1.8 g, 7.417 mmol, 1 equiv.) in 1,4-dioxane (30 mL) and HO (10 mL), and NaHCO (3.13 g, 37.1910 mmol, 5 equiv.) and 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (2.01 g, 5.9526 mmol, 0.8 equiv.) were added at room temperature under air. The resulting mixture was stirred at room temperature for 16 h. The mixture was acidified to pH 6 with 2 N HCl (aq.) and extracted with EtOAc (3 x 100 mL). The organic layers were combined and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave (2S)-3-[5-chloro-2-(dimethylamino)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (708.6 mg, 20.55%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 464.15

[0463] Building Block 65: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(methoxymethyl)phenyl)propanoic acid [ka]

[0464] To a stirred solution of (4-chloro-2-iodophenyl)methanol (3 g, 11.174 mmol, 1 equiv.) in DMF (60 mL) was added NaH (0.80 g, 33.522 mmol, 3 equiv.) in small portions at 0 °C under air atmosphere. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. CHCl (7.93 g, 55.870 mmol, 5 equiv.) was added to the solution and stirred for 16 h at room temperature. The reaction was quenched with saturated NHCl (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient from 0% to 100% in 40 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to give 4-chloro-2-iodo-1-(methoxymethyl)benzene (3.3 g, 104.54%) as a pale yellow oil.

[0465] To a solution of Zn (2.11 g, 32.282 mmol, 2.4 equiv) in DMA (20 mL) was added 1,2-dibromoethane (0.26 g, 1.345 mmol, 0.1 equiv) in one portion under nitrogen. TMSCl (97.91 mg, 0.901 mmol, 0.067 equiv) was then added dropwise to give 20 mL of Zn. oThe mixture was added at 80°C and stirred for 30 minutes at room temperature. Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (8.85 g, 26.902 mmol, 2 equiv.) in DMA (20 mL) was added to the mixture, the temperature was raised to 50°C, and the mixture was stirred for 1.5 hours at room temperature under a nitrogen atmosphere. To the above mixture was added a solution of 4-chloro-2-iodo-1-(methoxymethyl)benzene (3.8 g, 13.451 mmol, 1 equiv.), CuI (0.51 g, 2.690 mmol, 0.2 equiv.), and Pd(dppf)Cl2 (0.98 g, 1.345 mmol, 0.1 equiv.) in DMA (30 mL). The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction was quenched with saturated NH4Cl (aq.) at 0°C and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% FA), gradient from 0% to 100% in 40 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to provide methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propanoate (3.8 g, 78.95%) as a light brown solid. LCMS: (ESI, m / z): [M+H] + =380.15

[0466] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propanoate (200 mg, 0.559 mmol, 1 equiv.) and LiOH (0.67 g, 27.945 mmol, 5 equiv.) in THF (30 mL) / HO (10 mL) was stirred for 2 h at room temperature. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (1N) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under vacuum to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propanoic acid (1.9 g, 98.88%) as a yellow oil. LCMS: (ESI, m / z): [M+H] + =366.10

[0467] A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propanoic acid (1.8 g, 5.236 mmol, 1 equiv.) in HCl (gas) in 1,4-dioxane (40 mL) was stirred for 2 hours at room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo to provide the crude product (2S)-2-amino-3-[5-chloro-2-(methoxymethyl)phenyl]propanoic acid (1.2 g, 94.05%) as a light brown oil, which was used in the next step without further purification. LCMS: (ESI, m / z): [M+H] + =244.10

[0468] To a solution of (2S)-2-amino-3-[5-chloro-2-(methoxymethyl)phenyl]propanoic acid (1.5 g, 6.155 mmol, 1 equiv.) in THF (30 mL, 370.283 mmol) / HO (10 mL, 555.093 mmol), NaHCO (3.88 g, 46.163 mmol, 7.5 equiv.) and 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (2.28 g, 6.771 mmol, 1.1 equiv.) were added. The resulting solution was stirred for 16 h at room temperature. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (1 N) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude product (1.8 g) was purified by preparative HPLC under the following conditions: Column: XBridge BEH C18 OBD Prep Column, 19*250 mm, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 59% B to 59% B in 22 min; Wavelength: 220 nm; RT1 (min): 16.5; Run number: 0). This gave (2S)-3-[5-chloro-2-(methoxymethyl)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid (1.8025 g, 62.76%) as a white solid. LCMS: (ESI, m / z): [M+H] + =488.1

[0469] Building Block 66: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-6-oxo-6-(piperidin-1-yl)hexanoic acid [ka]

[0470] To a stirred solution of aminoadipate (20 g, 124.103 mmol, 1.00 equiv.) in dioxane (1 L) was added sodium bicarbonate (52.13 g, 620.515 mmol, 5 equiv.) in HO (300 mL). To the above mixture was added 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (50.24 g, 148.924 mmol, 1.2 equiv.). o C. The resulting mixture was further stirred at room temperature overnight. The reaction was monitored by LCMS. The mixture was cooled to -5°C and acidified with dilute HCl to pH 1-2. The aqueous layer was extracted with ethyl acetate (3x200 mL). The organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA:PE (1:1) to give (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanedioic acid (35 g, 73.56%) as a white solid. LCMS: (ESI, m / z): [M+Na] + = 406

[0471] A solution / mixture of (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanedioic acid (5 g, 13.041 mmol, 1.00 equiv.), polyoxymethylene (7.5 g, 6.5 equiv.), and paratoluenesulfonate (0.22 g, 1.304 mmol, 0.1 equiv.) in toluene (300 mL) was heated for 16 h at 120°C. o C under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered. The filter cake was washed with ethyl acetate (100 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 4-[(4S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl]butanoic acid (5.1 g) as a white solid. LCMS: (ESI, m / z): [M+H] + = 396.41

[0472] A solution of 4-[(4S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl]butanoic acid (6.007 g, 12.153 mmol, 1.00 equiv), piperidine (1.03 g, 12.153 mmol, 1.0 equiv), [chloro(dimethylamino)methylidene]dimethylazanium; hexafluoro-l^[5]-phosphamide (5.11 g, 18.230 mmol, 1.5 equiv), and 1-methyl-1H-imidazole (2.99 g, 36.459 mmol, 3.0 equiv) in CH3CN (300 mL, 49.94 equiv) was heated overnight for 50 min. o The mixture was stirred at RT under a nitrogen atmosphere at 170°C. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated NaCl (3 x 100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography (EA: PE, 1:3) under the following conditions to afford 9H-fluoren-9-ylmethyl (4S)-5-oxo-4-[4-oxo-4-(piperidin-1-yl)butyl]-1,3-oxazolidine-3-carboxylate (4.7 g, 83.61%) as a colorless semi-solid. LCMS: (ESI, m / z): [M+H] + = 463

[0473] To a solution of 9H-fluoren-9-ylmethyl (4S)-5-oxo-4-[4-oxo-4-(piperidin-1-yl)butyl]-1,3-oxazolidine-3-carboxylate (5.46 g, 11.804 mmol, 1.00 equiv.) in THF (100 mL) was added NaOH (1.89 g, 47.216 mmol, 4.0 equiv.) and HO (47 mL). o C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred overnight. The desired product could be detected by LCMS. The reaction mixture was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 229

[0474] To a stirred solution of (2R)-2-amino-6-oxo-6-(piperidin-1-yl)hexanoic acid (3.63 g, 15.901 mmol, 1.00 equiv.) in dioxane (150 mL) and NaHCO (4.01 g, 47.703 mmol, 3 equiv.) in HO (50 mL) was added 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (6.44 g, 19.081 mmol, 1.2 equiv.) at room temperature under a nitrogen atmosphere. After stirring overnight, the mixture was acidified with concentrated hydrochloric acid to pH 1-2. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA:PE (1:1) to give (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-oxo-6-(piperidin-1-yl)hexanoic acid (1.38 g, 19.01%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 451

[0475] Building Block 67: Preparation of (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-6-(4,4-difluoropiperidin-1-yl)hexanoic acid [ka]

[0476] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(methanesulfonyloxy)hexanoate (5 g, 14.732 mmol, 1.00 equiv.) and 4,4-difluoropiperidine (1.96 g, 16.205 mmol, 1.1 equiv.) in DMF (100 mL) was added KI (0.12 g, 0.737 mmol, 0.05 equiv.) and DIPEA (7.62 g, 58.928 mmol, 4 equiv.) dropwise over a period of 15-25 minutes. o The resulting mixture was stirred for 24 hours at 55-60°C under a nitrogen atmosphere. oThe mixture was stirred at RT under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure and filtered. The crude product was purified by preparative HPLC to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(4,4-difluoropiperidin-1-yl)hexanoate (1.8 g, 33.53%) as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 365.22

[0477] To a 250 mL round-bottom flask, methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(4,4-difluoropiperidin-1-yl)hexanoate (1.8 g, 4.939 mmol, 1.00 equiv) and concentrated HCl (36 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 265.16

[0478] To a stirred solution of methyl (2S)-2-amino-6-(4,4-difluoropiperidin-1-yl)hexanoate (1.3 g, 4.918 mmol, 1.00 equiv.) in THF (20 mL) and HO (20 mL) was added LiOH (0.35 g, 14.754 mmol, 3 equiv.) in small portions at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to remove THF. The aqueous layer was acidified to pH 5-6 with HCl (aq.) and then basified to pH 8 with solid NaHCO. The final mixture was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 251.15

[0479] 2,5-Dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (2.72 g, 8.064 mmol, 1.1 equiv.) was added to dioxane (5.00 mL) at room temperature. The above solution was added dropwise to the above batch mixture over 5 minutes at room temperature. The resulting mixture was stirred for an additional 14 hours at room temperature. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 45% to 50% gradient in 10 minutes; detector, UV 220 nm. This gave (2S)-6-(4,4-difluoropiperidin-1-yl)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (1.4938 g) as a white solid. LCMS: (ESI, m / z): [M+H] + = 473.22

[0480] Building Block 68: Preparation of N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2,N6-dimethyl-L-lysine [ka]

[0481] To a mixture of N6-(tert-butoxycarbonyl)-L-lysine (1.50 kg, 6.09 mol, 1.00 equiv) and benzaldehyde (646 g, 6.09 mol, 615 mL, 1 equiv) in MeOH (15 L) was added TFA (34.7 g, 304 mmol, 22.5 mL, 0.05 equiv) at 20–25 °C. The mixture was stirred at 20–25 °C for 2 h. MeOH (7.5 L) was added to the mixture. Then, NaBH(OAc)3 (2.84 kg, 13.4 mol, 2.20 equiv) was added in 10 portions at 25–30 °C over 2 h. The mixture was stirred at 20–25 °C for an additional 10 h. LCMS showed the desired product was detected. To the reaction mixture was added dropwise saturated aqueous NH4Cl (7.5 L) at 25-30°C for 75 min. The residue was dissolved in H2O (15 L) and MTBE (30 L) for 20 min. o C for 30 minutes. The mixture was filtered, and the filter cake was dried in an oven to provide the product. N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (1.75 kg, 5.16 mol, 84.7% yield, 99.0% purity) was obtained as a white solid, which was confirmed by LCMS. LCMS: (ESI, m / z): [M+H] + = 336.22

[0482] To a mixture of N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (1.70 kg, 5.00 mol, 99.0% purity, 1.00 equiv.) and formaldehyde (812 g, 10.0 mol, 745 mL, 37% purity, 2.00 equiv.) in MeOH (17 L) was added TFA (28.5 g, 250.13 mmol, 18.52 mL, 0.05 equiv.) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. NaBH(OAc)3 (2.33 kg, 11.01 mol, 2.2 equiv.) was then added in 10 portions at 25–30 °C over 1 h. The mixture was stirred at 25 °C for 1 h. LCMS showed complete consumption of the starting material and one peak of the desired product. Saturated aqueous NH4Cl (3.4 L) was added dropwise to the mixture over 40 minutes at 25-30°C. The mixture was then concentrated to 7 L under reduced pressure. The residue was extracted with EtOAc (4 L x 3). The combined organic layers were washed with saturated aqueous NaCl (3 L), dried over Na2SO4 (2.00 kg), filtered, and concentrated under reduced pressure to provide the residue. The residue was triturated with MTBE (11 L) at 25°C for 30 minutes, filtered, and dried in an oven to give N2-benzyl-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (1.75 kg, crude) as a white solid, which was confirmed by LCMS (EC4247-24-P1A3). LCMS: (ESI, m / z): [M+H] + = 351, RT = 0.517 mins

[0483] To a solution of N2-benzyl-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (600 g, 1.71 mol, 1.00 equiv.) in MeOH (5.00 L) was added Pd / C (30.0 g, 10% purity) and Pd(OH)2 (30.0 g, 20% purity) under an Ar atmosphere. The suspension was degassed and purged with Ar three times. The mixture was stirred under H2 (3 MPa) at 60 °C for 12 h. LCMS (EC4402-59-P1A2) showed complete consumption of the starting material. The reaction was filtered and concentrated in vacuo and combined with the cake. The crude product, N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (approximately 297 g) in HO (3.00 L) was used in the next step.

[0484] To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-lysine (297 g, 1.14 mol, 1.00 equiv.) in THF (1.50 L) and HO (1.50 L), NaHCO (287 g, 3.42 mol, 133 mL, 3.00 equiv.) and FMOC-OSU (462 g, 1.37 mol, 1.20 equiv.) were added at 0 °C and stirred at 15 °C for 16 h. TLC (PE:EA = 1:1, R f = 0.23) indicated complete consumption of the starting material. The reaction was acidified to pH = 5-6 with 1 M HCl and extracted with EtOAc (2 L * 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The combined organic phase was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA = 10 / 1 to 0 / 1). N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (467 g, 0.93 mol, 81.37% yield, 96% purity) was obtained as a yellow gum. LCMS: RT = 0.627 mins, MS+23 = 505

[0485] To a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (350 g, 696 mmol, 96.0% purity, 1.00 equiv.) in dioxane (2 L) was added dropwise HCl / dioxane (4 M, 1.04 L, 6.00 equiv.) at 0 °C and stirred at 0 °C for 16 h. LCMS showed that the starting material was completely consumed and the desired product was detected. The reaction was filtered, and the filter cake was washed with MTBE (500 mL × 2), and concentrated to provide N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-L-lysine (227 g, 541 mmol, 88.3% yield) as a white solid. LCMS: RT = 0.447 mins, MS+1 = 383

[0486] To a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-L-lysine (278 g, 663 mmol, 1.00 equiv) in DCM (2250 mL) was added Me3SiCl (216 g, 1.99 mol, 252 mL, 3 equiv) and DIEA (343 g, 2.65 mol, 462 mL, 4.00 equiv) at 25 °C and stirred at 50 °C for 2 h. The mixture was then cooled to 0-10 °C, and DIEA (257 g, 1.99 mol, 346 mL, 3.00 equiv) and TrtCl (222 g, 796 mmol, 1.20 equiv) were added. The final reaction was stirred at 40 °C for 28 h. LCMS showed complete consumption of the starting material. The reaction mixture was concentrated in vacuo to remove DCM, diluted with 2.5 L of EtOAc, washed with saturated NaHPO (1 L) and brine (1 L), dried over NaSO, filtered, and concentrated in vacuo. N-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N-methyl-N-trityl-L-lysine (423 g, crude) was obtained as a yellow gum and used in the next step without purification. LCMS: RT = 0.635 mins, MS+1 = 625

[0487] To a mixture of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-N6-trityl-L-lysine (363 g, 581 mmol, 1.00 equiv.), NaH2PO4 (139 g, 1.16 mol, 2.00 equiv.), and HCHO (165 g, 2.03 mol, 151 mL, 37% purity, 3.50 equiv.) in DCM (3000 mL) was added NaBH(OAc)3 (246.28 g, 1.16 mol, 2 equiv.) at 0 °C and stirred at 20 °C for 2 h. LCMS showed that the starting material was completely consumed. The reaction mixture was washed with 3 L of water and 3 L of brine, dried over Na2SO4, filtered, and concentrated in vacuo. N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-N6-trityl-L-lysine (395 g, crude) was obtained as a yellow gum and used in the next step without purification.

[0488] To a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-N6-trityl-L-lysine (395 g, 618 mmol, 1.00 equiv.) in dioxane (2.50 L) was added HCl / dioxane (4 M, 618 mL, 4.00 equiv.) at 0 °C and stirred at 15 °C for 16 h. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo, poured into 3 L of MTBE, and filtered. The cake was dried under reduced pressure to provide the product. N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-L-lysine hydrochloride (318 g, 691.18 mmol, 55.9% yield, 94.1% purity) was obtained as a yellow gum, which was confirmed by LCMS. LCMS: RT = 0.447 mins, MS+1 = 397

[0489] To a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-L-lysine hydrochloride (297 g, 686 mmol, 1.00 equiv.) in THF (1000 mL) and HO (2000 mL), NaHCO3 (172.89 g, 2.06 mol, 80.04 mL, 3 equiv.) and (Boc)2O (179 g, 823 mmol, 189 mL, 1.20 equiv.) were added at 0 °C, and the mixture was stirred at 15 °C for 12 h. LCMS showed that the starting material was completely consumed. The reaction was acidified to pH = 5-6 with 1 M HCl, extracted with EtOAc (1.5 L × 2), washed with brine (2 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA = 100 / 1 to 1 / 1, Plate 1, PE:EA = 1:1, R f = 0.26). N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2,N6-dimethyl-L-lysine (147 g, 582 mmol, 42.4% yield, 98.7% purity) was obtained as a pale yellow solid, which was confirmed by LCMS. LCMS: RT = 0.661 mins, MS+23 = 519

[0490] Building Block 69: Preparation of (2S,4R)-1-(3,3-Difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0491] This compound was prepared according to the general synthetic procedure described for the preparation of building block 6 using 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylic acid. ESI MS m / z 319.06.

[0492] Building Block 70: Preparation of (2S,4R)-4-Fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0493] A mixture of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (1.6 g, 9.786 mmol, 1 equiv., 90%), 4-(trifluoromethyl)oxane-4-carboxylic acid (1.94 g, 9.786 mmol, 1.00 equiv.), TCFH (4.12 g, 14.679 mmol, 1.50 equiv.), and NMI (4.02 g, 48.930 mmol, 5 equiv.) in ACN (30 mL) was stirred for 16 h at 25 °C under a nitrogen atmosphere. The reaction mixture was directly purified by reverse flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water, gradient from 5% to 60% in 25 min; detector, UV 220 nm. This gave methyl (2S,4R)-4-fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylate (2.2 g, 68.69%) as a white solid. LCMS: (ESI, m / z): [M+H] + = 328

[0494] A mixture of methyl (2S,4R)-4-fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylate (3.4 g, 10.389 mmol, 1 equiv.) and NaOH (2.08 g, 51.945 mmol, 5.0 equiv.) in MeOH (80 mL) / HO (30 mL) was stirred for 16 h at 20 °C. The organic solvent was evaporated in vacuo, and the water was acidified with 1N HCl. The resulting precipitate was collected by filtration and dried in air. This gave (2S,4R)-4-fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylic acid (3.2509 g, 97.52%) as a white solid. LCMS: (ESI, m / z): [M+H] + =314.0

[0495] B. Solid Phase Synthesis, Cleavage, and Crystallization to Prepare Compounds of Formula I The compounds of Formula I described herein were prepared as described herein. Generally, the above monomer building blocks were covalently linked via solid-phase synthesis to form a linear peptide on the resin, followed by cleavage and cyclization in solution. Additional transformations to prepare compounds of Formula I often include, but are not limited to, alkylation, deprotection, cleavage from the solid-phase resin, and cyclization.

[0496] The following paragraphs and subheadings provide general descriptions and procedures for the preparation of compounds of formula I.

[0497] Tables 2A and B below show the building blocks and procedures used to prepare the listed exemplary compounds of Formula I. The building blocks in Tables 2A and B are shown using the abbreviations specified in Table 1. The procedures in Tables 2A and B are described using the abbreviations shown in the subheadings below.

[0498] Solid-phase linear synthesis of peptides containing N-alkylated amino acid monomers has been successfully completed using either pre-N-alkylated amino acid building blocks or by the sequential on-resin Mitsunobu alkylation method (Chatterjee et al., "Synthesis of N-methylated cyclic peptides," Nature Protocols, Vol. 7, pp. 432-444, 2012).

[0499] Certain compounds of Formula I described herein include building blocks whose side chains have been modified on-resin after incorporation into a linear peptide. Exemplary methods are described in the following paragraphs. See, for example, Example 3, in which the side chain of Res5(KDde) is deprotected and functionalized with a morpholine moiety (building block: B2BE); Example 10, in which the side chain of Res4(KDde) is deprotected and functionalized with a morpholine moiety (building block: B2BE); Example 216, in which Res6(KDde) is deprotected and functionalized with a deuterated methyl group (MeOD); and Example 308, in which Res5(ODde) is deprotected and functionalized with an acyl group (RA245).

[0500] The appropriate choice of functionalized solid support allows for sufficient resin loading and C-terminal carboxylic acid functionality. Generally, the solid supports used herein are derived from polystyrene cross-linked with divinylbenzene and functionalized with a 2-chlorotrityl linker.

[0501] The solid phase peptide synthesis methods described herein can be performed manually or automated using specialized liquid handlers.

[0502] Although the methods of the present invention can be advantageously performed as described herein when performed as a parallel array synthesis using a Biotage Syro II automated peptide synthesizer or when performed manually, it will be readily apparent to one of skill in the art how these procedures can be modified to synthesize single compounds of the present disclosure on a multi-gram scale.

[0503] A number of reaction vessels equal to the total number of compounds to be synthesized by the parallel method are loaded with 50-150 mg of an appropriate functionalized solid support, preferably polystyrene 2-chlorotrityl chloride resin.

[0504] The solvent used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF), and ethanol (EtOH).

[0505] Linear peptides can be cleaved from the 2-chlorotrityl chloride resin under mildly acidic conditions (24% HFIP in DCM) without removing acid-labile side-chain protecting groups (Pbf, Boc). Alternatively, harsher cleavage conditions (20% TFA / DCM, or 95% TFA / 2.5% H2O / 2.5% TIS) can be applied to remove Boc, Mtt, Trt, or Pbf and tBu, respectively, during resin cleavage.

[0506] 9-Fluorenylmethoxycarbonyl (Fmoc) protected amino acid derivatives are preferably used as building blocks for the construction of compounds of Formula I in the present disclosure. For deprotection, i.e., removal of Fmoc, 20% piperidine in DMF or 2% DBU / 2% piperidine in DMF can be used. It is understood that alternative protecting groups can be used.

[0507] The amount of reactant, i.e., amino acid derivative, is usually 1-20 equivalents based on milliequivalents per gram (meq / g) of functionalized solid support (typically 0.3-1.4 m eqv / g for 2-chlorotrityl chloride polystyrene resin). It is initially weighed into a reaction vessel. If necessary, additional equivalents of reactant can be used to complete the reaction within a reasonable time. A preferred (but not limited to) workstation is the Biotage Syro II synthesizer, equipped with a transfer unit and a reservoir box used in the resin cleavage step. This synthesizer can provide a controlled environment, e.g., reactions can be carried out at elevated temperatures and under inert gas, if desired.

[0508] Amide bond formation is facilitated by activation of the α-carboxyl group for the acylation step. Excess amounts of coupling reagent and base (2-24 molar equivalents) can be used to drive the coupling reaction to completion. Coupling of amino acids to unalkylated or N-methylated amino termini is most commonly achieved by HATU coupling. Coupling of amino acids to highly sterically hindered N-alkylated amino termini is achieved by DIC-mediated coupling. Since near-quantitative coupling reactions are highly favorable, experimental evidence of reaction completion is desirable. Periodic reaction checks by ninhydrin testing or LCMS are essential to ensure the absence of unbound starting material on the resin. Alternative methods have been developed to attach strongly acidic or difficult-to-activate carboxylic acids to the N-terminus of growing peptide chains, such as using K-Oxyma (CAS No. 158014-03-0) as an activating agent and / or maintaining a narrow pH range during the reaction.

[0509] On-resin alkylation of α-amino groups on solid phases is known in the art. The methyl group introduction procedure (described in Chatterjee et al., "Synthesis of N-methylated cyclic peptides," Nature Protocols, 2012, Vol. 7, pp. 432-444) can be achieved, for example, by 1) protecting the N-terminal amine with a 2-nosyl group, 2) Mitsunobu alkylation using methanol, triphenylphosphine, and DIAD or a related reagent, and 3) deprotecting the 2-nosyl group using a thiol such as DBU and mercaptoethanol. Several cyclic peptides in this disclosure were obtained using a modification of the published on-resin Mitsunobu method for the attachment of large primary alcohols to activated amino groups (main chain or side chain) on the solid phase, as an alternative to the more widely used reductive amination method (Pels et al., Solid-Phase Synthesis of Diverse Peptide Tertiary Amides by Reductive Amination. ACS Combinatorial Science, 2015, 17, 3, 152-155).

[0510] After each reaction, the resin-bound intermediate in each reaction vessel is washed of excess or residual reagents, solvent, and by-products by repeated exposure to pure solvent (DCM, DMF, or MeOH, depending on the reaction). The reaction vessel is filled with solvent (preferably 5 mL), stirred for 1 minute, and the solvent is drained and removed; this process is repeated two more times.

[0511] The above procedure of reacting the resin-bound compound with reagents in a reaction tube, followed by removal of excess reagents, by-products, and solvent, is repeated for each successive conversion until the desired resin-bound, fully protected linear peptide is obtained.

[0512] Side chain modifications along linear peptides (including, but not limited to, side chain acylation and alkylation) utilize residues bearing side chains modified with base-stable protecting groups such as Dde or 2-nosyl. Once linear synthesis is complete, the orthogonally protected side chains are deprotected and subsequently modified in subsequent chemistries. Dde-protected side chains can be removed on-resin using 10% hydrazine in DMF. The resulting primary amine at the branch point serves as a substrate for subsequent on-resin acylation, reductive amination, or alkylation reactions. 2-nosyl-protected side chains can be N-alkylated using the Mitsunobu conditions described above, followed by removal of the 2-nosyl group to yield a secondary amine.

[0513] Cleavage of the fully protected linear peptide from the solid support is achieved by exposing the loaded resin to the reagent solution (preferably 3-5 mL) used for cleavage. Temperature control, stirring, and reaction monitoring are performed as described above. The reaction vessel is connected to a reservoir box containing a reservoir tube via a transfer unit, efficiently collecting the cleaved product solution. The resin remaining in the reaction vessel is then washed 2-5 times with 3-5 mL of an appropriate solvent as described above to extract as much of the cleaved product as possible. The resulting product solutions are then combined, taking care to avoid intermixing. The individual solutions / extracts are then manipulated as necessary to isolate the final compound. Typical manipulations include, but are not limited to, evaporation, concentration, liquid-liquid extraction, acidification, basification, neutralization, or additional reactions in solution.

[0514] The solution containing the fully deprotected linear peptide is then evaporated, resuspended in DMSO, purified by RP-HPLC and lyophilized.

[0515] The lyophilized linear peptide is then subjected to cyclization. Cyclization can be achieved using various cyclization reagents (e.g., PyBop, PyAop, HATU, HBTU, T3P) at various concentrations in various pure or mixed solvents (e.g., ACN / THF, NMP, DCM, DMF, EtOAc, etc.). To facilitate rapid cyclization, low dimer formation, and easy purification of the macrocyclic compounds described herein, 3 equivalents of T3P and 8 equivalents of DIEA in a 1.5 mL DCM:NMP solution are preferred. At small scales (50 μmol), the reaction is typically complete within 10 minutes. For larger-scale reactions, the volume is diluted up to 250 mL and the reaction is allowed to proceed for up to 12 hours. The reaction progress is monitored by monitoring the disappearance of starting materials using LCMS. After completion of the reaction, excess solvent is removed by evaporation, and the compound is purified by RP-HPLC and lyophilized.

[0516] 1. Solid Phase Synthesis - General Methods General methods i-xiv were generally carried out in 50 μmol scale reactions on 50-100 mg of 2-chlorotrityl chloride polystyrene resin.

[0517] i. CTC-resin loading Fmoc-AA-OH (4 equiv.) was dissolved in 1.0 mL of anhydrous NMP. To this Fmoc-AA-OH solution, neat DIEA (8 equiv.) was added. This solution was dispensed into a peptide reaction vessel containing 100 mg of 2-chlorotrityl chloride (CTC) resin and stirred at room temperature for 2 h. After draining the Fmoc-AA-OH solution, the resin was washed three times with 1.0 mL of DMF. Unreacted CTC resin was capped with 1.0 mL of a solution of methanol:DMF (50:50) and DIEA (8 equiv.) for 10 min at room temperature. After draining the methanol solution, the resin was washed three times with 1.0 mL of DMF. After coupling was complete, the Fmoc protecting group was replaced using method ii.

[0518] ii. Fmoc deprotection A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and stirred at room temperature for 10-15 minutes. After draining the piperidine solution, the resin was washed three times with 1.0 mL of DMF.

[0519] iii. HATU-peptide coupling followed by Fmoc deprotection A solution of Fmoc-AA-OH (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was reacted at room temperature for 5 minutes, then added to the resin and stirred at 35-45°C for 10-90 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of DMF.

[0520] If the reaction was incomplete (less than 95% coupling as determined by LCMS) or if the coupling was performed on an N-methylated amine substrate, the coupling was repeated twice.

[0521] After coupling was complete (determined by LCMS), the Fmoc protecting group was replaced using method ii.

[0522] iv. HATUnf-peptide coupling without Fmoc deprotection A solution of carboxylic acid or Fmoc-AA-OH (4 equivalents), HATU (4 equivalents), and DIEA (8 equivalents) in 1.0 mL of anhydrous NMP was prepared. The mixture was reacted at room temperature for 5 minutes, then added to the resin and stirred at 35-45°C for 10-90 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of DMF.

[0523] If the reaction was incomplete (as determined by LCMS) or if the coupling was performed on an N-methylated amine substrate, the coupling was repeated twice.

[0524] v. KO-sterically hindered peptide coupling followed by Fmoc deprotection Fmoc-AA-OH or carboxylic acid (4 equiv.), K-oxime (3.8 equiv.), and DIC (3.8 equiv.) were dissolved in 1.0 mL of anhydrous NMP. The mixture was reacted at room temperature for 5 minutes, then added to the resin and stirred at 35-45°C for 10-90 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of DMF. This procedure was repeated twice.

[0525] After coupling was complete (determined by LCMS), the Fmoc protecting group was replaced using method ii.

[0526] vi. EEDQ-sterically hindered peptide coupling followed by Fmoc deprotection Coupling to N-alkylated amines when the N-alkyl group is larger than the N-methyl group. Fmoc-AA-OH (6 equivalents) and EEDQ (5 equivalents) were dissolved in 1.0 mL of anhydrous NMP. The mixture was allowed to react for 15 minutes. The mixture was then added to the resin and stirred at 45°C for 3 hours. After draining the mixture, the resin was washed three times with 1.0 mL of DMF. This procedure was repeated twice.

[0527] The Fmoc protecting group was replaced using method ii.

[0528] vii. DIC-sterically hindered peptide coupling followed by Fmoc deprotection Coupling to N-alkylated amines when the N-alkyl group is larger than the N-methyl group. Fmoc-AA-OH (24 equiv.) was dissolved in 1.5 mL of anhydrous NMP:DCE (50:50). NMP can be added dropwise to completely dissociate Fmoc-AA-OH. DIC (23 equiv.) was added to the Fmoc-AA-OH solution. The mixture was added to the resin and stirred at room temperature for 12-24 hours. After draining the slurry, the resin was washed four times with 1.0 mL of methanol and three times with 1.0 mL of DMF.

[0529] If the reaction was not complete (less than 95% coupling as determined by LCMS), a second coupling was performed.

[0530] After coupling was complete, the Fmoc protecting group was replaced using method ii.

[0531] viii. DIC_KMe2 - Neutral peptide coupling used to incorporate KMe2 Fmoc-KMe2-OH (4 equiv.) was dissolved in 1 mL of anhydrous NMP. DIC (4 equiv.) was added to the Fmoc-KMe2-OH solution. The mixture was added to the resin and stirred at room temperature for 2 hours. After draining the slurry, the resin was washed three times with 1.0 mL of methanol and three times with 1.0 mL of DMF.

[0532] The Fmoc protecting group was replaced using method ii.

[0533] ix. Onto_KMe2-peptide coupling was used to couple amino acids onto the KMe2 residue.

[0534] A solution of Fmoc-AA-OH (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was reacted at room temperature for 5 minutes, then added to the resin and stirred at 25 °C for 10 to 90 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of DMF.

[0535] After coupling was complete, the Fmoc protecting group was replaced using method ii.

[0536] x. DdeR-hydrazine-mediated Dde removal 1.0 mL of 10% hydrazine monohydrate in NMP was added to the resin and stirred at room temperature for 20 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of DMF.

[0537] xi. RA - Reductive Amination The aldehyde (20%) was dissolved in 1.0 mL of anhydrous NMP. The mixture was added to the resin and stirred at room temperature for 30 minutes. The mixture was then drained, and the resin was washed three times with 1.0 mL of DMF.

[0538] To the resin was added 1.0 mL of DCM:MeOH (3:1). Sodium borohydride (NaBH4, 20 equivalents) was then added to the resin. The slurry was stirred at room temperature for 1 hour. The slurry was drained, and the resin was washed six times with 1.0 mL of methanol, followed by three times with 1.0 mL of DMF.

[0539] xii. MITS-nosylation, Mitsunobu, nosyl deprotection Nosyl protection. 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 of anhydrous toluene was added to the resin, followed by stirring at 40-45 °C for 10-15 minutes. The mixture was drained, and the resin was then washed three times with 1.0 mL of anhydrous toluene. This procedure was repeated twice.

[0540] Alkylation using Mitsunobu conditions. Triphenylphosphine (10 equivalents) dissolved in 0.7 mL of anhydrous toluene was added to the resin. An appropriate primary alcohol (20 equivalents of methanol, ethanol, propanol, butanol, etc.) was added to the resin suspension. Azodicarboxylate (10 equivalents) was added to the resin, and the suspension was stirred at 35–45°C for 15–30 minutes. The mixture was drained, and the resin was then washed three times with 1.0 mL of anhydrous DMF. This procedure was repeated twice.

[0541] Deprotection of the nosyl group. 2-Mercaptoethanol (5 equivalents) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5 equivalents) in 1.0 mL of NMP were added to the resin and stirred at 35–45°C for 15–30 minutes. After draining the mixture, the resin was washed three times with 1.0 mL of anhydrous DMF....

Claims

1. Formula (I) 【Chemical 1】 (In the above formula, R 3 teeth (a)C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 haloalkyl, where each R is 0 to 5 3a has been replaced by (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH 2 CH 2 O) 1-4 -C 1-4 Alkyl, -O-(CH 2 CH 2 O) 1-4 -heterocycloalkyl, C 1-3 Haloalkoxy, -NR 3a1 R 3a2 , -OC(O)C 1-4 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 independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR 3b1 R 3b2 , -N(R 3b3 )C(O)R 3b4 phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3c independently, C 1-4 Alkyl, C 1-4 Haloalkyl, oxo or C 3-6 is cycloalkyl, Each R 3a1 , R 3a2 , R 3b1 , R 3b2 and R 3b3 are independently H or C 1-4 is alkyl, Each R 3b4 is C 1-4 Alkyl or C 1-4 is haloalkyl, R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, -NR 4c1 R 4c2 ,-C 1-4 Alkyl-NR 4c1 R 4c2 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 Alkyl-heterocycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heterocycloalkyl is 4 to 6 ring members and has 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl is 5 to 6 ring members and has 1 to 3 heteroatoms, each independently N, O, or S; Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, said heterocycloalkyl comprising 0 to 2 R 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 Alkyl or C 2-6 is an alkoxyalkyl; Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 Alkoxy, halo or -N(R 4a2 )S(O) 2 -C 1-4 is alkyl, R 4a2 is H or C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkyl-OH, C 1-4 alkoxy or halo; R 5a is H or C 1-4 is alkyl, R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, -C 1-4 Alkyl-NR 5b1 R 5b2 , -C 1-3 Alkyl-C(O)NR 5b1 R 5b2 , C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and each cycloalkyl and heteroaryl has 0 to 3 R 5b5 is replaced by Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl or -C(O)C 1-4 is haloalkyl, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and the heterocycloalkyl is 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and 0 to 3 R 5b5 is replaced by Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl, -NH 2 , -N(C 1-4 alkyl) 2 or NH(C 1-4 alkyl), X 6 is C 2-5 is alkylene, R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl or C 1-4 alkyl-heterocycloalkyl, wherein the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; R 6b is H or C 1-6 having an alkyl group; R 6d is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, -OH or C 2-6 is an alkoxyalkyl; R 7a is H or C 1-4 is alkyl, R 7b and R 7c are each independently H, C 1-8 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H or C 1-4 is alkyl, Alternatively, R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 forming a cycloalkyl, Ring B is phenyl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently N, O, or S; the subscript m8 is an integer between 0 and 5; Each R 8f independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 , -C(O)NR 8f1 R 8f2 ,-N(R 8f1 )C(O)R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-phenyl, or heteroaryl, where each heterocycloalkyl is 4 to 6 ring members and has 1 to 3 heteroatoms, each independently N, O, or S, and each heteroaryl is 5 to 6 ring members and has 1 to 3 heteroatoms, each independently N, O, or S, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is selected from 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are independently H or C 1-4 is alkyl, Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, -SH, -SC 1-4 Alkyl, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S; X 9 is R 9b and R 9c C is replaced by 1-3 is alkylene, R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 cycloalkyl, heteroaryl or C 1-4 alkyl-heteroaryl, where each heteroaryl is 5 to 6 ring members and has 1 to 3 heteroatoms, each independently N, O, or S, and each cycloalkyl and heteroaryl independently has 0 to 3 R 9c1 is replaced by Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 9c2 is replaced by Each R 9c1 and R 9c2 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl or C 1-4 is haloalkoxy, and Ring A contains 15 to 17 ring atoms) or a pharmaceutically acceptable salt thereof.

2. R 3 teeth, (a) 0 to 5 R 3a C is replaced by 1-6 Alkyl, C 2-6 Alkynyl or C 1-6 haloalkyl, (b) 0 to 5 R 3b C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH 2 CH 2 O) 1-3 -C 1-4 Alkyl, -O-(CH 2 CH 2 O) 1-2 -heterocycloalkyl, C 1-3 Haloalkoxy, -NR 3a1 R 3a2 , -OC(O)C 1-4 Alkyl, C 3-6 cycloalkyl, phenyl, or heteroaryl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, -N(R 3b3 )C(O)R 3b4 phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3c independently, C 1-4 Alkyl, C 1-4 Haloalkyl, oxo or C 3-6 is cycloalkyl, Each R 3a1 , R 3a2 and R 3b3 are independently H or C 1-4 is alkyl, and Each R 3b4 is C 1-4 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

3. R 3 teeth, (a) 0 to 5 R 3a C is replaced by 1-6 Alkyl, C 2-6 Alkynyl or C 1-6 haloalkyl, (b) 0 to 5 R 3ｂ C is replaced by 3-12 cycloalkyl, or (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is selected from 0 to 5 R 3c has been replaced by and each R 3a are independently -OH, C 1-3 Alkoxy, -O-(CH 2 CH 2 O) 1-3 -C 1-4 Alkyl, -O-(CH 2 CH 2 O) 1-2 -heterocycloalkyl, C 1-3 Haloalkoxy, -NH 2 , -OC(O)C 1-4 Alkyl, C 3-6 cycloalkyl or phenyl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; Each R 3b independently, C 1-4 Alkyl, C 2-4 Alkynyl, Halo, C 1-4 Haloalkyl, cyano, or -NHC(O)C 1-4 is alkyl, and Each R 3c independently, C 1-4 Alkyl, C 1-4 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is haloalkyl or oxo.

4. R 3 teeth, 【Chemistry 2】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R 3 teeth, 【Chemistry 3】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

6. R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 1-4 Alkyl-NR 4c1 R 4c2 , C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, C 1-4 Alkyl-heterocycloalkyl or C 1-4 alkyl-heteroaryl, where 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; Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 Alkyl or C 2-6 is an alkoxyalkyl; Each R 4a1 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, halo or -N(H)S(O) 2 -C 1-4 is alkyl, Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 are independently -OH, C 1-4 Alkyl-OH or C 1-4 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is alkoxy.

7. R 4a is H or C 1-4 is alkyl, R 4b and R 4c are each independently H, C 1-8 Alkyl or C 1-4 Alkyl-NR 4c1 R 4c2 and Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 4a1 is replaced by Each R 4c1 and R 4c2 independently, C 1-4 is alkyl, Each R 4a1 are independently —OH or halo; Alternatively, two R on adjacent ring atoms 4a1 The groups are combined to form 0 to 2 R 4a3 forming a phenyl ring substituted with Each R 4a3 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is -OH.

8. R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl or tert-butyl, 【Chemistry 4】 and Alternatively, R 4c and R 4a are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, said heterocycloalkyl being 4a1 is replaced by, and Each R 4a1 are independently methyl, -OH, methoxy, fluoro or -N(H)S(O) 2 CH 3 and Alternatively, two R on adjacent ring atoms 4a1 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the groups are combined to form a phenyl ring substituted with 0 to 2 -OH.

9. R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, 【Chemistry 5】 or R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being 4a1 is replaced by, and Each R 4a1 are independently —OH or fluoro; Alternatively, two R on adjacent ring atoms 4a1 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the groups combine to form a phenyl ring substituted with 0 to 1 -OH.

10. R 5a is H, R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, -C 1-4 Alkyl-NR 5b1 R 5b2 , -C 1-3 Alkyl-C(O)NR 5b1 R 5b2 , -C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 , C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 cycloalkyl, each cycloalkyl having 0 to 3 R 5b5 is replaced by Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, or -C(O)C 1-4 haloalkyl, where R 5b1 and R 5b2 at most one of is H, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, said heterocycloalkyl comprising 0 to 2 R 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and 0 to 1 R 5b5 is replaced by, and Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl or NH(CH 3 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein

11. R 5b and R 5c are each independently H, C 1-8 Alkyl, C 1-8 Alkyl-OH, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 cycloalkyl, each cycloalkyl having 0 to 3 R 5b5 is replaced by, and Each R 5b5 independently, C 1-4 Alkyl, halo or C 1-4 The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

12. R 5b and R 5c are each independently H, C 1-4 Alkyl-NR 5b1 R 5b2 , C 1-3 Alkyl-C(O)NR 5b1 R 5b2 or -C 1-4 Alkyl-N(R 5b3 )C(O)R 5b4 and Each R 5b1 and R 5b2 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 haloalkyl, where R 5b1 and R 5b2 at most one of is H, Alternatively, R on the same nitrogen atom 5b1 and R 5b2 are combined to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, said heterocycloalkyl comprising 0 to 2 R 5b5 is replaced by Each R 5b3 is H or C 1-4 is alkyl, Each R 5b4 is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and 0 to 1 R 5b5 is replaced by, and Each R 5b5 independently, C 1-4 Alkyl, Halo, C 1-4 Haloalkyl or NH(CH 3 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein

13. R 5a is H, R 5b is H, and R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 【Chemistry 6】 13. The compound according to any one of claims 1 to 12, wherein:

14. R 5a is H, R 5b is H, and R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 【Chemistry 7】 The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein

15. R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl or C 1-4 alkyl-heterocycloalkyl, wherein the heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; R 6b is H, and R 6d is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, -OH or C 2-6 The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is alkoxyalkyl.

16. R 6a is H, C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 1-4 Alkyl-C 3-6 is cycloalkyl, R 6b is H, and R 6d is H, C 1-4 Alkyl or C 1-4 16. The compound according to any one of claims 1 to 15, which is a deuteroalkyl, or a pharmaceutically acceptable salt thereof.

17. R 6a H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CD 3 , 【Chemistry 8】 and R 6b is H, and R 6d is H, methyl, ethyl, n-propyl, isopropyl, -CD 3 , or 【Chemistry 9】 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. R 6a is H, methyl, ethyl, n-propyl, isopropyl, -CD 3 Or, 【Chemistry 10】 and R 6b is H, and R 6d is H, methyl, isopropyl or -CD 3 The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein

19. X 6 teeth, 【Chemistry 11】 The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein

20. X 6 teeth, 【Chemistry 12】 The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein

21. X 6 teeth, 【Chemistry 13】 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein:

22. R 7a is H, and R 7b and R 7c are each independently H, C 1-8 Alkyl or C 1-4 Alkyl-C 3-6 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

23. R 7a is H, R 7b is H, and R 7c is isobutyl, 【Chemistry 14】 23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein:

24. R 7a is H, R 7b is H, and R 7c The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein is isobutyl.

25. Formula Ia 【Chemistry 15】 The compound according to any one of claims 1 to 24, having the structure: or a pharmaceutically acceptable salt thereof.

26. Formula Ia1 【Chemistry 16】 The compound according to any one of claims 1 to 24, having the structure: or a pharmaceutically acceptable salt thereof.

27. 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Ring B is heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each heteroatom being N.

28. 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein ring B is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S.

29. 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Ring B is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each heteroatom being N.

30. 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein ring B is pyridyl or thiophenyl.

31. Ring B is 【Chemistry 17】 31. The compound according to any one of claims 1 to 28 or 30, or a pharmaceutically acceptable salt thereof, wherein:

32. R 8a is C 1-4 Alkyl, C 1-4 Deuteroalkyl, C 2-6 Alkoxyalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H; Alternatively, R 8b and R 8d are combined with the carbon to which they are attached to form C 3-6 forming a cycloalkyl, the subscript m8 is an integer between 0 and 5; Each R 8f independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 ,-C(O)NR 8f1 R 8f2 , -N(R 8f1 )C(O)R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-4 alkyl-heterocycloalkyl, phenyl, -O-phenyl, or heteroaryl, where 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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are independently H or C 1-4 is alkyl, and Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, which is alkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently being N, O, or S.

33. R 8a is C 1-4 Alkyl, C 1-4 Deuteroalkyl or C 1-4 Alkyl-C 3-6 is cycloalkyl, R 8b , R 8d and R 8e are each independently H; the subscript m8 is an integer between 0 and 5; Each R 8f independently, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-8 Alkoxyalkyl, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Cyano, -NR 8f1 R 8f2 , C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, C 1-4 alkyl-heterocycloalkyl, phenyl, -O-phenyl, or heteroaryl, where 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, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 is replaced by Each R 8f1 and R 8f2 are C 1-4 is alkyl, and Each R 8f3 independently, C 1-4 Alkyl, -OH, C 1-4 Alkoxy, Halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 33. The compound according to any one of claims 1 to 32, which is a cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently being N, O, or S, or a pharmaceutically acceptable salt thereof.

34. R 8a is methyl, ethyl, n-propyl, n-butyl, -CD 3 , 【Chemistry 18】 and R 8b , R 8d and R 8e are H, Alternatively, R 8b and R 8d or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 33, wherein each of the carbons to which it is attached is combined with the carbon to form cyclopropyl.

35. R 8a is methyl, ethyl, n-propyl, n-butyl, -CD 3 Or, 【Chemistry 19】 and R 8b , R 8d and R 8e The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein each of

36. m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo, 【Chemistry 20】 36. The compound according to any one of claims 1 to 35, wherein:

37. m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, 【Chemical 21】 37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein:

38. 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the subscript m8 is 2.

39. Part-C(O)-X 9 -NR 9a -teeth, 【Chemical 22】 The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein

40. Part-C(O)-X 9 -NR 9a -teeth, 【Chemical 23】 40. The compound according to any one of claims 1 to 39, wherein:

41. Part-C(O)-X 9 -NR 9a -teeth, 【Chemistry 24】 41. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein:

42. R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 1-6 Alkyl-OH, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl or C 1-4 alkyl-heteroaryl, each heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S; Alternatively, R 9b and R 9c Each of these is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is 9c2 is replaced by Each R 9c1 are independently haloes, and Each R 9c2 The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein: is independently -OH or halo.

43. R 9a is H or C 1-4 is alkyl, R 9b and R 9c are each independently H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl or C 3-6 is cycloalkyl, Alternatively, R 9b and R 9c Each of these is combined with the carbon to which it is attached to form 0 to 2 R 9c2 C is replaced by 3-4 forming a cycloalkyl, or Alternatively, R 9c and R 9a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms, each independently N, O, or S, and said heterocycloalkyl is selected from the group consisting of 0 or 2 R 9c2 is replaced by, and Each R 9c2 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein: is independently -OH or halo.

44. R 9a is H or methyl, R 9b is H, methyl or ethyl, and R 9c is H, methyl, ethyl, n-propyl, sec-butyl, 【Chemistry 25】 and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form a C substituted with 0 to 2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a and R 1 and R 2 are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having from 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or -OH group, or a pharmaceutically acceptable salt thereof.

45. R 9a is H or methyl, R 9b is H or methyl, and R 9c is H, methyl, ethyl, n-propyl, 【Chemical 26】 and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0 to 2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a and R 1 and R 2 are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having from 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or -OH group, or a pharmaceutically acceptable salt thereof.

46. X 6 teeth, 【Chemical 27】 and Part-C(O)-X 9 -NR 9a -teeth, 【Chemical Formula 28】 46. ​​The compound according to any one of claims 1 to 45, wherein:

47. X 6 teeth, 【Chemical 29】 and Part-C(O)-X 9 -NR 9a -teeth, 【Chemistry 30】 46. ​​The compound according to any one of claims 1 to 45, wherein:

48. Formula Ib 【Chemical 31】 46. ​​The compound according to any one of claims 1 to 45, having the structure: or a pharmaceutically acceptable salt thereof.

49. Formula Ib1 【Chemical 32】 46. ​​The compound according to any one of claims 1 to 45, having the structure: or a pharmaceutically acceptable salt thereof.

50. X 6 teeth, 【Chemical 33】 and Part-C(O)-X 9 -NR 9a -teeth, 【Chemical 34】 46. ​​The compound according to any one of claims 1 to 45, wherein:

51. X 6 teeth, 【Chemistry 35】 and Part-C(O)-X 9 -NR 9a -teeth, 【Chemical 36】 46. ​​The compound according to any one of claims 1 to 45, wherein:

52. R 3 teeth 【Chemical 37】 【Chemical Formula 38】 and R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, tert-butyl, 【Chemical 39】 and Alternatively, R 4c and R 4a are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, said heterocycloalkyl being 4a1 is replaced by Each R 4a1 are independently methyl, —OH, methoxy, fluoro or —N(H)S(O) 2 CH 3 and Alternatively, two R on adjacent ring atoms 4a1 the groups combine to form a phenyl ring substituted with 0 to 2 -OH; R 5a is H, R 5b is H, R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 【Chemistry 40】 and X 6 teeth, 【Chemistry 41】 and R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CD 3 , 【Chemistry 42】 and R 6b is H, R 6d is H, methyl, ethyl, n-propyl, isopropyl, -CD 3 or 【Chemistry 43】 and R 7a is H, R 7b is H, R 7c is isobutyl, 【Chemical 44】 and R 8a is methyl, ethyl, n-propyl, n-butyl, -CD 3 , 【Chemistry 45】 and R 8b , R 8d and R 8e are H, Alternatively, R 8b and R 8d are combined with the carbon to which each is attached to form a cyclopropyl; m8 is 0, 1, 2 or 3, Each R 8f are independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo, 【Chemistry 46】 and X 9 teeth, 【Chemistry 47】 and R 9a is H or methyl, R 9b is H, methyl or ethyl, and R 9c is H, methyl, ethyl, n-propyl, sec-butyl, 【Chemistry 48】 and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0 to 2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a and R 1 and R 2 are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or -OH group, or a pharmaceutically acceptable salt thereof.

53. R 3 teeth 【Chemistry 49】 and R 4a is H or methyl, R 4b is H, R 4c is methyl, ethyl, isopropyl, 【Chemistry 50】 and Alternatively, R 4c and R 4a each taken together with the carbon and nitrogen to which it is attached forms a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being 4a1 is replaced by Each R 4a1 are independently —OH or fluoro; Alternatively, two R on adjacent ring atoms 4a1 the groups combined to form a phenyl ring substituted with 0 to 1 -OH; R 5a is H, R 5b is H, R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 【Chemistry 51】 and X 6 teeth 【Chemistry 52】 and R 6a is H, methyl, ethyl, n-propyl, isobutyl, -CD 3 , or 【Chemistry 53】 and R 6b is H, R 6d is H, methyl, isopropyl or -CD, R 7b is isobutyl, 【Chemical 54】 and R 7a is H, R 7b is H, R 7c is isobutyl, 【Chemistry 55】 and R 8a is methyl, ethyl, n-propyl, n-butyl, -CD 3 , or 【Chemical Formula 56】 and R 8b , R 8d and R 8e are H, m8 is 0, 1, 2, or 3, and Each R 8f are independently methyl, methoxy, fluoro, chloro, bromo, iodo, 【Chemical 57】 and X 9 teeth, 【Chemistry 58】 and R 9a is H or methyl, R 9b is H or methyl, and R 9c is H, methyl, ethyl, n-propyl, 【Chemical 59】 and Alternatively, R 9b and R 9c are combined with the carbon to which they are attached to form C substituted with 0 to 2 fluoro groups. 3-4 forming a cycloalkyl, Alternatively, R 9c and R 9a and R 1 and R 2 are each combined together with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluoro or -OH group, or a pharmaceutically acceptable salt thereof.

54. Formula Ic 【Chemistry 60】 54. The compound according to any one of claims 1 to 53, having the structure: or a pharmaceutically acceptable salt thereof.

55. Formula Ic1 【Hua 61】 54. The compound according to any one of claims 1 to 53, having the structure: or a pharmaceutically acceptable salt thereof.

56. The compound according to claim 1, which has the structure of any one of Examples 1 to 693, or a pharmaceutically acceptable salt thereof.

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 and / or a pharmaceutically acceptable excipient.

58. 58. A method for treating cancer mediated at least in part by one or more cyclins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, thereby treating the disorder or condition.

59. 58. A compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, for use in a method for treating cancer which is at least in part mediated by one or more cyclins.

60. 58. Use of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, for the manufacture of a medicament for treating cancer that is at least in part mediated by one or more cyclins.

Images