Cyclin inhibitors

Abstract

Disclosed herein are compounds of Formula I and methods of making the same. Also described herein are the use of such compounds, compositions for the treatment of diseases and conditions mediated, at least in part, by one or more cyclin proteins, including cancer, and intermediates useful in the preparation of these compounds. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 380,562, filed on October 21, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0003] Background

[0004] Cyclins are a family of proteins that play a central role in the regulation of the cell cycle. Specific cyclins, including cyclin D, E, A, and B, are expressed at different stages of the cell cycle, during which they bind to and activate their respective homologous cyclin-dependent kinases (CDKs), including CDK 1, 2, 4, and 6, to form cyclin-CDK complexes that coordinate the progression and transition of different stages of the cell cycle. Disruption of the normal regulatory function of cyclin-CDK complexes is a common driver of tumorigenesis and rapid proliferation of cancer cells. The central role of cyclins and CDKs in the cell cycle makes these proteins and their complexes attractive targets for the treatment of proliferative disorders and cancer. To date, most inhibitors of cyclin-CDK complexes target the kinase activity of CDKs ("CDK inhibitors"), including both therapeutics under development and those approved for clinical use. Alternative approaches may include disrupting the association of cyclins with CDKs or the interaction of specific cyclin-CDK complexes with their substrates or regulators.

[0005] Although CDK inhibitors have been developed and shown to be successful in treating certain cancers, they are currently limited by relatively low selectivity, a narrow therapeutic window, and ultimately the development of drug resistance. Thus, there is a need to develop agents that provide alternative ways to inhibit the function of cyclin-CDK complexes as a means of regulating the cell cycle. Such agents could provide new tools for the treatment of proliferative diseases. The present disclosure addresses this need by providing compounds that inhibit the binding of substrates to different cyclins, thereby disrupting the function of cyclin-CDK complexes. SUMMARY OF THE INVENTION

[0006] In one embodiment, the present disclosure provides compounds of formula (I):

[0007]

[0008] wherein

[0009] R 3 is

[0010] (a) C 1-8 alkyl, C 2-8Alkenyl, C 2-8 alkynyl or C 1-8 haloalkyl, each substituted with 0 to 5 R 3a ;

[0011] (b) C 3b cycloalkyl substituted with 0 to 5 R 3-12 ; or

[0012] (c) Heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently N, O or S, wherein said heterocycloalkyl is substituted with 0 to 5 R 3c ;

[0013] Each R 3a is 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 、–O–C(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;

[0014] Each R 3b is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, 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 N, O or S;

[0015] Each R 3c is independently C 1-4 alkyl, C 1-4 haloalkyl, oxo or C 3-6 cycloalkyl;

[0016] Each R 3a1 、R 3a2 、R 3b1 、R3b2 and R 3b3 are each independently H or C 1-4 alkyl;

[0017] Each R 3b4 is C 1-4 alkyl or C 1-4 haloalkyl;

[0018] R 4a is H or C 1-4 alkyl;

[0019] 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;

[0020] Alternatively, R 4c and R 4a combine with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently N, O or S, where the heterocycloalkyl is substituted with 0 to 2 R 4a1 groups;

[0021] Each R 4c1 and R 4c2 are each independently C 1-4 alkyl or C 2-6 alkoxyalkyl;

[0022] Each R 4a1 is each independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy, halogen or –N(R 4a2 )S(O)2–C 1-4 alkyl;

[0023] R 4a2 is H or C 1-4 alkyl;

[0024] Alternatively, two Rs on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 Rs 4a1 groups; 4a3

[0025] Each R 4a3 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen;

[0026] R 5a is H or C 1-4 alkyl;

[0027] 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 where each cycloalkyl and heteroaryl is substituted with 0 to 3 Rs 5b5 groups;

[0028] Each R 5b1 and R 5b2 are each independently H, C 1-4 alkyl, C 1-4 haloalkyl, –C(O)C 1-4 alkyl or –C(O)C 1-4 haloalkyl;

[0029] Alternatively, Rs 5b1 and R 5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently N, O or S, where the heterocycloalkyl is substituted with 0 to 3 Rs 5b5 groups;

[0030] ​Each R 5b3 is H or C 1-4 alkyl;

[0031] Each R 5b4 is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 0 to 3 R 5b5 ;

[0032] Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl, –NH2, –N(C 1-4 alkyl)2 or NH(C 1-4 alkyl);

[0033] X 6 is C 2-5 alkylene;

[0034] R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, 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;

[0035] R 6b is H or C 1-6 alkyl;

[0036] R 6d is H, C 1-4 alkyl, C 1-4 deuterated alkyl, –OH or C 2-6 alkoxyalkyl;

[0037] R 7a is H or C 1-4 alkyl;

[0038] 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 cycloalkyl;

[0039] R 8a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-6an alkoxyalkyl, C 3-6 a cycloalkyl or –C 1-4 an alkyl–C 3-6 a cycloalkyl;

[0040] R 8b 、R 8d and R 8e are each independently H or C 1-4 an alkyl;

[0041] Alternatively, R 8b and R 8d together with the carbon to which they are attached combine to form a C 3-6 a cycloalkyl;

[0042] Ring B is phenyl or a heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms each independently being N, O or S;

[0043] The subscript m8 is an integer from 0 to 5;

[0044] Each R 8f is independently C 1-4 an alkyl, C 2-4 an alkenyl, C 2-4 an alkynyl, C 1-4 an alkoxy, C 2-8 an alkoxyalkyl, a halogen, C 1-4 a haloalkyl, C 1-4 a haloalkoxy, a cyano, –NR 8f1 R 8f2 、–C(O)NR 8f1 R 8f2 、–N(R 8f1 )C(O)R 8f2 、C 3-6 a cycloalkyl, –O–C 3-6 a cycloalkyl, C 1-4 an alkyl–C 3-6 a cycloalkyl, –O–C 1-4 an alkyl–C 3-6 a cycloalkyl, a heterocycloalkyl, C 1-4 an alkyl–heterocycloalkyl, phenyl, –O–phenyl or a heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 ;

[0045] Each R 8f1 and R 8f2 are each independently H or C 1-4 an alkyl;

[0046] Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, –SH, –S–C 1-4 alkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl, –O–C 3-6 cycloalkyl, –O–C 1-4 alkyl–C 3-6 cycloalkyl or a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S;

[0047] X 9 is a C 9b alkylidene substituted by R 9c and R 1-3 ;

[0048] R 9a is H or C 1-4 alkyl;

[0049] 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, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each cycloalkyl and heteroaryl is independently substituted by 0 to 3 R 9c1 ;

[0050] Alternatively, R 9b and R 9c together with the carbon to which they are attached combine to form a C 9c2 cycloalkyl substituted by 0 to 2 R 3-4 ; or

[0051] Alternatively, R 9c and R 9a together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein the heterocycloalkyl is substituted by 0 to 2 R 9c2 ;

[0052] Each R 9c1 and R9c2 Independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy; and

[0053] Ring A contains 15 to 17 ring atoms;

[0054] or a pharmaceutically acceptable salt thereof.

[0055] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0056] In another embodiment, the present invention provides a method for treating a disease or disorder at least partially mediated 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.

[0057] In another embodiment, the present invention provides a method for treating cancer at least partially mediated 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.

[0058] In another embodiment, the present invention provides an intermediate useful for preparing a compound of formula (I).

[0059] Other objects, features and advantages of the present disclosure will be apparent to those skilled in the art in light of the following detailed description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1A and 1B shows a Western blot from an H1048 cell lysate following treatment with Example 458, compared to its enantiomer Example 680, showing that two substrates, E2F1 (1A) and CDC6 (1B), are displaced from their complexes with cyclin A2 only by the active Example.

[0061] Figure 2A and 2B shows that IV administration of an exemplary compound (Example 456) in the present application at a tolerated dose level (weight change plot, 2B) results in tumor regression (tumor volume plot, 2A) in an in vivo SCLC model. DETAILED DESCRIPTION

[0062] I. GENERAL OVERVIEW

[0063] The present disclosure provides compounds and compositions that disrupt the canonical cellular functions of cyclins. The present disclosure also provides methods for treating or preventing, for example, a disease, disorder, or condition or a symptom thereof mediated by cyclin activity.

[0064] Complexes of cyclins with cyclin-dependent kinases (CDKs) are responsible for phosphorylating a wide range of substrates, thereby regulating the activity of the substrates. Many of these substrates are important in the cell cycle, and thus the cyclins and CDKs that regulate these substrates play a key role in regulating the cell cycle, including cyclins D, A, E, and B, and CDKs 1, 2, 4, and 6. Without being bound by any particular theory, certain substrates (including p21, p27, Rb, E2F, and CDC6) first bind to the cyclin-CDK complex via a conserved RxL motif within the substrate (Adams et al., Mol Cell Biol. 1996. 16(12):6223-33.) and bind to a region of the cyclin that is referred to as the RxL-binding domain or "hydrophobic patch" (Brown et al., Nat Cell Biol. 1999. 1(7):438-43) and contains the highly conserved MRAIL motif. Compounds that disrupt the binding of the substrate to the cyclin are thought to have potential therapeutic utility, including disrupting cancer cell proliferation (Chen et al., Proc Natl Acad Sci U S A. 1999. 96(8):4325-9).

[0065] Without being bound by any particular theory, it is believed that the compounds of the present disclosure inhibit the binding of substrates to the hydrophobic patch regions of cyclins (including but not limited to cyclins A, E, and B). The compounds of the present disclosure include compounds that bind more potently to one or more cyclins.

[0066] II. Definitions

[0067] As used herein, the term "about" refers to a range of values including the specified value that is reasonably similar to the specified value as understood by a person of ordinary skill in the art. In some embodiments, the term "about" refers to within one standard deviation using standard measurement methods generally accepted in the art. In some embodiments, about refers to a range extending from + / −10% of the specified value. In some embodiments, about refers to the specified value.

[0068] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic group having the indicated number of carbon atoms. Alkyl can contain any number of carbons, such as C 1-2 、C 1-3 、C 1-4 、C 1-5 、C1-6 , 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 groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. The alkyl group can also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. The alkyl group can be substituted or unsubstituted.

[0069] "Alkylene" refers to a straight-chain or branched-chain saturated aliphatic group having the specified number of carbon atoms and connecting at least two other groups, that is, a divalent hydrocarbon group. The two moieties connected to the alkylene can be connected to the same atom or different atoms of the alkylene group. For example, the straight-chain alkylene can be a divalent group -(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.

[0070] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one double bond. The alkenyl can contain any number of carbons, such as C2, 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 5-6and C6. The alkenyl group 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-hexatriene. The alkenyl group can be substituted or unsubstituted.

[0071] "Alkynyl" means a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. The alkynyl group can contain any number of carbons, such as C2, 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 5-6 and C6. Examples of alkynyl groups include but are not limited to ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl or 1,3,5-hexatriynyl. The alkynyl group can be substituted or unsubstituted.

[0072] "Alkoxy" means an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. Like the alkyl group, the alkoxy group can have any suitable number of carbon atoms, such as C 1-6 . The alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The alkoxy group can be substituted or unsubstituted.

[0073] "Alkoxyalkyl" means an alkyl group connected to an oxygen atom, which is further connected to a second alkyl group, and the second alkyl group is the point of attachment to the rest of the molecule: alkyl-O-alkyl. The alkyl moiety can have any suitable number of carbon atoms, such as C 2-6The alkoxyalkyl group includes, for example, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. The alkoxy group may be substituted or unsubstituted.

[0074] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0075] "Haloalkyl" refers to an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. As with alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, such as C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0076] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups may be substituted with 1, 2, 3 or more halogens. When all hydrogens are replaced with halogens (e.g., fluorine), the compound is fully substituted, e.g., perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0077] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, spirocyclic, fused or bridged polycyclic ring assembly containing 3 to 12 ring atoms or the indicated number of atoms. Cycloalkyl can contain any number of carbon atoms, such as C 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 3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decalin, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in 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), norbornyl, and norbornadienyl. When the cycloalkyl group is C 3-6When the cycloalkyl is monocyclic, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers). When the cycloalkyl is C 5-10 When the cycloalkyl is a fused bicyclic cycloalkyl, exemplary groups include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl, and octahydro-1H-indenyl. When the cycloalkyl is C 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. When the cycloalkyl is C 5-10 When the cycloalkyl is a spirocycloalkyl, exemplary groups include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[2.5]octane, and spiro[2.4]heptane. The cycloalkyl group can be substituted or unsubstituted.

[0078] "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 heteroatoms of N, O, and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. The heterocycloalkyl group can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. The heterocycloalkyl group can contain any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, 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. The heterocycloalkyl group can be unsubstituted or substituted.

[0079] 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.

[0080] When the heterocycloalkyl is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl can also be a monocyclic heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0081] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The aryl group can contain any suitable number of ring atoms, such as 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. The aryl group can be monocyclic, fused to form a bicyclic or tricyclic group, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. The aryl group can be substituted or unsubstituted.

[0082] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 12 ring atoms, wherein 1 to 6 ring atoms are heteroatoms such as N, O or S. The heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O)2-. The heteroaryl group can contain any number of ring atoms, such as 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12 or 9 to 12 ring members. The heteroaryl group can contain any suitable number of heteroatoms, such as 1, 2, 3, 4, 5 or 6, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5 or 3 to 6. The heteroaryl group 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. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. The heteroaryl group can also be fused to an aromatic ring system, such as a benzene ring, to form members including but not limited to benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine such as phthalazine and cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include heteroaryl rings connected by a bond, such as bipyridine. The heteroaryl group can be substituted or unsubstituted.

[0083] The heteroaryl group can be attached via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

[0084] Some heteroaryl groups include those 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 those 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 those 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. Other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring atoms (including N, O, or S), such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0085] "Oxo" means an oxygen atom is attached to the point of attachment by a double bond (=O).

[0086] "Pharmaceutically acceptable excipient" means a substance that aids in formulating an active agent and / or administering the active agent to a subject. Pharmaceutic excipients that can be used in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutic excipients can also be used in the present disclosure.

[0087] "Subject" means an animal such as a mammal, including but not limited to a primate (e.g., human), bovine, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In some embodiments, the subject is a human.

[0088] "Administering" means administering orally to a subject, administering as a suppository, topical contact, parenterally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, or subcutaneously, intrathecally, or implanting a sustained release device such as a microosmotic pump.

[0089] "Therapeutically effective amount" means the dose administered which produces a therapeutic effect. The exact dose will depend upon the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0090] "Treat / treating / treatment" means any successful indication of the treatment or amelioration of an injury, pathology, condition or symptom (e.g., pain), including any objective or subjective parameter such as alleviation; remission; diminishment of symptoms or making the symptoms, injury, pathology or condition more tolerable to the patient; or reduction in the frequency or duration of the symptoms or condition. The treatment or amelioration of a symptom can be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0091] III. Compounds

[0092] In some embodiments, the present invention provides a compound of formula (I):

[0093]

[0094] wherein

[0095] R 3 is

[0096] (a) C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 1-8 haloalkyl, each optionally substituted with 0 to 5 R 3a ;

[0097] (b) C 3b cycloalkyl optionally substituted with 0 to 5 R 3-12 ; or

[0098] (c) a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently N, O or S, wherein said heterocycloalkyl is optionally substituted with 0 to 5 R 3c ;

[0099] Each R 3a is 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 、–O–C(O)C 1-4 alkyl, C 3-6 cycloalkyl, phenyl or heteroaryl, where each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0100] Each R 3b is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, 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;

[0101] Each R 3c is independently C 1-4 alkyl, C 1-4 haloalkyl, oxo or C 3-6 cycloalkyl;

[0102] Each R 3a1 、R 3a2 、R 3b1 、R 3b2 and R 3b3 are independently H or C 1-4 alkyl;

[0103] Each R 3b4 is C 1-4 alkyl or C 1-4 haloalkyl;

[0104] R 4a is H or C 1-4 alkyl;

[0105] R 4b and R 4cEach independently is 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0106] Alternatively, R 4c and R 4a combine with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, where the heterocycloalkyl is substituted with 0 to 2 R 4a1 ;

[0107] Each R 4c1 and R 4c2 is independently C 1-4 alkyl or C 2-6 alkoxyalkyl;

[0108] Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy, halogen or –N(R 4a2 )S(O)2–C 1-4 alkyl;

[0109] R 4a2 is H or C 1-4 alkyl;

[0110] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R 4a3 ;

[0111] Each R 4a3 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen;

[0112] R 5a is H or C1-4 Alkyl;

[0113] 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 where each cycloalkyl and heteroaryl is substituted with 0 to 3 R 5b5 ;

[0114] Each R 5b1 and R 5b2 is independently H, C 1-4 alkyl, C 1-4 haloalkyl, –C(O)C 1-4 alkyl or –C(O)C 1-4 haloalkyl;

[0115] Alternatively, R 5b1 and R 5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently N, O or S, where the heterocycloalkyl is substituted with 0 to 3 R 5b5 ;

[0116] Each R 5b3 is H or C 1-4 alkyl;

[0117] Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O or S, which is substituted with 0 to 3 R 5b5 ;

[0118] Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl, –NH2, –N(C1-4 2 or NH(C 1-4 alkyl);

[0119] X 6 is C 2-5 alkylene;

[0120] R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, 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;

[0121] R 6b is H or C 1-6 alkyl;

[0122] R 6d is H, C 1-4 alkyl, C 1-4 deuterated alkyl, –OH or C 2-6 alkoxyalkyl;

[0123] R 7a is H or C 1-4 alkyl;

[0124] R 7b and R 7c each independently is H, C 1-8 alkyl, C 3-6 cycloalkyl or C 1-4 alkyl–C 3-6 cycloalkyl;

[0125] R 8a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-6 alkoxyalkyl, C 3-6 cycloalkyl or –C 1-4 alkyl–C 3-6 cycloalkyl;

[0126] R 8b 、R 8d and R 8e each independently is H or C 1-4 alkyl;

[0127] Or, R 8b and R 8d together with the carbon to which each is attached combine to form C 3-6Cycloalkyl;

[0128] Ring B is phenyl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms each independently being N, O or S;

[0129] The subscript m8 is an integer from 0 to 5;

[0130] Each R 8f is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, 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, –O–C 3-6 cycloalkyl, C 1-4 alkyl–C 3-6 cycloalkyl, –O–C 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 ;

[0131] Each R 8f1 and R 8f2 are independently H or C 1-4 alkyl;

[0132] Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, –SH, –S–C 1-4 alkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl, –O–C 3-6 cycloalkyl, –O–C 1-4 alkyl–C 3-6Cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S;

[0133] X 9 is C 9b alkylidene 9c substituted by R 1-3 and R

[0134] R 9a is H or C 1-4 alkyl;

[0135] 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 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each cycloalkyl and heteroaryl is independently substituted by 0 to 3 R 9c1 ;

[0136] Or, R 9b and R 9c together with the carbon to which they are attached combine to form a C 9c2 cycloalkyl substituted by 0 to 2 R 3-4 ; or

[0137] Or, R 9c and R 9a together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, where the heterocycloalkyl is substituted by 0 to 2 R 9c2 ;

[0138] Each R 9c1 and R 9c2 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy; and

[0139] Ring A contains 15 to 17 ring atoms;

[0140] Or a pharmaceutically acceptable salt thereof.

[0141] 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.

[0142] Residue 3

[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

[0144] R 3 is

[0145] (a) C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, each substituted with 0 to 5 R 3a ;

[0146] (b) C 3b cycloalkyl substituted with 0 to 5 R 3-12 ; or

[0147] (c) a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein the heterocycloalkyl is substituted with 0 to 5 R 3c ;

[0148] Each R 3a is 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 、–O–C(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 being N, O or S, having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0149] Each R3b Independently C 1-4 alkyl, C 2-4 alkynyl, halogen, 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;

[0150] Each R 3c independently is C 1-4 alkyl, C 1-4 haloalkyl, oxo or C 3-6 cycloalkyl;

[0151] Each R 3a1 , R 3a2 and R 3b3 independently is H or C 1-4 alkyl; and

[0152] Each R 3b4 is C 1-4 alkyl.

[0153] 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

[0154] R 3 is

[0155] (a) C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, each being substituted with 0 to 5 R 3a ;

[0156] (b) C 3b cycloalkyl substituted with 0 to 5 R 3-12 ; or

[0157] (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein the heterocycloalkyl is substituted with 0 to 5 R 3c ;

[0158] Each R 3a independently is –OH, C 1-3 alkoxy, –O–(CH2CH2O) 1-3 –C 1-4 alkyl, –O–(CH2CH2O) 1-2 –heterocycloalkyl, C 1-3 haloalkoxy, –NH2, –O–C(O)C 1-4alkyl, C 3-6 heterocycloalkyl or phenyl, wherein each heterocycloalkyl has from 4 to 6 ring members and from 1 to 3 heteroatoms each independently being N, O or S;

[0159] each R 3b is independently C 1-4 alkyl, C 2-4 alkynyl, halogen, C 1-4 haloalkyl, cyano or –NHC(O)C 1-4 alkyl; and

[0160] each R 3c is independently C 1-4 alkyl, C 1-4 haloalkyl or oxo.

[0161] 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) C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, each substituted with from 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 C 3a alkyl substituted with from 0 to 5 R 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 C 3a alkynyl substituted with from 0 to 5 R 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 C 3a haloalkyl substituted with from 0 to 5 R 1-6 . These embodiments of R 3 can be combined with any of the embodiments described herein for R 3a .

[0162] 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 substituted with 0 R3a is substituted by a group. 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 substituted by one R 3a group. 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 substituted by two R 3a groups. 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 substituted by three R 3a groups. 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 substituted by four R 3a groups. 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 substituted by five R 3a groups. These embodiments of R 3 can be combined with any of the embodiments described herein for R 3a .

[0163] 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 is independently –OH, C 1-3 alkoxy, C 1-3 haloalkoxy, –NH2, –O–C(O)C 1-4 alkyl, C 3-6 cycloalkyl or phenyl. 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 is independently –OH, C 1-3 alkoxy, C 1-3 haloalkoxy, –NH2, –O–C(O)C 1-4 alkyl or C 3-6Naphthenyl. 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 is independently –OH, C 1-3 alkoxy, C 1-3 haloalkoxy, –NH2 or –O–C(O)C 1-4 alkyl. 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 is independently –OH, C 1-3 alkoxy or C 1-3 haloalkoxy. These embodiments of R 3a can be combined with any of the embodiments described herein for R 3 .

[0164] 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 at least one R 3a is –O–(CH2CH2O) 1-2 –heteroalkyl, wherein each heteroalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S. These embodiments of R 3a can be combined with any of the embodiments described herein for R 3 .

[0165] 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 (b) C 3b naphthenyl substituted with 0 to 5 R 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 monocyclic C 3b naphthenyl substituted with 0 to 5 R 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 C 3b naphthenyl substituted with 0 to 5 R 5-10Fused bicyclic cycloalkyl. 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 C 3b bridged polycyclic cycloalkyl substituted with 0 to 5 R 5-10 groups. 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 C 3b bridged polycyclic cycloalkyl substituted with 0 to 5 R 5-10 groups. Spirocycloalkyl. These embodiments of R 3 can be combined with any of the embodiments described herein for R 3b .

[0166] 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 unsubstituted with 0 R 3b groups. 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 substituted with 1 R 3b group. 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 substituted with 2 R 3b groups. 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 substituted with 3 R 3b groups. 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 substituted with 4 R 3b groups. 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 substituted with 5 R 3b groups. These embodiments of R 3 can be combined with any of the embodiments described herein for R3b Any combination of the described embodiments.

[0167] 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 independently C 1-4 alkyl, C 2-4 alkynyl, halogen, C 1-4 haloalkyl or cyano. 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 independently C 1-4 alkyl, halogen or C 1-4 haloalkyl. 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. These embodiments of R 3b can be combined with any of the embodiments described herein for R 3 Any combination of the described embodiments.

[0168] 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 (c) a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 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 3 is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 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 3 is a monocyclic heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms each independently being O or S, wherein said heterocycloalkyl is substituted with 0 to 5 R 3c . These embodiments of R 3 can be combined with any of the embodiments described herein for R 3cAny combination of the described embodiments.

[0169] 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 substituted with zero R 3c groups. 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 substituted with one R 3c group. 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 substituted with two R 3c groups. 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 substituted with three R 3c groups. 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 substituted with four R 3c groups. 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 substituted with five R 3c groups. These embodiments of R 3 can be combined with any of the embodiments described herein for R 3c Any combination of the described embodiments.

[0170] 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 is independently C 1-4 alkyl, C 1-4 haloalkyl or oxo. 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 is independently C 1-4 alkyl or C 1-4 haloalkyl. R3c These embodiments may be combined with any of the embodiments described herein for R 3 described herein.

[0171] Any of the embodiments described herein for R 3a may be combined with any of the embodiments described herein for R 3 being (a) C 3a alkyl, C 1-8 alkynyl or C 2-8 haloalkyl, each independently substituted with from 0 to 5 R 1-8 groups. Any of the embodiments described herein for R 3b may be combined with any of the embodiments described herein for R 3 being (b) C 3b cycloalkyl substituted with from 0 to 5 R 3-12 groups. Any of the embodiments described herein for R 3c may be combined with any of the embodiments described herein for R 3 being (c) heterocycloalkyl having from 3 to 6 ring members and from 1 to 3 heteroatoms each independently selected from N, O or S, wherein said heterocycloalkyl is substituted with from 0 to 5 R 3c groups.

[0172] 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

[0173]

[0174] 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

[0175]

[0176] 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

[0177]

[0178] Any embodiment described herein for residue 3 can be combined with any embodiment described herein for residues 4, 5, 6, 7, 8, and 9. For example, any embodiment of R as described herein 3 can be combined with any embodiment described herein for 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 described herein.

[0179] Residue 4

[0180] 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

[0181] R 4a is H or C 1-4 alkyl;

[0182] 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, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O, or S;

[0183] Alternatively, R 4c and R 4aCombined together with the respective carbon and nitrogen to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 ;

[0184] Each R 4c1 and R 4c2 is independently C 1-4 alkyl or C 2-6 alkoxyalkyl;

[0185] Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen or –N(H)S(O)2–C 1-4 alkyl;

[0186] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R 4a3 ; and

[0187] Each R 4a3 is independently –OH, C 1-4 alkyl–OH or C 1-4 alkoxy.

[0188] 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

[0189] R 4a is H or C 1-4 alkyl;

[0190] 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–C 3-6 cycloalkyl, C 1-4 alkyl–heterocycloalkyl or C 1-4 alkyl–heteroaryl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0191] Alternatively, R 4c and R 4aCombined with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents;

[0192] Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen or –N(H)S(O)2–C 1-4 alkyl;

[0193] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R 4a3 substituents; and

[0194] Each R 4a3 is independently –OH, C 1-4 alkyl–OH or C 1-4 alkoxy.

[0195] 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

[0196] R 4a is H or C 1-4 alkyl;

[0197] R 4b and R 4c are each independently H, C 1-8 alkyl or C 1-4 alkyl–NR 4c1 R 4c2 ;

[0198] Alternatively, R 4c and R 4a combine with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents;

[0199] Each R 4c1 and R 4c2 are each independently C 1-4 alkyl;

[0200] Each R 4a1 is independently –OH or halogen;

[0201] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R4a3 a substituted phenyl ring; and

[0202] each R 4a3 is –OH.

[0203] 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

[0204] R 4a is H or C 1-4 alkyl;

[0205] R 4b and R 4c are each independently H or C 1-8 alkyl;

[0206] Alternatively, R 4c and R 4a together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents;

[0207] each R 4c1 and R 4c2 are independently C 1-4 alkyl;

[0208] each R 4a1 is independently –OH or halogen;

[0209] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R 4a3 substituents; and

[0210] each R 4a3 is –OH.

[0211] 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 alkyl. 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 4ais methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-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 is methyl. 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. These embodiments of R 4a can be combined with any of the embodiments described herein for R 4b and R 4c .

[0212] 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 4c2 . 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 C 1-8 alkyl. 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 tert-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. These embodiments of R 4b can be combined with any of the embodiments described herein for R 4a and R 4c .

[0213] 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 4c2or cycloalkyl. 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 is C 1-4 alkyl. 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 3-6 cycloalkyl. 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. 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 tert-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 monocyclic cycloalkyl. 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. These embodiments of R 4c can be combined with any of the embodiments described herein for R 4a and R 4b .

[0214] 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 together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein the heterocycloalkyl is substituted with 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 R4c and R 4a combine with the respective connected carbon and nitrogen to form a heterocycloalkyl selected from pyrrolidinyl, azetidinyl and piperidinyl, wherein the heterocycloalkyl is substituted with 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 combine with the respective connected carbon and nitrogen to form pyrrolidinyl, wherein the pyrrolidinyl is substituted with 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 combine with the respective connected carbon and nitrogen to form azetidinyl, wherein the azetidinyl is substituted with 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 combine with the respective connected carbon and nitrogen to form piperidinyl, wherein the piperidinyl is substituted with 0 to 2 R 4a1 R 4a and R 4c These embodiments of R 4b can be combined with any of the embodiments described herein for R

[0215] 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 the heterocycloalkyl containing R 4a / R 4c is substituted with 0 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 the heterocycloalkyl containing R 4a / R 4c is substituted with 1 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 the heterocycloalkyl containing R 4a / R 4c is substituted with 2 R4a1 is replaced. R 4a and R 4c These embodiments of 4b can be combined with any of the embodiments described herein for R

[0216] 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 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen or –N(H)S(O)2–C 1-4 alkyl. 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 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy or halogen. 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 is independently C 1-4 alkyl or halogen. 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 is independently –OH or halogen. These embodiments of R 4a1 can be combined with any of the embodiments described herein for R 4b and the combined R 4a and R 4c described.

[0217] 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 two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 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 the phenyl ring is substituted with 0 R 4a3is replaced. 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 the phenyl ring is substituted with one R 4a3 is replaced. 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 the phenyl ring is substituted with two Rs 4a3 is replaced. R 4a1 of these embodiments can be combined with any of the embodiments described herein for R 4b and combined Rs 4a and R 4c .

[0218] 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 4a3 is independently –OH, C 1-4 alkyl–OH or C 1-4 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), wherein 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), wherein 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), wherein each R 4a3 is independently C 1-4 alkoxy. R 4a3 of these embodiments 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 .

[0219] 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 combine with the carbon and nitrogen to which they are attached together to form a group that is substituted with two Rs 4a1pyrrolidinyl substituted by a group, wherein said two Rs 4a1 groups are on adjacent ring atoms and combine to form a phenyl ring substituted by 0 to 2 Rs 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 combine with the carbon and nitrogen to which they are attached to form an azetidinyl group substituted by 2 Rs 4a1 groups, wherein said two Rs 4a1 groups are on adjacent ring atoms and combine to form a phenyl ring substituted by 0 to 2 Rs 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 combine with the carbon and nitrogen to which they are attached to form a piperidinyl group substituted by 2 Rs 4a1 groups, wherein said two Rs 4a1 groups are on adjacent ring atoms and combine to form a phenyl ring substituted by 0 to 2 Rs 4a3 The combined Rs 4c and R 4a and the two combined Rs 4a1 groups in these embodiments can be combined with any of the embodiments described herein for R 4b and R 4a3 .

[0220] 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

[0221] R 4a is H or methyl;

[0222] R 4b is H;

[0223] R 4c is methyl, ethyl, isopropyl, tert-butyl,

[0224] Alternatively, R 4c and R 4a combine 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, wherein said heterocycloalkyl is substituted by 0 to 2 Rs 4a1 ; and

[0225] Each R 4a1 is independently methyl, –OH, methoxy, fluoro or –N(H)S(O)2CH3;

[0226] Alternatively, two Rs on adjacent ring atoms 4a1 combine to form a phenyl ring substituted with 0 to 2 –OH groups.

[0227] 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 are as follows:

[0228] R 4a is H or methyl;

[0229] R 4b is H;

[0230] R 4c is methyl, ethyl, isopropyl,

[0231] Alternatively, R 4c and R 4a combine with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, wherein the heterocycloalkyl is substituted with 0 to 2 Rs 4a1 ; and

[0232] each R 4a1 is independently –OH or fluoro;

[0233] Alternatively, two Rs on adjacent ring atoms 4a1 combine to form a phenyl ring substituted with 0 to 1 –OH group.

[0234] The embodiments described herein for R 4a , R 4b and R 4c can exist 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, any of the embodiments for R 4a , R 4b and R 4c described herein can be combined with any of the embodiments for R 3 , R 5a , R 5b , R 5c , X 6 , R 6a , R6b , 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 Any combination of the embodiments described.

[0235] Residue 5

[0236] 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

[0237] R 5a is H;

[0238] 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, wherein each cycloalkyl is substituted with 0 to 3 R 5b5 ;

[0239] 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, provided that no more than one of R 5b1 and R 5b2 is H;

[0240] Alternatively, R on the same nitrogen atom5b1 and R 5b2 combine to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 R 5b5 ;

[0241] Each R 5b3 is H or C 1-4 alkyl;

[0242] Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 0 to 1 R 5b5 ; and

[0243] Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl or NH(CH3).

[0244] 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

[0245] 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, wherein each cycloalkyl is substituted with 0 to 3 R 5b5 ;

[0246] Each R 5b5 is independently C 1-4 alkyl, halogen or C 1-4 haloalkyl.

[0247] 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

[0248] 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 –C1-4 alkyl–N(R 5b3 )C(O)R 5b4 ;

[0249] Each R 5b1 and R 5b2 is independently H, C 1-4 alkyl, C 1-4 haloalkyl, –C(O)C 1-4 alkyl, –C(O)C 1-4 haloalkyl, provided that no more than one of R 5b1 and R 5b2 is H;

[0250] Or, R 5b1 and R 5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 R 5b5 ;

[0251] Each R 5b3 is H or C 1-4 alkyl;

[0252] Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently N, O or S, which is substituted with 0 to 1 R 5b5 ; and

[0253] Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl or NH(CH3).

[0254] 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 tert-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. These embodiments of R 5a can be combined with any of the embodiments described herein for R 5b and R 5c .

[0255] 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 tert-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. These embodiments of R 5b can be combined with any of the embodiments described herein for R 5a and R 5c .

[0256] 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, C 1-4 alkyl–C 3-6 cycloalkyl, wherein each cycloalkyl is substituted with 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 haloalkyl. 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 haloalkyl. 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 3-6A cycloalkyl group, wherein each cycloalkyl group is substituted with 0 to 2 halogens. 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 cycloalkyl, wherein each cycloalkyl group is substituted with 0 to 2 halogens. 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 cyclopropyl, cyclobutyl, cyclopropylmethyl or cyclobutylmethyl which is substituted with 0 to 2 halogens. These embodiments of R 5c can be combined with any of the embodiments described herein for R 5a and R 5b .

[0257] 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 haloalkyl. 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 at least one of R 5b1 and R 5b2 is not 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 each R 5b1 and R 5b2 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 5b1 and R5b2 Combining to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 R 5b5 . These embodiments of R 5c can be combined with any of the embodiments described herein for R 5a and R 5b .

[0258] 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 1-3 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 haloalkyl. 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 at least one of R 5b1 and R 5b2 is not 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 each R 5b1 and R 5b2 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 5b1 and R 5b2 on the same nitrogen atom combine to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 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 5b1 and R 5b2 on the same nitrogen atom combine to form a piperidine or a morpholine, each substituted with 0 to 2 R 5b5is replaced. 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 halogen. 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 fluorine. These embodiments of R 5c can be combined with any of the embodiments described herein for R 5a and R 5b .

[0259] 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–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 alkyl. 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 alkyl. 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 heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 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 5b4 is pyridine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole or isoxazole, each being substituted with 0 to 1 R 5b5is replaced. 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 tert-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. These embodiments of R 5c can be combined with any of the embodiments described herein for R 5a and R 5b .

[0260] 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, R 5c These embodiments of can be combined with any of the embodiments described herein for R 5a and R 5b .

[0261] In some embodiments, R 5c is H, methyl, ethyl, R 5c These embodiments of can be combined with any of the embodiments described herein for R 5a and R 5b .

[0262] 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

[0263] R 5c These embodiments of can be combined with any of the embodiments described herein for R 5a and R 5b .

[0264] 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

[0265] R 5a is H;

[0266] R 5b is H; and

[0267] R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,

[0268] 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

[0269] R 5a is H;

[0270] R 5b is H; and

[0271] R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,

[0272] The embodiments described herein for R 5a and R 5b和 and R 5c can exist in any combination. Additionally, the embodiments described herein for residue 5 can be combined with any of the embodiments described herein for residues 3, 4, 6, 7, 8, and 9. For example, any of the embodiments for R 5a and R 5b and R 5c described herein can be combined with any of the embodiments for R 3 and R 4a and R 4b and R 4c and X 6 and R 6a and R 6b and R 6d and R 7a and R 7b and R 7c and R 8a and R8b , R 8d , R 8e , ring B, m8, R 8f , X 9 , R 9a , R 9b and R 9c any combination of the embodiments described.

[0273] Residue 6

[0274] 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

[0275] R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl or C 1-4 alkyl–heteroalkyl, wherein the heteroalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0276] R 6b is H; and

[0277] R 6d is H, C 1-4 alkyl, C 1-4 deuterated alkyl, –OH or C 2-6 alkoxyalkyl. R 6a , R 6b and R 6d These embodiments of R 6 can be combined with any of the embodiments described herein for X

[0278] 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

[0279] R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl;

[0280] R 6b is H; and

[0281] R 6d is H, C 1-4 alkyl or C 1-4Deuterated alkyl. R 6a 、R 6b and R 6d These embodiments of can be combined with any of the embodiments described herein for X 6 .

[0282] 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 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl. 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 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl. 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 alkyl. 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 alkyl. 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 tert-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. These embodiments of R 6a can be combined with any of the embodiments described herein for R 6b , R 6d and X 6 .

[0283] 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 tert-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. These embodiments of R 6b can be combined with any of the embodiments described herein for R 6a , R 6d and X 6 .

[0284] 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 deuterated alkyl. 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 alkyl. 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 tert-butyl. These embodiments of R 6d can be combined with any of the embodiments described herein for R 6a , R 6b and X 6 .

[0285] 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

[0286] R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, –CD3,

[0287] R 6b is H; and

[0288] R 6d is H, methyl, ethyl, n-propyl, isopropyl, –CD3, or R 6a 、R 6b and R 6d These embodiments of can be combined with any of the embodiments described herein for X 6 described.

[0289] 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

[0290] R 6a is H, methyl, ethyl, n-propyl, isobutyl, –CD3, or

[0291] R 6b is H; and

[0292] R 6d is H, methyl, isopropyl, or –CD3. R 6a 、R 6b and R 6d These embodiments of can be combined with any of the embodiments described herein for X 6 described.

[0293] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), or (Ia1), wherein X 6 is

[0294]

[0295] X 6 These embodiments of can be combined with any of the embodiments described herein for R 6a 、R 6b 、R 6d and X 9 described.

[0296] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), or (Ia1), wherein X 6 is

[0297]

[0298] X 6 These embodiments of can be combined with any of the embodiments described herein for R 6a 、R6b , R 6d and X 9 Any combination of the embodiments described.

[0299] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), or (Ia1), wherein X 6 is

[0300]

[0301] X 6 These embodiments of X can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d and X 9 Any combination of the embodiments described.

[0302] The embodiments described herein for X 6 , R 6a , R 6b and R 6d Any combination of the embodiments described. Additionally, the embodiments described herein for residue 6 can be combined with any of the embodiments described herein for residues 3, 4, 5, 7, 8, and 9. For example, any of the embodiments of X 6 , R 6a , R 6b and R 6d can be combined with any of the embodiments described herein for 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 Any combination of the embodiments described.

[0303] Residue 7

[0304] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), or (Ib1), wherein

[0305] R 7ais H; and

[0306] R 7b and R 7c are each independently H, C 1-8 alkyl or C 1-4 alkyl–C 3-6 cycloalkyl.

[0307] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein

[0308] R 7a is H;

[0309] R 7b is H; and

[0310] R 7c is isobutyl and

[0311] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein

[0312] R 7a is H;

[0313] R 7b is H; and

[0314] R 7c is isobutyl.

[0315] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib) or (Ib1), wherein

[0316] R 7a is H;

[0317] R 7b is H; and

[0318] R 7c is isobutyl;

[0319] 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-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 7aThese embodiments may be combined with any of the embodiments described herein for R 7b and R 7c described herein.

[0320] 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. These embodiments of R 7b may be combined with any of the embodiments described herein for R 7a and R 7c described herein.

[0321] 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 is isobutyl. 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 is R 7c These embodiments of R 7a and R 7b described herein.

[0322] 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 is R 7c These embodiments of R 7a and R 7b described herein.

[0323] 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 is R 7c These embodiments of R 7a and R 7b described herein.

[0324] The embodiments described herein for R 7a 、R 7b and R 7c described herein may exist in any combination. Additionally, the embodiments described herein for residue 7 may be combined with any of the embodiments described herein for residues 3, 4, 5, 6, 8 and 9. For example, as described herein R 7a 、R7b and R 7c Any embodiment of may be combined with any of 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 9c described.

[0325] Residue 8

[0326] 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):

[0327]

[0328] 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 may each independently be as defined for any embodiment of formula (Ia) described herein.

[0329] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having a structure of formula (Ia1):

[0330]

[0331] 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 may each independently be as defined for any embodiment of formula (Ia1) as described herein.

[0332] 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 can be combined with any embodiment described herein for R 8a 、R 8b 、R 8d 、R 8e 、m8 and R 8f described.

[0333] 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 being N, O or S. These embodiments of ring B can be combined with any embodiment described herein for R 8a 、R 8b 、R 8d 、R 8e 、m8 and R 8f described.

[0334] 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 heteroatom being N. These embodiments of ring B can be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8d 、R 8e 、m8 and R 8f .

[0335] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), wherein ring B is pyridyl or thienyl. These embodiments of ring B can be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8d 、R 8e 、m8 and R 8f .

[0336] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), wherein ring B is

[0337]

[0338] These embodiments of ring B can be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8d 、R 8e 、m8 and R 8f .

[0339] The embodiments described herein for ring B can be combined with any of the embodiments described herein for R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and 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 、R8b , R 8d , R 8e , m8, R 8f , X 9 , R 9a , R 9b and R 9c may each independently be as defined for any embodiment of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) as described herein.

[0340] 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

[0341] R 8a is C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-6 alkoxyalkyl or C 1-4 alkyl–C 3-6 cycloalkyl;

[0342] R 8b , R 8d and R 8e are each independently H;

[0343] Alternatively, R 8b and R 8d together with the carbon to which each is attached combine to form a C 3-6 cycloalkyl;

[0344] The subscript m8 is an integer from 0 to 5;

[0345] Each R 8f is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, 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, –O–C 3-6 cycloalkyl, C 1-4 alkyl–C 3-6 cycloalkyl, –O–C 1-4 alkyl–C3-6 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 substituents;

[0346] Each R 8f1 and R 8f2 is independently H or C 1-4 alkyl; and

[0347] Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, 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 being N, O or S.

[0348] 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.

[0349] 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

[0350] R 8a is C 1-4 alkyl, C 1-4 deuterated alkyl or C 1-4 alkyl–C 3-6 cycloalkyl;

[0351] R 8b , R 8d and R 8e are each independently H;

[0352] The subscript m8 is an integer from 0 to 5;

[0353] Each R 8f is independently C 1-4 alkyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, C1-4 haloalkyl, C 1-4 haloalkoxy, cyano, –NR 8f1 R 8f2 、C 3-6 cycloalkyl, –O–C 3-6 cycloalkyl, –O–C 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 ;

[0354] Each R 8f1 and R 8f2 are each C 1-4 alkyl; and

[0355] Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl, –O–C 1-4 alkyl–C 3-6 cycloalkyl or heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S.

[0356] 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.

[0357] 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

[0358] R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3, and

[0359] R 8b 、R 8d and R 8e are each H;

[0360] Alternatively, R 8b and R 8d combine with the respective connected carbons to form a cyclopropyl group.

[0361] R 8a , R 8b , R 8d and R 8e These embodiments of R 8f and ring B can be combined with any of the embodiments described herein for m8, R

[0362] 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

[0363] R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3 or and

[0364] R 8b , R 8d and R 8e are each H.

[0365] R 8a , R 8b , R 8d and R 8e These embodiments of R 8f and ring B can be combined with any of the embodiments described herein for m8, R

[0366] 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

[0367] m8 is 0, 1, 2 or 3; and

[0368] each R 8f is independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo,

[0369] These embodiments of m8 and R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e and ring B.

[0370] 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

[0371] m8 is 0, 1, 2 or 3; and

[0372] each R 8f is independently methyl, methoxy, fluoro, chloro, bromo, iodo,

[0373] These embodiments of m8 and R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e and ring B.

[0374] 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 is independently methyl, methoxy, fluoro, chloro, bromo, iodo,

[0375]

[0376] These embodiments of m8 and R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e and ring B.

[0377] 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 deuterated alkyl or C 1-4 alkyl–C 3-6 cycloalkyl. 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 1-4Alkyl. 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, isopropyl, n-butyl, isobutyl, sec-butyl or tert-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 deuterated alkyl. 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 cycloalkyl. These embodiments of R 8a can be combined with any of the embodiments described herein for R 8b , R 8d , R 8e , m8, R 8f and ring B.

[0378] 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 tert-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. These embodiments of R 8b can be combined with any of the embodiments described herein for R 8a , R 8d , R 8e , m8, R 8f and ring B.

[0379] 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 tert-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 8dThese embodiments may be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8e 、m8、R 8f and Ring B.

[0380] 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 tert-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. These embodiments of R 8e may be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8d 、m8、R 8f and Ring B.

[0381] 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 together with the carbon atoms to which they are attached combine to form a C 3-6 cycloalkyl. These embodiments of R 8b and R 8d may be combined with any of the embodiments described herein for R 8a 、R 8e 、m8、R 8f and Ring B.

[0382] 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 the 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), wherein the 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), wherein the 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), wherein the 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), wherein the 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), wherein the subscript m8 is 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 the subscript m8 is 5. These embodiments of m8 can be combined with any of the embodiments described herein for R 8a 、R 8b 、R 8d 、R 8e 、R 8f and Ring B.

[0383] 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 at least one R 8f is C 1-4 alkyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano or –NR 8f1 R 8f2 . 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 at least one R 8f is C 3-6 cycloalkyl, –O–C 3-6 cycloalkyl, –O–C1-4 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl or C 1-4 Alkyl-heterocycloalkyl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, and wherein each cycloalkyl and heterocycloalkyl is substituted with 0 to 3 R 8f3 . 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 at least one R 8f is phenyl, -O-phenyl or heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, and wherein each phenyl and heteroaryl is substituted with 0 to 3 R 8f3 . These embodiments of R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8 and ring B.

[0384] In some embodiments, at least one R 8f is C 3-6 Cycloalkyl, -O-C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, -O-C 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 selected from N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 ; In some embodiments, at least one R 8f is C 8f3 Cycloalkyl substituted with 0 to 3 R 3-6 . In some embodiments, at least one R 8f is -O-C 8f3 Cycloalkyl substituted with 0 to 3 R 3-6 . In some embodiments, at least one R 8f is C 8f3 Alkyl-C 1-4 Cycloalkyl substituted with 0 to 3 R 3-6 . In some embodiments, at least one R 8f is C8f3 substituted –O–C 1-4 alkyl–C 3-6 cycloalkyl. In some embodiments, at least one R 8f is a heterocycloalkyl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and each heterocycloalkyl is substituted with 0 to 3 R 8f3 . In some embodiments, at least one R 8f is C 1-4 alkyl–heterocycloalkyl, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and each heterocycloalkyl is substituted with 0 to 3 R 8f3 . In some embodiments, at least one R 8f is a phenyl substituted with 0 to 3 R 8f3 . In some embodiments, at least one R 8f is an –O–phenyl substituted with 0 to 3 R 8f3 . In some embodiments, at least one R 8f is a heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O, or S, and each heterocycloalkyl is substituted with 0 to 3 R 8f3 . These embodiments of R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, and ring B.

[0385] 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, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, or –O–C 1-4 alkyl–C 3-6 cycloalkyl. 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, halogen, C 1-4 haloalkyl, or C 1-4Halogenated 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), wherein each R 8f3 is C 1-4 alkyl, halogen, C 1-4 haloalkyl. 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, chlorine or trifluoromethyl. These embodiments of R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , R f , m8 and ring B.

[0386] The embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8 and R 8f can exist in any combination. Additionally, the embodiments described herein for residue 8 can be combined with any of the embodiments described herein for residues 3, 4, 5, 6 and 9. For example, any of the embodiments of R 8a , R 8b , R 8d , R 8e , m8 and R 8f can be combined with any of 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 7a , R 7b , R 7c , X 9 , R 9a , R 9b and R 9c .

[0387] Residue 9

[0388] 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 – is

[0389]

[0390] the moiety –C(O)–X 9 –NR 9a – These embodiments can be combined with any of the embodiments described herein for X 6 、R 9a 、R 9b and R 9c described.

[0391] 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 – is

[0392]

[0393] the moiety –C(O)–X 9 –NR 9a – These embodiments can be combined with any of the embodiments described herein for X 6 、R 9a 、R 9b and R 9c described.

[0394] 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 9 –NR 9a – is

[0395]

[0396] the moiety –C(O)–X 9 –NR 9a – These embodiments can be combined with any of the embodiments described herein for X 6 、R 9a 、R 9b and R 9c described.

[0397] 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

[0398] R9a is H or C 1-4 alkyl;

[0399] 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, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S;

[0400] Alternatively, R 9b and R 9c combine with the carbon to which they are attached to form a C 9c2 cycloalkyl substituted with 0 to 2 R 3-4 ; or

[0401] Alternatively, R 9c and R 9a combine with the carbon and nitrogen to which they are attached to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 or 2 R 9c2 ;

[0402] Each R 9c1 is independently halogen; and

[0403] Each R 9c2 is independently –OH or halogen.

[0404] R 9a , R 9b and R 9c in these embodiments can be combined with any of the embodiments described herein for X 9 ;

[0405] 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

[0406] R 9a is H or C 1-4 alkyl;

[0407] R 9b and R 9c are each independently H, C 1-6 alkyl, C 2-6 alkoxyalkyl or C 3-6Cycloalkyl;

[0408] Alternatively, R 9b and R 9c combine with the carbon atoms to which they are attached to form a C 9c2 cycloalkyl optionally substituted with 0 to 2 R 3-4 groups; or

[0409] Alternatively, R 9c and R 9a combine with the carbon and nitrogen atoms to which they are attached to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently selected from N, O, or S, wherein said heterocycloalkyl is optionally substituted with 0 or 2 R 9c2 groups; and

[0410] each R 9c2 is independently –OH or halogen.

[0411] R 9a , R 9b and R 9c in these embodiments can be combined with any of the embodiments described herein for X 9 .

[0412] 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 alkyl. 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 alkyl. 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 tert-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 is methyl. 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 R9a is ethyl. R 9a These embodiments of can be combined with any of the embodiments described herein for R 9b , R 9c and X 9 described.

[0413] 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 1-4 alkyl. 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. 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 alkyl. 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 tert-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 is methyl. 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 can be combined with any of the embodiments described herein for R 9a , R 9c and X 9 described.

[0414] 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 1-4An alkyl–heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being 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), wherein 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 alkyl. 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 tert-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 alkoxyalkyl. 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 cycloalkyl. 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. These embodiments of R 9c can be combined with any of the embodiments described herein for R 9a , R 9b , and X 9 .

[0415] 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 together with the carbon to which they are each attached combine to form a C 9c2 cycloalkyl substituted with 0 to 2 R 3-4 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), wherein the cycloalkyl is substituted with 0 R 9c2is replaced. 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 the cycloalkyl is substituted with one R 9c2 is replaced. 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 the cycloalkyl is substituted with two R 9c2 is replaced. R 9b and R 9c These embodiments of can be combined with any of the embodiments described herein for R 9a and X 9 .

[0416] 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 halogen 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 halogen. 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 –OH. These embodiments of R 9c2 can be combined with any of the embodiments described herein for R 9a , combined R 9b and R 9c , and X 9 .

[0417] 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 together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being 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), wherein the heterocycloalkyl is substituted with 0 or 2 R 9c2is replaced. 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 the heterocycloalkyl is substituted with 0 R 9c2 is replaced. 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 the heterocycloalkyl is substituted with 1 R 9c2 is replaced. 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 the heterocycloalkyl is substituted with 2 R 9c2 is replaced. R 9c and R 9a These embodiments can be combined with any of the embodiments described herein for R 9b and X 9 .

[0418] 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 halogen 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 halogen. 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 –OH. R 9c2 These embodiments can be combined with any of the embodiments described herein for R 9b , combined R 9c and R 9a , and X 9 .

[0419] 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

[0420] R 9a is H or methyl;

[0421] R 9b is H, methyl or ethyl; and

[0422] R9c is H, methyl, ethyl, n-propyl, sec-butyl,

[0423] alternatively, R 9b and R 9c together with the carbon to which they are attached combine to form a C 3-4 cycloalkyl which is substituted with from 0 to 2 fluorine groups;

[0424] alternatively, R 9c and R 9a together with the carbon and nitrogen to which they are respectively attached combine to form a heterocycloalkyl having from 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

[0425] R 9a 、R 9b and R 9c These embodiments of 9 R, R and R can be combined with any of the embodiments described herein for X.

[0426] 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

[0427] R 9a is H or methyl;

[0428] R 9b is H or methyl; and

[0429] R 9c is H, methyl, ethyl, n-propyl,

[0430] alternatively, R 9b and R 9c together with the carbon to which they are attached combine to form a C 3-4 cycloalkyl which is substituted with from 0 to 2 fluorine groups;

[0431] alternatively, R 9c and R 9a together with the carbon and nitrogen to which they are respectively attached combine to form a heterocycloalkyl having from 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

[0432] R 9a 、R 9b and R 9c These embodiments of 9 R, R and R can be combined with any of the embodiments described herein for X.

[0433] This text is directed to X 9 , R 9a , R 9b and R 9c The described embodiments can exist in any combination. Additionally, the embodiments described herein for residue 9 can be combined with any of the embodiments described herein for residues 3, 4, 5, 6, 7, and 8. For example, as described herein X 9 , R 9a , R 9b and R 9c Any of the embodiments can be combined with any of 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 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , Ring B, m8 and R 8f described in any combination.

[0434] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia) or (Ia1), wherein

[0435] X 6 is and

[0436] the moiety –C(O)–X 9 –NR 9a – is

[0437] For the foregoing embodiments, 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 may each independently be as defined for any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0438] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia) or (Ia1), wherein

[0439] X 6 is and

[0440] moiety –C(O)–X 9 –NR 9a – is

[0441] For the foregoing embodiments, 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 may each independently be as defined for any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0442] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ib):

[0443]

[0444] R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , m8, R 8f , R 9a , R 9b and R 9c may each independently be as defined for any embodiment of formula (Ib) as described herein.

[0445] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ib1):

[0446]

[0447] 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 may each independently be as defined for any embodiment of formula (Ib1) as described herein.

[0448] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia) or (Ia1), wherein

[0449] X 6 is and

[0450] moiety –C(O)–X 9 –NR 9a – is

[0451] For the foregoing embodiments, R 3 , R 4a , R 4b , R 4c , R5a , 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 may each independently be as defined for any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0452] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia) or (Ia1), wherein

[0453] X 6 is and

[0454] moiety –C(O)–X 9 –NR 9a – is

[0455] For the foregoing embodiments, 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 may each independently be as defined for any embodiment of formula (I), (Ia) or (Ia1) as described herein.

[0456] Residues 3 to 9

[0457] 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

[0458] R 3 is

[0459] R 4a is H or methyl;

[0460] R 4b is H;

[0461] R 4c is methyl, ethyl, isopropyl, tert-butyl,

[0462] Or, R 4c and R 4a together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, wherein the heterocycloalkyl is substituted with 0 to 2 R 4a1 groups;

[0463] Each R 4a1 is independently methyl, –OH, methoxy, fluoro, or –N(H)S(O)2CH3;

[0464] Or, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 –OH groups;

[0465] R 5a is H;

[0466] R 5b is H;

[0467] R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,

[0468] X 6 is

[0469] R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, –CD3,

[0470] R 6b is H;

[0471] R 6d is H, methyl, ethyl, n-propyl, isopropyl, –CD3 or

[0472] R 7a is H;

[0473] R 7b is H;

[0474] R 7c is isobutyl,

[0475] R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3,

[0476] R 8b , R 8d and R 8e are each H;

[0477] Or, R 8b and R 8d together with the carbon to which each is attached form cyclopropyl;

[0478] m8 is 0, 1, 2 or 3;

[0479] Each R 8f is independently methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo,

[0480]

[0481] X 9 is

[0482] R 9a is H or methyl;

[0483] R 9b is H, methyl or ethyl; and

[0484] R 9c is H, methyl, ethyl, n-propyl, sec-butyl,

[0485] Or, R 9b and R 9cCombined with the carbon to which they are attached to form a C substituted with 0 to 2 fluorine groups 3-4 cycloalkyl;

[0486] Alternatively, R 9c and R 9a Combined with the respective attached carbon and nitrogen to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, the heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

[0487] For the foregoing embodiments, 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 may each independently be as defined for any embodiment of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) as described herein.

[0488] 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

[0489] R 3 is

[0490] R 4a is H or methyl;

[0491] R 4b is H;

[0492] R 4c is methyl, ethyl, isopropyl,

[0493] Alternatively, R 4c and R 4aCombined with the respective connected carbon and nitrogen to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, wherein the heterocycloalkyl is substituted with 0 to 2 R 4a1 and is substituted;

[0494] Each R 4a1 is independently –OH or fluorine;

[0495] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 1 –OH;

[0496] R 5a is H;

[0497] R 5b is H;

[0498] R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,

[0499] X 6 is

[0500] R 6a is H, methyl, ethyl, n-propyl, isobutyl, –CD3, or

[0501] R 6b is H;

[0502] R 6d is H, methyl, isopropyl or –CD3,

[0503] R 7a is H;

[0504] R 7b is H;

[0505] R 7c is isobutyl,

[0506] R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3 or

[0507] R 8b 、R 8d and R 8e are each H;

[0508] m8 is 0, 1, 2 or 3; and

[0509] Each R 8f is independently methyl, methoxy, fluoro, chloro, bromo, iodo,

[0510]

[0511] X 9 is

[0512] R 9a is H or methyl;

[0513] R 9b is H or methyl; and

[0514] R 9c is H, methyl, ethyl, n-propyl,

[0515] Or, R 9b and R 9c together with the carbon to which they are attached combine to form a C cycloalkyl substituted with 0 to 2 fluoro groups 3-4 ;

[0516] Or, R 9c and R 9a together with the respective carbon and nitrogen to which they are attached combine 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.

[0517] 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

[0518] R 3 is

[0519] R 4a is H or methyl;

[0520] R 4b is H;

[0521] R 4c is methyl, ethyl, isopropyl,

[0522] Or, R 4c and R 4aCombine with the respective connected carbon and nitrogen to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, wherein the heterocycloalkyl is substituted with 0 to 2 R 4a1 ;

[0523] Each R 4a1 is independently –OH or fluorine;

[0524] Alternatively, two R 4a1 groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 1 –OH;

[0525] R 5a is H;

[0526] R 5b is H;

[0527] R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,

[0528] X 6 is

[0529] R 6a is H, methyl, ethyl, n-propyl, isobutyl, –CD3 or

[0530] R 6b is H;

[0531] R 6d is H, methyl, isopropyl or –CD3,

[0532] R 7a is H;

[0533] R 7b is H;

[0534] R 7c is isobutyl,

[0535] R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3 or

[0536] R 8b 、R 8d and R 8e are each H;

[0537] m8 is 0, 1, 2 or 3; and

[0538] Each R 8f independently is methyl, methoxy, fluoro, chloro, bromo, iodo,

[0539] X 9 is

[0540] R 9a H or methyl;

[0541] R 9b H or methyl; and

[0542] R 9c is H, methyl, ethyl, n-propyl,

[0543] Alternatively, R 9b and R 9c together with the carbon to which they are attached combine to form a C cycloalkyl substituted with 0 to 2 fluoro groups 3-4 ring alkyl;

[0544] Alternatively, R 9c and R 9a together with the carbon and nitrogen to which they are respectively attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, the heterocycloalkyl being substituted with 0 or 1 fluoro or -OH group.

[0545] For the foregoing embodiments, 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 for any embodiment of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) as described herein.

[0546] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ic):

[0547]

[0548] R 3 , R 4a , R 4c , R 5c , R 6a , R 6d , R 8a 、m8、R 8f , R 9a , R 9b and R 9c may each independently be as defined for any embodiment of Formula (Ic) as described herein.

[0549] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ic1):

[0550]

[0551] R 3 , R 4a , R 4c , R 5c , R 6a , R 6d , R 8a 、m8、R 8f , R 9a , R 9b and R 9c and R and R are each independently as defined for any embodiment of Formula (Ic1) as described herein.

[0552] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has 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), which has the structure of any one of Examples 651 - 693.

[0553] The present disclosure includes all tautomers and stereoisomers of the compounds described herein, whether in a mixture or in pure or substantially pure form. The compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may have asymmetric centers at one or more carbon atoms and, accordingly, the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may exist in the form of diastereoisomers or enantiomers or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereoisomers), racemates, diastereoisomers and other mixtures of such isomers, as well as solvates, hydrates and tautomers are within the scope of the present disclosure. The compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may be prepared using diastereoisomers, enantiomers or racemic mixtures as starting materials. In addition, diastereoisomeric and enantiomeric products may be separated by chromatography, fractional crystallization or other methods known to those skilled in the art.

[0554] Compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) may also exist in the form of salts, such as acid salts or base salts of the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1). Schematic examples of pharmaceutically acceptable salts include salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. More information on 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.

[0555] 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 salts, and ammonium salts, such as ammonium salts, trimethylammonium salts, diethylammonium salts, and tris(hydroxymethyl)methylammonium salts.

[0556] Similarly, it can also be an acid addition salt such as an addition salt of a mineral acid, an organic carboxylic acid, and an organic sulfonic acid (e.g., hydrochloric acid, methanesulfonic acid, maleic acid), provided that a basic group such as a pyridyl group forms part of the structure.

[0557] The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present disclosure, the salt is equivalent to the parent form of the compound in other respects.

[0558] The present disclosure also includes isotopically labeled compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1), wherein one or more atoms are replaced with one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and36 Cl). Isotopically labeled compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) can be used to determine the tissue distribution of the compounds, their prodrugs and metabolites; preferred isotopes for such determinations include 3 H and 14 C. Additionally, in some cases, substitution with heavier isotopes such as deuterium ( 2 H) can provide increased metabolic stability, thereby conferring therapeutic advantages such as an extended in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) can generally be prepared by methods known in the art.

[0559] IV. Compositions

[0560] The compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein can be used to manufacture 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 the compounds of the present invention and pharmaceutically acceptable excipients. In some embodiments, a pharmaceutical composition or medicament comprising one or more compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) can be administered to a subject to treat cancer.

[0561] The pharmaceutical compositions or medicaments for the present disclosure can be formulated using one or more physiologically acceptable carriers or excipients by standard techniques or methods known in the pharmaceutical art. Suitable pharmaceutical carriers are described herein and, for example, in "Remington’s Pharmaceutical Sciences" by E.W. Martin. The compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) and their physiologically acceptable salts and solvates 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, the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) are dissolved in a liquid such as water. In any given case, the most suitable route of administration of the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) depends in part on the nature, severity and optionally the stage of the cancer.

[0562] The pharmaceutical compositions or medicaments of the present disclosure may comprise a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) as an active ingredient, as well as a pharmaceutically acceptable carrier and / or excipient or diluent. Any carrier and / or excipient suitable for the desired dosage form of administration is contemplated for use with the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) disclosed herein.

[0563] In some embodiments, the pharmaceutical compositions or medicaments described herein are suitable for systemic administration. Systemic administration includes enteral administration (e.g., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion or implantation). In some embodiments, the pharmaceutical composition or medicament may be administered via syringe or intravenously. In a preferred embodiment, the pharmaceutical composition or medicament is administered subcutaneously.

[0564] For oral administration, the pharmaceutical composition or medicament may take the form of, for example, tablets or capsules, which are prepared by conventional means with pharmaceutically acceptable excipients. Preferred are tablets and gelatin capsules, which contain the active ingredient and (a) diluents or fillers 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) lubricants such as silica, anhydrous colloidal silica, talc, stearic acid, its magnesium or calcium salts (e.g., magnesium stearate or calcium stearate), metal stearates, colloidal silica, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and / or polyethylene glycol; for tablets, there is also (c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and / or hydroxypropylmethyl cellulose; if desired, there may also be included (d) disintegrants such as starch (e.g., potato starch or sodium starch glycolate), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents such as sodium lauryl sulfate, and / or (f) absorbents, colorants, flavorants and sweeteners. In some embodiments, the tablets contain a mixture of hydroxypropylmethyl cellulose, polyethylene glycol 6000 and titanium dioxide. The tablets may be film-coated or enteric-coated according to methods known in the art.

[0565] Liquid formulations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as dry products and reconstituted with water or other suitable vehicle before use. Such liquid formulations can be prepared by conventional means with pharmaceutically acceptable additives (for example, suspending agents such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats; emulsifying agents such as lecithin or gum arabic; non-aqueous vehicles such as almond oil, oily esters, ethanol or fractionated vegetable oils; and preservatives such as methyl or propyl hydroxybenzoates or sorbic acid). The formulations may also optionally contain buffering salts, flavoring agents, coloring agents and / or sweetening agents. If desired, formulations for oral administration can be suitably formulated to give controlled release of the active compound.

[0566] Typical formulations for topical administration include creams, ointments, sprays, lotions and patches. However, the pharmaceutical compositions can be formulated for any type of administration, for example intradermal, subcutaneous, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrathoracic, intracoronary or intratumoral injection, using a syringe or other device. Formulations for administration by inhalation (for example, aerosols) or for oral, rectal or vaginal administration are also contemplated.

[0567] Pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of powders of the compounds or their salts described herein and suitable carriers and / or lubricants. The compositions for pulmonary administration can be inhaled by any suitable dry powder inhaler device known to those skilled in the art. In certain cases, a suitable propellant (for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas) can be used to conveniently deliver the composition in the form of an aerosol spray from a pressurized package or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator, such as gelatin capsules and cartridges, can be formulated to contain a powder mixture of the compound and a suitable powder base (for example, lactose or starch).

[0568] Compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) can also be formulated as rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0569] The compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein can be formulated for parenteral administration by injection (e.g., by bolus injection). Formulations for injection can be presented in unit dosage form, e.g., in an ampoule or in a multi-dose container, with an added preservative. Injectable compositions are preferably isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifying agents, solubilizing agents, salts for regulating 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, they can also contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulating or coating methods and contain about 0.1 to 75%, preferably about 1 to 50%, of the said compound.

[0570] In some embodiments, the compositions described herein are prepared to have 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 alginates.

[0571] 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-β-cyclodextrin (HP-βCD), glycerol, maltose, mannitol, sucrose, and mixtures thereof.

[0572] V. Methods

[0573] The present disclosure encompasses the use of the 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 at least partially regulated by one or more cyclins. In some embodiments, the cyclin-mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present invention provides a method for treating cancer that is at least partially mediated 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 cancer.

[0574] In some embodiments, the present invention provides compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) for use in therapy.

[0575] The present disclosure encompasses the use of the compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is at least partially regulated by cyclin A. In some embodiments, the cyclin A-mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present invention provides a method for treating cancer that is at least partially mediated 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.

[0576] In some embodiments, provided herein are methods for treating a proliferative condition or disorder that is at least partially mediated by cyclin A, which comprise administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein.

[0577] In some embodiments, provided herein are compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) for use in a method for treating a proliferative condition or disorder that is at least partially mediated by cyclin A.

[0578] 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 condition or disorder that is at least partially mediated by cyclin A.

[0579] The present disclosure encompasses the use of the compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is at least partially regulated by cyclin B. In some embodiments, the cyclin B-mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present invention provides a method for treating cancer that is at least partially mediated by cyclin B, 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.

[0580] In some embodiments, provided herein are methods for treating a proliferative condition or disorder that is at least partially mediated by cyclin B, which comprise administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein.

[0581] In some embodiments, provided herein are compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) for use in a method of treating a proliferative condition or disorder that is at least partially mediated by cyclin B.

[0582] 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 condition or disorder that is at least partially mediated by cyclin B.

[0583] This disclosure encompasses the use of the compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein in the treatment or prevention of a disease or disorder that is at least partially regulated by cyclin E. In some embodiments, the cyclin E-mediated disease is a proliferative condition or disorder, including cancer. In some embodiments, the present invention provides a method of treating cancer that is at least partially mediated by cyclin E, 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.

[0584] In some embodiments, provided herein is a method of treating a proliferative condition or disorder that is at least partially mediated by cyclin E, the method comprising administering a compound of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein.

[0585] In some embodiments, provided herein are compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) for use in a method of treating a proliferative condition or disorder that is at least partially mediated by cyclin E.

[0586] 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 condition or disorder that is at least partially mediated by cyclin E.

[0587] In some embodiments, the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein can be used to treat or prevent proliferative conditions or disorders, including cancer, e.g., uterine cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, gastrointestinal cancers (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or large intestine cancer, colon cancer or rectal cancer), kidney cancer, renal cell carcinoma, bladder cancer, bone cancer, bone marrow cancer, skin cancer, head and 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 cancer, thyroid cancer, brain cancer, ganglionic cancer, central nervous system (CNS) cancer, and peripheral nervous system (PNS) cancer, as well as cancers of the hematopoietic and immune systems (e.g., spleen or thymus).

[0588] The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, including, for example, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma in situ, melanoma, leukemia, myeloma, sarcoma, teratoma, chemically-induced cancers, metastasis, and angiogenesis.

[0589] In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia.

[0590] In some embodiments, the tumor or cancer is small cell lung cancer (SCLC).

[0591] The use of the term “cancer-related diseases, disorders, and conditions” is intended to broadly refer to conditions that are directly or indirectly associated with cancer and includes, for example, angiogenesis and pre-cancerous lesions such as dysplasia.

[0592] In some embodiments, the cancer is a blood cancer (e.g., leukemia, lymphoma, multiple myeloma).

[0593] In some embodiments, the leukemia is acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or hairy cell leukemia.

[0594] In some embodiments, the lymphoma is non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell lymphoma, or Burkitt lymphoma.

[0595] In some embodiments, the cancer is an Rb mutant cancer. In some embodiments, the cancer has a mutation in the Rb / E2F pathway.

[0596] VI. Administration

[0597] The present disclosure encompasses the administration of the compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) and their compositions in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intra-articular, intraperitoneal, intracerebral (intraparenchymal), and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation.

[0598] The pharmaceutical compositions containing the compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) are preferably in unit dosage forms. The unit dosage form can be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be the capsule, tablet, cachet, or lozenge itself, or any suitable number of any of these in packaged form.

[0599] The compounds of (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1), or their pharmaceutical compositions or medicaments can be administered to a subject diagnosed with or suspected of having a disease or disorder that is at least partially mediated by cyclin A in an amount sufficient to elicit an effective therapeutic response in the subject.

[0600] The dosage of the administered compound depends on various factors, including the body weight, age, individual condition, and / or form of administration of the subject. The magnitude of the dose will also be determined by the presence, nature, and extent of any adverse reactions accompanying the administration of the specific compound in the specific subject. Generally, the dose of the active compound is a dose sufficient to achieve the desired effect. The optimal dosing regimen can be calculated from measurements of the accumulation of the compound in the subject. Usually, the dose can be administered once or multiple times daily, weekly, or monthly. One of ordinary skill in the art can readily determine the optimal dose, method of administration, and rate of repetition.

[0601] In some embodiments, the unit dose for orally administering the compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein to a subject (e.g., a human) weighing from about 50 to about 70 kg can contain from about 1 to about 5,000 mg, from about 1 to about 3,000 mg, from about 1 to about 2,000 mg, or from about 1 to about 1,000 mg of the said compound.

[0602] In some embodiments, a unit dose for subcutaneous administration of a compound of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic), or (Ic1) described herein to a subject (e.g., a human) of about 50 to about 70 kg may contain 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 of the compound.

[0603] The dose may be administered once daily, or divided into sub-doses and administered in multiple doses, such as twice, three times, or four times daily. However, as will be understood by a skilled artisan, depending on the route of administration, different amounts may be administered at different times.

[0604] In some embodiments, the compound is administered for about 1 to 31 days, or about 1 to 12 months. In some embodiments, the compound is administered for one week or more, such as 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, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more.

[0605] The optimal dose, toxicity, and efficacy of such compounds may vary with the relative potency of the various compounds and can be determined by standard pharmacological procedures in experimental animals, e.g., by determining the LD 50 (the dose that kills 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index and can be expressed as the ratio LD 50 / ED 50 . Compounds with a large therapeutic index are preferred. Although compounds showing toxic side effects may be used, the delivery system should be carefully designed such that such compounds are targeted to the affected site to minimize potential damage to normal cells and thus reduce side effects.

[0606] The dose of the pharmaceutical composition or drug of the present disclosure can be monitored and adjusted throughout the course of treatment, depending on the severity of the symptoms, the frequency of recurrence, and / or the physiological response to the treatment regimen. Such adjustments to the treatment regimen are typically made by those skilled in the art.

[0607] The pharmaceutical composition or drug can be administered singly or multiple times depending on the dose and frequency required and tolerated by the patient. In any case, the composition or drug should provide a sufficient amount of the compound of the present disclosure to effectively treat the patient. Generally, in treating cancer, the dose should be sufficient to halt tumor growth or cause tumor regression without unacceptable toxicity or side effects to the patient.

[0608] VII. Intermediate

[0609] In some embodiments, the present disclosure provides intermediates useful for preparing the compounds of formula (I). Certain intermediates useful for preparing the compounds of formula (I) can be found, for example, in the Examples section of the present disclosure.

[0610] In some embodiments, the intermediate useful for preparing the compounds of formula (I) is an intermediate of formula (II)

[0611]

[0612] wherein

[0613] R 3 is a C 3b cycloalkyl substituted with 0 to 5 R 3-6 ;

[0614] Each R 3b is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, 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;

[0615] The subscript m4 is an integer from 0 to 2; and

[0616] Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen;

[0617] or a pharmaceutically acceptable salt thereof.

[0618] In some embodiments, the intermediate useful for preparing the compounds of formula (I) is an intermediate of formula (IIa)

[0619]

[0620] wherein

[0621] The subscript m3 is an integer from 0 to 5;

[0622] Each R 3b is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, C 1-4haloalkyl, 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;

[0623] the subscript m4 is an integer from 0 to 2; and

[0624] each R 4a1 independently is C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen;

[0625] or a pharmaceutically acceptable salt thereof.

[0626] 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. 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 2 to 5. 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 2 to 4. 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 2 to 3. 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 3 to 4. 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 3 to 4. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (IIa), wherein the subscript m3 is 3.

[0627] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein each R 3b independently is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, C 1-4 haloalkyl or cyano. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein each R 3b independently is C 1-4 alkyl, halogen or C 1-4 haloalkyl. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein each R 3b independently is halogen or C 1-4Halogenated alkyl. 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 fluorine or trifluoromethyl.

[0628] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein the 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), wherein the subscript m4 is 0. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein the subscript m4 is 1. In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (II) or (IIa), wherein the subscript m4 is 2.

[0629] 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 C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen. 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 C 1-4 alkyl or halogen. 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 halogen. 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 fluorine.

[0630] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (IIa), wherein

[0631] the subscript m3 is an integer from 1 to 5;

[0632] each R 3b is independently C 1-4 alkyl, halogen or C 1-4 halogenated alkyl;

[0633] the subscript m4 is an integer from 0 to 2; and

[0634] each R 4a1 is independently C 1-4 alkyl or halogen.

[0635] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (IIa), wherein

[0636] the subscript m3 is an integer from 1 to 5;

[0637] each R 3b independently is halogen or C 1-4 haloalkyl;

[0638] the subscript m4 is an integer from 0 to 2; and

[0639] each R 4a1 independently is halogen.

[0640] In some embodiments, the intermediate or a pharmaceutically acceptable salt thereof is an intermediate of formula (IIa), wherein

[0641] the subscript m3 is an integer from 2 to 3;

[0642] each R 3b independently is halogen or C 1-4 haloalkyl;

[0643] the subscript m4 is an integer from 0 to 2; and

[0644] each R 4a1 independently is halogen.

[0645] Any embodiment described herein for an intermediate of formula (II) or (IIa) can be combined with any embodiment described in this section. For example, any embodiment of R 3 , m3, R 3b , m4, R 4a1 described herein can be combined.

[0646] In some embodiments, the intermediate is a building block described herein. In some embodiments, the intermediate is one 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.

[0647] In some embodiments, the intermediate is a combination of one or more covalently linked building blocks.

[0648] VIII. Kit

[0649] The present disclosure encompasses kits comprising compounds of formula (I), (Ia), (Ia1), (Ib), (Ib1), (Ic) or (Ic1) described herein and their pharmaceutical compositions. The kits are generally in the physical form of a structure containing the various components described below and can be used, for example, to carry out the methods described above.

[0650] The kit may contain one or more compounds disclosed herein (provided, for example, in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein may be provided in a ready-to-use form (e.g., tablets, capsules, injections) or in a form that requires 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 may also contain diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., which are packaged together with or separately from the compounds described herein. Each component of the kit may be encapsulated in a separate container, and all the various containers may be within a single package. The kits of the present disclosure may be designed for the conditions (e.g., refrigeration or freezing) required for proper storage of the components contained therein.

[0651] The kit may contain a label or package insert, including identification information of the components therein and instructions for use (e.g., dosing parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse reactions, contraindications, etc.). The label or insert may contain manufacturer information such as batch number and expiration date. The label or package insert may, for example, be integrated into the physical structure containing the components, separately contained within the physical structure, or affixed to the parts of the kit (e.g., ampoules, tubes or vials).

[0652] The label or insert may also include or incorporate a computer-readable medium, such as a disk (e.g., hard disk, card, storage disk), an optical disk such as a CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape or an electronic storage medium such as RAM and ROM or a hybrid medium such as a magnetic / optical storage medium, flash memory medium or storage type card. In some embodiments, there is no actual insert in the kit, but means are provided for obtaining the insert from a remote source (e.g., via the Internet).

[0653] IX. Examples

[0654] The following examples illustrate how to prepare various building blocks and exemplary compounds of formula I. The following examples are provided to illustrate but not limit the claimed disclosure.

[0655] A. Building Blocks

[0656] The compounds of formula I described herein are prepared by covalently linking the building blocks described in this section. The building blocks of the present disclosure are identified in Table 1 below by abbreviated names, reagent names, and CAS numbers (if known). For those building blocks without CAS numbers, experimental records are provided herein. The upper and lower case letters in the abbreviated names are relevant as they can indicate stereochemistry (i.e., 25ClF refers to Fmoc-L-2,5-dichlorophenylalanine, while 25Clf refers to Fmoc-D-2,5-dichlorophenylalanine). The order and details of covalently linking these building blocks will be described in another section.

[0657] Table 1: Building Blocks of the Present Disclosure

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670] Preparation of Building Block 1: (S)-4,4 - difluoro - 1-(1-(trifluoromethyl)cyclohexane - 1 - carbonyl)pyrrolidine - 2 - carboxylic acid

[0671]

[0672] 1-(Trifluoromethyl)cyclohexane-1-carboxylic acid (500 mg, 2.55 mmol) was dissolved in thionyl chloride (3.6 ml, 51 mmol) and heated under reflux for 3 hours. The mixture was allowed to cool and the thionyl chloride was removed by azeotroping with toluene. The crude product was carried on to the next step without further purification.

[0673] Dissolve methyl (S)-4,4-difluoropyrrolidine-2-carboxylate in 5 ml of DCM. Add pyridine (615 μl, 7.65 mmol) and cool the mixture to 0 °C. Add dropwise a solution of 1-(trifluoromethyl)cyclohexane-1-carbonyl chloride to this reaction. Warm the reaction to room temperature and allow the reaction to proceed for 12 h. Quench the reaction with NaHCO3 and extract the mixture with DCM three times. Combine the extracts, dry over MgSO4, filter and concentrate to give methyl (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylate (743 mg, 85%), ESI MS m / z 343.1

[0674] Dissolve methyl (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylate (500 mg, 1.36 mmol) in 10 ml of dioxane. Add a solution of LiOH (112 mg, 2.73 mmol) in 5 ml of water to this reaction and allow the reaction to proceed for 2 h. Quench the reaction with 1 N HCl and extract with EtOAc three times. Combine the extracts, dry over MgSO4, filter and concentrate. Purify the crude product by column chromatography (80% EtOAC / hexane) to give (S)-4,4-difluoro-1-(1-(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidine-2-carboxylic acid as a white powder (450 mg, 93%), ESI MS m / z 329.1

[0675] Preparation of Building Block 2: (1-(trifluoromethyl)cyclohexane - 1 - carbonyl)-L - proline

[0676]

[0677] This compound was prepared using methyl L-proline in place of methyl (S)-4,4-difluoropyrrolidine-2-carboxylate according to the general synthetic sequence described for the preparation of building block 1. ESI MS m / z 293.12

[0678] Preparation of Building Block 3: (2S,4R)-4 - fluoro - 1-(2-(trifluoromethyl)bicyclo[2.2.1]heptane - 2 - carbonyl)pyrrolidine - 2 - carboxylic acid

[0679]

[0680] This compound was prepared using 2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate according to the general synthetic sequence described for the preparation of building block 1. ESI MS m / z 323.12

[0681] Preparation of Building Block 4: (2S,4R)-4 - fluoro - 1-(1-(trifluoromethyl)cyclohexane - 1 - carbonyl)pyrrolidine - 2 - carboxylic acid

[0682]

[0683] This compound was prepared using 1-(trifluoromethyl)cyclohexane-1-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate according to the general synthetic sequence described for the preparation of Building Block 1. ESI MS m / z 311.10

[0684] Preparation of Building Block 5: (2S,4R)-4 - fluoro - 1-(1-(trifluoromethyl)cyclopropane - 1 - carbonyl)pyrrolidine - 2 - carboxylic acid

[0685]

[0686] This compound was prepared using 1-(trifluoromethyl)cyclopropane-1-carboxylic acid and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate according to the general synthetic sequence described for the preparation of Building Block 1, ESI MS m / z 269.07

[0687] Preparation of Building Block 6: (2S,4R)-4 - fluoro - 1 - [2-(trifluoromethyl)oxane - 2 - carbonyl]pyrrolidine - 2 - carboxylic acid acid

[0688]

[0689] 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 at 25 °C for 16 h under a nitrogen atmosphere. The mixture was purified directly by reverse-phase flash chromatography together 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.

[0690] Methyl (2S,4R)-4-fluoro-1-[2-(trifluoromethyl)oxan-2-carbonyl]pyrrolidine-2-carboxylate (4.5 g, 13.750 mmol, 1 eq) and NaOH (2.75 g, 68.750 mmol, 5 eq) in a mixture of MeOH (50 mL) / water (50 mL) were stirred at 20 °C for 16 h. Methanol was evaporated in vacuo. The aqueous phase was acidified by addition of HCl (1 N) and extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. This gave (2S,4R)-4-fluoro-1-[2-(trifluoromethyl)oxan-2-carbonyl]pyrrolidine-2-carboxylic acid as a pale yellow solid (4.0020 g, 92.03%). LCMS: (ESI, m / z): [M+H] + = 314.0.

[0691] Preparation of Building Block 7: (2S,4R)-4 - fluoro - 1 - ((R)-3,3,3 - trifluoro - 2-(2-(2 - methoxyethoxy)ethoxy)- 2 - methylpropanoyl)pyrrolidine - 2 - carboxylic acid

[0692]

[0693] To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (6.7 g, 42.38 mmol, 1 eq) in DMF (200 mL) was added K2CO3 (11.72 g, 84.77 mmol, 2 eq) and benzyl bromide (8.70 g, 50.86 mmol, 6.04 mL, 1.2 eq). The mixture was stirred at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated that (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid was completely consumed and a new spot was formed. The reaction mixture was poured onto 100 mL of ammonium chloride and then extracted with ethyl acetate 200 mL (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 200:1 to 5:1) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methylphenylpropionate as a white oil (7.2 g, crude).

[0694] At 0 °C, NaH (638.14 mg, 15.96 mmol, purity 60%, 1.1 eq) was added to a solution of (R)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (3.6 g, 14.50 mmol, 1 eq) and 1-(2-bromoethoxy)-2-methoxy-ethane (5.31 g, 29.01 mmol, 2 eq) in DMF (150 mL). The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated completion of the reaction. The reaction mixture was poured into 100 mL of ammonium chloride solution and then extracted with ethyl acetate (180 mL, 90 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 200:1 to 5:1) to give (R)-benzyl 3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoate (6.7 g, crude) as a yellow oil.

[0695] At 20 °C, Pd / C (3 g, purity 10%) was added to a mixture of (R)-benzyl 3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoate (4.3 g, 12.27 mmol, 1 eq) in MeOH (150 mL), then the mixture was degassed and purged with H2 three times, and then the mixture was stirred at 50 °C for 2 h under a H2 atmosphere (15 psi). TLC (petroleum ether:ethyl acetate = 1:1) indicated complete consumption of the starting material. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (6.2 g, crude) as a yellow oil.

[0696] At 0 °C, oxalyl chloride (8.19 g, 64.56 mmol, 5.65 mL, 3 eq) and DMF (157.31 mg, 2.15 mmol, 165.59 μL, 0.1 eq) were added to a solution of (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoic acid (5.6 g, 21.52 mmol, 1 eq) in DCM (90 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give (R)-3,3,3-trifluoro-2-(2-(2-methoxyethoxy)ethoxy)-2-methylpropanoyl chloride (6 g, crude) as a colorless oil.

[0697] At 0 °C, TEA (6.22 g, 61.44 mmol, 8.55 mL, 3 eq) was added to a solution of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (3.76 g, 20.48 mmol, 1 eq, HCl) in DCM (50 mL). 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 eq) in DCM (50 mL) was added to the above mixture at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed that the reaction was complete and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 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, yield 91.56%) as a yellow oil.

[0698] At 0 °C, LiOH·H2O (1.67 g, 39.76 mmol, 2 eq) was added 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 eq) in THF (60 mL) and MeOH (60 mL). The mixture was stirred at 20 °C for 12 h. LCMS showed that compound 6 was completely consumed and the desired mass was detected. The reaction mixture was adjusted to pH ~ 5 with saturated citric acid solution, some solid was separated, then filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 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, yield 40.01%, purity 95.668%) as a white solid. LCMS (ESI+): m / z 376.0 (M+H)

[0699] Preparation of Building Block 8: (2S,4R)-1 - [6,6 - difluoro - 2-(trifluoromethyl)spiro[3.3]heptane - 2 - carbonyl]-4 - fluoropyrro idine - 2 - carboxylic acid

[0700]

[0701] Under an argon atmosphere at -78 °C, LDA (52.58 mL, 105.158 mmol, 2.00 equivalents) was added dropwise to a stirred solution of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate (10 g, 52.579 mmol, 1 equivalent) in THF (150 mL). The resulting mixture was stirred at -78 °C for 45 minutes under an argon atmosphere and 1-(trifluoromethyl)-1λ3,2-benziodaoxol-3-one (33.23 g, 105.158 mmol, 2 equivalents) was added at -78 °C. The resulting mixture was stirred from -78 °C to room temperature for 4 hours under an argon atmosphere. The desired product could be detected by GCMS. Then, LiOH (6.30 g, 262.895 mmol, 5 equivalents) and H2O (200 mL) were added dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. 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 phase was washed with 4 x 100 mL of 1N NaOH. The mixture was acidified to pH 5 with concentrated HCl at 0 °C. The aqueous layer was extracted with EtOAc (2 x 500 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with MeCN (2 x 200 mL). The filtrate was concentrated under reduced pressure. The crude product (20 g) was purified by Ms-guided preparative-HPLC using the following conditions (column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 41% B to 54% B in 7 minutes, 54% B; wavelength: 254; 220 nm; RT1 (min): 6.140; number of runs: 0) to give 6,6-difluoro-2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid as a pale yellow solid (900 mg, 6.31%). LCMS: (ESI, m / z): [M+H] - = 243.

[0702] Under an argon atmosphere at 0 °C, TCFH (861.87 mg, 3.072 mmol, 1.5 equiv) and NMI (1261.01 mg, 15.360 mmol, 7.5 equiv) were added dropwise 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). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN / H2O (0.1% FA), 40% to 100% gradient in 15 minutes; detector, UV 210 nm. This gave 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.

[0703] At room temperature, LiOH (44.91 mg, 1.876 mmol, 2 equiv) was added 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) / H2O (3 mL). 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 (aqueous solution). 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.

[0704] Preparation of Building Block 9: (2S,4R)-1 - [3,3 - difluoro - 1-(trifluoromethyl)cyclopentanecarbonyl]-4 - fluoropyrrolidine - 2 - carboxylic acid acid

[0705]

[0706] This compound was prepared according to the general synthetic sequence described for the preparation of building block 8 using methyl 3,3-difluorocyclopentane-1-carboxylate in place of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate. ESI MS m / z 332.

[0707] Preparation of Building Block 10: (2S,4R)-1 - [4,4 - difluoro - 1-(trifluoromethyl)cyclohexanecarbonyl]-4 - fluoropyrrolidine - 2 - carboxylic acid

[0708]

[0709] This compound was prepared according to the general synthetic sequence described for the preparation of building block 8 using ethyl 4,4-difluorocyclohexane-1-carboxylate in place of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate. ESI MS m / z 348.

[0710] Preparation of Building Block 11: (2S,4R)-1-(1-(difluoromethyl)-3,3 - difluorocyclobutane - 1 - carbonyl)-4 - fluoropyrrolidine - 2 - carboxylic acid

[0711]

[0712] Under an argon atmosphere at -78 °C, DIBAl-H (69.36 mL, 69.362 mmol, 2 equivalents, 1 M in DCM) was added dropwise to a stirred solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (10 g, 34.681 mmol, 1 equivalent) in DCM (100 mL). The resulting mixture was stirred at -78 °C under an argon atmosphere for 4 hours. The desired product could be detected by GCMS. The reaction was quenched with 2 N HCl (aqueous solution) at 0 °C. The aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried over anhydrous Na2SO4, 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.

[0713] A mixture of isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (2.1 g, 9.120 mmol, 1 equivalent) in 6 N HCl (25 mL) was stirred at room temperature overnight. The desired product could be detected by GCMS. The aqueous layer was extracted with CH2Cl2 (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, 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.

[0714] Under an argon atmosphere, at 0 °C, DAST (4.81 g, 29.860 mmol, 5.5 eq) was added dropwise to a stirred solution of isopropyl 1 - formyl - 3 - oxocyclobutane - 1 - carboxylate (1 g, 5.429 mmol, 1 eq) in DCM (20 mL). 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 adding saturated NaHCO3 (aqueous solution) (100 mL) at 0 °C. The residue was purified by silica gel column chromatography, eluting with CH2Cl2, to give isopropyl 1 - (difluoromethyl) - 3,3 - difluorocyclobutane - 1 - carboxylate as a colorless oil (1 g, 72.65%). LCMS: (ESI, m / z): [M + H] + = 228.

[0715] At 0 °C, NaOH (0.79 g, 19.722 mmol, 3 eq) in H2O (20 mL) was added dropwise to a stirred solution of isopropyl 1 - (difluoromethyl) - 3,3 - difluorocyclobutane - 1 - carboxylate (1.5 g, 6.574 mmol, 1 eq) in THF (20 mL). 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 (aqueous solution). The aqueous layer was extracted with EtOAc (2 x 30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. This gave 1 - (difluoromethyl) - 3,3 - difluorocyclobutane - 1 - carboxylic acid as a colorless oil (730 mg, 56.69%). LCMS: (ESI, m / z): [M + H] - = 185.

[0716] Under a nitrogen atmosphere, at 0 °C, NMI (3.31 g, 40.297 mmol, 7.5 eq) was added dropwise to a solution of 1 - (difluoromethyl) - 3,3 - difluorocyclobutane - 1 - carboxylic acid (1 g, 5.373 mmol, 1 eq), TCFH (2.26 g, 8.059 mmol, 1.5 eq), and methyl (2S,4R) - 4 - fluoropyrrolidine - 2 - carboxylate (0.87 g, 5.910 mmol, 1.1 eq) in ACN (20 mL). The mixture was stirred at room temperature for 16 h. The residue was purified by reverse - phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / 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 as a brown solid (300 mg, 15.94%). LCMS: (ESI, m / z): [M + H]+ = 315.24.

[0717] Under a nitrogen atmosphere at 0 °C, LiOH (136.75 mg, 5.709 mmol, 3 eq) in H2O (10 mL) was added to a solution of methyl (2S,4R)-1-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (600 mg, 1.903 mmol, 1 eq) in THF (10 mL). The resulting solution was stirred at room temperature for 16 h. 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 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. This gave (2S,4R)-1-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylic acid as a white solid (0.4957 g, 84.80%). LCMS: (ESI, m / z): [M+H] + = 301.21

[0718] Preparation of Building Block 12: (2R)-2 - [(tert - butoxycarbonyl)amino]-3,3,3 - trifluoropropionic acid

[0719]

[0720] Under a nitrogen atmosphere at room temperature, Boc2O (1.57 mL, 7.339 mmol, 1.5 eq) was added portionwise to a stirred solution of trifluoro-D-alanine (700 mg, 4.893 mmol, 1 eq) and TEA (4.08 mL, 29.358 mmol, 6.0 eq) in THF (14.00 mL). 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 (aqueous solution) (1 x 15 mL) and water (1 x 15 mL), dried, and concentrated under reduced pressure. The crude product was purified by preparative-HPLC to give (2R)-2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoropropanoic acid as a white solid (0.4712 g, 37.62%). LCMS: (ESI, m / z): [M-H] - = 242.2.

[0721] Preparation of Building Block 13: (2S)-2 - [(tert - butoxycarbonyl)amino]-3,3,3 - trifluoropropionic acid

[0722]

[0723] This compound was prepared using trifluoro-L-alanine according to the general synthetic sequence described for the preparation of building block 12. ESI MS m / z 242.2

[0724] Preparation of Building Block 14: (R)-2 - (difluoromethoxy)-3,3,3 - trifluoro - 2 - methylpropionic acid

[0725]

[0726] Dissolve (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7.0 g, 44.3 mmol) in DMF (70 mL), add K2CO3 (6.7 g, 48.7 mmol) and stir for 10 minutes. Add benzyl bromide (8.34 g, 48.7 mmol) and stir the reaction mixture at room temperature for another 4 hours. Quench the mixture with water (150 mL) and extract with EtOAc (70 mL × 3). Combine the organic layers, wash with brine (70 mL × 3), dry over anhydrous Na2SO4, and then concentrate in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc = 20:1) to give (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid benzyl ester as a colorless liquid (7.7 g, 73%). %). ESI MS m / z: 248.07

[0727] To a mixture of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid benzyl ester (7.3 g, 29.4 mmol) and DCM (150 mL) at 0 °C with vigorous stirring, add aqueous KOH solution (20 wt%, 41 mL, 176.4 mmol). Then add a solution of TMSCF2Br (9.0 g, 44.0 mmol) in DCM (30 mL) to the mixture at 0 °C. Stir the mixture at room temperature for 16 hours. Quench the reaction mixture by adding water (100 mL) and extract with CH2Cl2 (50 mL × 3). Combine the organic layers and dry over anhydrous MgSO4. Remove the solvent in vacuo and purify the residue by preparative-HPLC (water (0.01 mol / L NH4HCO3):ACN = 100% to 75%) to give the product (R)-2-(difluoromethoxy)-3,3,3-trifluoro-2-methylpropanoic acid benzyl ester as a colorless liquid (2.2 g, 25%). ESI MS m / z: 298.06

[0728] Under H2 atmosphere, stir a mixture of (R)-2-(difluoromethoxy)-3,3,3-trifluoro-2-methylpropanoic acid benzyl ester (2.2 g, 7.38 mmol) and 10% Pd / C (600 mg) in MeOH (100 mL) at room temperature for 1 hour. Then remove the Pd / C by filtration through a pad of diatomaceous earth. Concentrate the filtrate in vacuo and purify the residue by column chromatography on silica gel (DCM:MeOH = 100:0 to 50:1) to give the desired product as a light brown liquid (850 mg, 55%). ESI MS m / z: 208.06.

[0729] Preparation of Building Block 15: N2 - ((((9H - fluoren - 9 - yl)methoxy)carbonyl)-N6 - (tert - butoxycarbonyl)-N6 - (2,2,2 - trifluoroethyl)-L - lysine

[0730]

[0731] To a solution of ((benzyloxy)carbonyl)-L-lysine methyl ester (5 g, 16.99 mmol) in THF (84 mL) was added cesium carbonate (16.57 g, 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 h. After completion, the reaction was cooled, quenched with water and extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated (reduced). The crude product was carried on to the next reaction without further purification. ESIMS m / z 464.1

[0732] N2-((Benzyloxy)carbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine methyl ester (6.0 g, 12.93 mmol) was dissolved in dioxane (64 mL) and a solution of NaHCO3 (3.25 g, 38.79 mmol) in water (20 mL) was added thereto. Boc2O (5.5 g, 25.39 mmol) was added and the reaction was allowed to proceed at room temperature for 12 h. After completion of the reaction, water was added and the organic matter was extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (60% EtOAc / Hex) to give the desired product (5.7 g, 93%) ESI MS m / z 476.3

[0733] N2-((Benzyloxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine methyl ester (5.2 g, 10.92 mmol) was dissolved in dioxane (120 mL). A solution of lithium hydroxide (895 mg, 21.82 mmol) was added thereto and the reaction was allowed to proceed at room temperature for 2 h. Thereafter, the reaction was quenched with a saturated solution of citric acid and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated to give the crude product, which was carried on to the next reaction without further purification. ESI MS m / z 462.20.

[0734] Suspend N2-((benzyloxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine in MeOH (150 ml). Add palladium (10%, carbon supported, 1.09 mmol, 116 mg) and stir the mixture under hydrogen at 1 atm for 30 h. Filter the resulting suspension and concentrate. Redissolve the crude product in dioxane (110 ml) and add thereto a solution of NaHCO3 (4.5 g, 53.5 mmol) in water (80 ml) and FMOCOSu (3.8 g, 11.27 mmol). Let the mixture stir for 12 h. After completion, add a saturated solution of citric acid and extract the organic matter 3 times with EtOAc. Combine the organic layers, dry over MgSO4, filter, and concentrate. Purify the crude product by column chromatography (80% EtOAc) and obtain N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N6-(2,2,2-trifluoroethyl)-L-lysine as a white powder (5.7 g, 95%) after lyophilization, ESI MS m / z 550.18.

[0735] Preparation of Building Block 16: (S)-2 - ((((9H - fluoren - 9 - yl)methoxy)carbonyl)amino)-3-(5 - chloro - 2 - fluorophenyl)propanoic acid acid

[0736]

[0737] Step 1: Synthesis of (2-chloro-5-fluorophenyl)methanol

[0738]

[0739] Dissolve 2-chloro-5-fluorobenzaldehyde (1 g, 6.32 mmol) in MeOH (30 ml) and cool to 0 °C. Add NaBH4 (257 mg, 6.96 mmol) in two portions, then warm the mixture to room temperature and let the reaction proceed for 1 h. Quench the reaction with 1 N HCl thereafter and extract 3 times with EtOAc. Combine the organic layers, dry over MgSO4, filter, and reduce the solvent. Carry the crude product on to the next reaction without further purification.

[0740] Step 2: Synthesis of 2-(bromomethyl)-1-chloro-4-fluorobenzene

[0741]

[0742] Dissolve (2-chloro-5-fluorophenyl)methanol in DCM (80 ml) and cool to 0 °C. Add phosphorus tribromide (610 μl, 6.32 mmol) dropwise thereto. After addition, allow the reaction to proceed at room temperature for 4 h. After completion, cool the reaction in an ice bath. Slowly add saturated sodium bicarbonate until the mixture reaches pH 7. Then extract the organic matter with DCM 3 times. Combine the organic matter, dry over MgSO4, filter and reduce the solvent. The crude product is transferred to the next reaction without further purification.

[0743] Step 3: Synthesis of 2-(2-chloro-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

[0744]

[0745] Add (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (693 mg, 3.76 mmol) to a three-necked round-bottom flask equipped with a thermometer, septum and argon inlet. Add dry THF (37 ml) and cool the reaction to -78 °C. Add 2.5 M nBuLi (1.8 ml) dropwise thereto. Allow it to react at -78 °C for 30 min. Then, a solution of 2-(bromomethyl)-1-chloro-4-fluorobenzene (1.0 g, 4.52 mmol) dissolved in THF (20 ml). Allow the reaction to proceed at -78 °C for 2 h. After that, quench the reaction with saturated ammonium chloride and extract with EtOAc 3 times. Combine the organic matter, dry over MgSO4, filter, and reduce the solvent. The crude product is purified by column chromatography (15% EtOAc / Hex) to give the desired product (2S,5R)-2-(5-chloro-2-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a clear oil (1.5 g, 73%), ESI MS m / z 231.05

[0746] Step 4: Synthesis of methyl 2-amino-3-(2-chloro-5-fluorophenyl)propionate

[0747]

[0748] Dissolve 2-(2-chloro-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.5 g, 4.60 mmol) in THF (50 ml) and cool to 0 °C in an ice bath. Add 2N HCl (65 ml) dropwise. Then warm the reaction to room temperature and allow the reaction to proceed for 2 hours. After completion, cool the reaction in an ice bath and add NH4OH until the pH reaches 8 - 9. Then extract the reaction with EtOAc 3 times, combine the organic matter, dry over MgSO4, filter, and reduce the solvent. Purify the crude product by column chromatography (60% EtOAc / Hex) to obtain the desired product methyl 2-amino-3-(2-chloro-5-fluorophenyl)propionate as a clear oil. (800 mg, 75%)

[0749] Step 5: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-fluorophenyl)propanoic acid

[0750]

[0751] Dissolve methyl 2-amino-3-(2-chloro-5-fluorophenyl)propionate (800 mg, 3.46 mmol) in dioxane (12 ml) and add thereto a solution of LiOH (290 mg, 6.92 mmol) in water (23 ml). Allow the reaction to proceed for 1 hour. Thereafter, cool the mixture in an ice bath and add 2N HCl until the pH reaches 4 - 5. Add thereto a solution of NaHCO3 (1.4 gr, 16.6 mmol) in water (20 ml), followed by a solution of FmocOSu (1.2 gr, 3.56 mmol) in dioxane (30 ml). Allow it to react at room temperature for 12 hours. Quench the reaction with 1N HCl, then extract with EtOAc 3 times. Combine the organic matter, dry over MgSO4, filter, and reduce the solvent. Purify the crude product by column chromatography (50% EtOAc) to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-fluorophenyl)propanoic acid as a white solid. (1.3 gr, 85%) ESI MS m / z 439.10

[0752] Preparation of Building Block 17: (S)-2 - ((((9H - fluoren - 9 - yl)methoxy)carbonyl)amino)-3-(3,6 - dichloro - 2 - fluorophenyl) propanoic acid

[0753]

[0754] This compound was prepared using 3,6-dichloro-2-fluorobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 473.0

[0755] Preparation of Building Block 18: (S)-2 - ((((9H - fluoren - 9 - yl)methoxy)carbonyl)amino)-3-(2,5 - difluorophenyl)propanoic acid acid

[0756]

[0757] This compound was prepared using 2,5-difluorobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 423.13.

[0758] Building Block 19: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chloro-5-fluorophenyl)propanoic acid Preparation

[0759]

[0760] This compound was prepared using 2-chloro-5-fluorobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 439.10

[0761] Building Block 20: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-methylphenyl)prop Acid Preparation

[0762]

[0763] This compound was prepared using 5-chloro-2-methylbenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 435.12

[0764] Building Block 21: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(trifluoromethoxy yl)phenyl)propanoic acid Preparation

[0765]

[0766] This compound was prepared using 5-chloro-2-(trifluoromethoxy)benzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 505.09

[0767] Building Block 22: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-methoxyphenyl) Propanoic acid Preparation

[0768]

[0769] This compound was prepared using 5-chloro-2-methoxybenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 451.12

[0770] Building Block 23: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-bromo-2-chlorophenyl)propanoic acid Preparation

[0771]

[0772] The compound was prepared using 5-bromo-2-chlorobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 499.02

[0773] Building Block 24: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-bromo-5-chlorophenyl)propanoic acid Preparation

[0774]

[0775] The compound was prepared using 2-bromo-5-chlorobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 499.02

[0776] Building Block 25: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-iodophenyl)propanoic acid Preparation

[0777]

[0778] The compound was prepared using 5-chloro-2-iodobenzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 547.00

[0779] Building Block 26: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(difluoromethoxy yl)phenyl)propanoic acid Preparation

[0780]

[0781] The compound was prepared using 5-chloro-2-(difluoromethoxy)benzaldehyde as the starting material according to the general synthetic sequence described for the preparation of building block 16. ESI MS m / z 487.10

[0782] Building Block 27: (2S)-3-(3,3-Difluorocyclobutyl)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid Preparation

[0783]

[0784] The compound was prepared according to steps 3 to 5 of the general synthetic sequence described for the preparation of building block 16, where 3-(bromomethyl)-1,1-difluorocyclobutane was used instead of 2-(bromomethyl)-1-chloro-4-fluorobenzene. ESI MS m / z 402.3

[0785] Building Block 28: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy yl)phenyl)propanoic acid Preparation

[0786]

[0787] Step 1: Synthesis of 5-chloro-2-(cyclopropylmethoxy)benzaldehyde

[0788]

[0789] To a solution of 5-chloro-2-hydroxybenzaldehyde (1.5 gr, 9.61 mmol) in DMF (20 ml) was added K2CO3 (2.0 gr, 14.4 mmol). The reaction was allowed to proceed for 10 minutes and then bromomethylcyclopropane (2.5 gr, 15.3 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After completion, the mixture was quenched with water and the organic matter was extracted with DCM three times. The combined organic matter was 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 as a clear oil (1.8 gr, 90%). ESI MS m / z 210.04.

[0790] Step 2: Synthesis of 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene

[0791]

[0792] 5-Chloro-2-(cyclopropylmethoxy)benzaldehyde (2.1 gr, 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. After completion, the solvent was reduced and redissolved in DCM. 1 M HCl was added and the organic matter was extracted with DCM three times. The combined organic matter was dried over MgSO4, filtered, and the solvent was reduced to give the crude product (5-chloro-2-(cyclopropylmethoxy)phenyl)methanol, which was carried on to the next step without further purification.

[0793] (5-Chloro-2-(cyclopropylmethoxy)phenyl)methanol (2.1 gr, 9.9 mmol) was dissolved in DCM (40 ml) and cooled to 0 °C in an ice bath. Phosphorus tribromide (2.7 gr, 9.9 mmol) was added dropwise and the mixture was warmed to room temperature. The reaction was allowed to proceed for 4 hours. After completion, the reaction was cooled in an ice bath and a cold solution of saturated NaHCO3 was added until the pH was 7. The mixture was extracted with DCM three times, the combined organic matter was dried over MgSO4, filtered and the solvent was reduced. The crude product 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene was carried on to the next step without further purification.

[0794] Step 3: Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propionate

[0795]

[0796] Add O-allyl-N-(9-anthrylmethyl)cinchonidinium bromide (487 mg, 0.805 mmol) and tert-butyl N-(diphenylmethylene)glycinate (2.2 g, 8.05 mmol) to a 100 mL round-bottom flask. Dissolve them in DCM and cool the mixture to -20 °C. Add 2-(bromomethyl)-4-chloro-1-(cyclopropylmethoxy)benzene (2.5 g, 9.15 mmol) thereto, and then add 45% aqueous KOH solution (4.35 mL). Allow the reaction to proceed at -20 °C for 16 h. Thereafter, add water and extract the organic matter with DCM three times. Combine the organic matter, dry over MgSO4, filter, and concentrate. Then redissolve the crude product in dioxane. Add 2N HCl (20 mL) dropwise and allow the reaction to stir at room temperature for 1 h. After completion, cool the mixture in an ice bath and add saturated NaHCO3 until the pH is 7 - 9. Then, add a solution of FmocOSu (2.8 g, 8.30 mmol) and allow the mixture to react for 12 h. Quench the solution with water and extract the organic matter with EtOAc three times. Combine the organic matter, dry over MgSO4, filter, and reduce the solvent. Purify the crude product by column chromatography (25 - 50% EtOAc / hexane) to obtain the desired product tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propionate (3.5 gr, 85%) as a clear oil. ESI MS m / z 547.2.

[0797] Step 4: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propanoic acid

[0798]

[0799] Dissolve the starting material tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)phenyl)propionate (3.5 gr, 6.39 mmol) in DCM (20 mL), add 50% TFA / DCM (30 mL) thereto, and allow the reaction to proceed at room temperature until completion. Thereafter, reduce the solvent and purify the crude product by column chromatography (80% EtOAc / hexane) to obtain 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.

[0800] Building Block 29: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-phenoxyphenyl) Propanoic acid Preparation

[0801]

[0802] To a solution of 5-chloro-2-fluorobenzaldehyde (1.0 gr, 6.32 mmol) in DMF (20 ml) was added K2CO3 (3.93 gr, 28.4 mmol). The reaction was allowed to proceed for 10 minutes and then phenol (0.89 gr, 9.48 mmol) was added. The reaction was carried out at 110 °C overnight. After completion, the mixture was quenched with water and the organic matter was extracted with DCM three times. The combined organic matter was 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-phenoxybenzaldehyde (1.0 gr, 68%) as a clear oil. ESI MS m / z 232.03.

[0803] Building block 29 was prepared from 5-chloro-2-phenoxybenzaldehyde according to Steps 2 to 4 of the general synthetic sequence described for the preparation of building block 28. ESI MS m / z 513.13

[0804] Building Block 30: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopentylmethoxy yl)phenyl)propanoic acid Preparation

[0805]

[0806] This compound was prepared according to the general synthetic sequence described for the preparation of building block 28 using (bromomethyl)cyclopentane instead of bromomethylcyclopropane. ESI MS m / z 519.18

[0807] Building Block 31: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopentyloxy) phenyl)propanoic acid Preparation

[0808]

[0809] This compound was prepared according to the general synthetic sequence described for the preparation of building block 28 using bromocyclopentane instead of bromomethylcyclopropane. ESI MS m / z 505.17

[0810] Building Block 32: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclohexyloxy) phenyl)propanoic acid Preparation

[0811]

[0812] This compound was prepared according to the general synthetic sequence described for the preparation of building block 28 using bromocyclohexane instead of bromomethylcyclopropane. ESI MS m / z 519.17

[0813] Building Block 33: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2,2,2-trifluoro ethoxy)phenyl)propanoic acid Preparation

[0814]

[0815] This compound was prepared according to the general synthetic sequence described for the preparation of building block 28 but using 2,2,2-trifluoroethyl trifluoromethanesulfonate in place of bromomethylcyclopropane. ESI MS m / z 519.11

[0816] Building Block 34: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclobutylmethoxy yl)phenyl)propanoic acid Preparation

[0817]

[0818] 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 under a nitrogen atmosphere for 2 h. 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 as a white solid (7.3 g, 95.97%). No MS signal was found on LCMS.

[0819] Under a nitrogen atmosphere at 20 °C, (2R)-methyl 2-[(tert-butoxycarbonyl)amino]-3-(iodozincio)propionate (24.80 mL, 24.800 mmol, 2.0 equiv) was added dropwise to a stirred mixture 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)Cl2CH2Cl2 (0.10 g, 0.124 mmol, 0.01 equiv) in DMA (30 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was purified directly by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 210 nm. This yielded methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propionate as a dark brown oil (3.1 g, 62.83%). LCMS: (ESI, m / z): [M+Na] + = 420.

[0820] At 0 °C, an aqueous solution of sodium hydroxide (1.51 g, 37.775 mmol, 5 equivalents) was added dropwise to a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxyphenyl)propionate (2.9 g, 7.555 mmol, 1 equivalent) in THF (30 mL). The resulting mixture was stirred at room temperature for an additional 12 hours. The reaction was acidified to pH = 5 with HCl (1 N). The resulting mixture was extracted with EtOAc (2 * 50 mL). The organic layers were combined, 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)propionic acid as a white solid (2.3129 g, 82.78%). LCMS: (ESI, m / z): [M+Na] + = 406.20.

[0821] A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propionic acid (2.2 g, 5.731 mmol, 1 equivalent) in HCl (4 M, in EtOAc) was stirred at room temperature for 12 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. This gave (2S)-2-amino-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propionic acid as a white solid (2.0688 g, 127.22%). LCMS: (ESI, m / z): [M+H] + = 283.90.

[0822] At 0 °C, 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (2.28 g, 6.767 mmol, 1.2 eq) was added portionwise to a stirred mixture of (2S)-2-amino-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]propanoic acid (1.6 g, 5.639 mmol, 1 eq) and NaHCO3 (2.37 g, 28.195 mmol, 5 eq) in 1,4-dioxane:H2O (3:1, 50 mL). The resulting mixture was stirred at room temperature for an additional 12 h. The reaction was acidified to pH = 5 with HCl (1 N aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN / water, 0% to 100% gradient over 40 min; detector, UV 254 nm. This gave (2S)-3-[5-chloro-2-(cyclobutylmethoxy)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid as a white solid (1.3205 g, 46.28%). LCMS: (ESI, m / z): [M+H] + = 506.15.

[0823] Building Block 35: (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-cyclobutoxyphenyl yl)propanoic acid Preparation

[0824]

[0825] This compound was prepared using bromocyclobutane instead of (bromomethyl)cyclobutane according to the general synthetic sequence described for the preparation of building block 34. ESI MS m / z 492.1

[0826] Building Block 36: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid Preparation of Building Block 37: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl)propanoic acid

[0827]

[0828] Under a nitrogen atmosphere at room temperature, 2-chloroethyl p-toluenesulfonate (13.84 g, 58.952 mmol, 1.1 eq) was added dropwise to a stirred mixture of methyl 5-chloro-2-hydroxybenzoate (10 g, 53.593 mmol, 1 eq) and K2CO3 (14.81 g, 107.186 mmol, 2 eq) in DMF. The resulting mixture was stirred at 50 °C for 16 h 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 x 100 mL). The organic layers were combined, washed successively with NH4Cl (3 x 150 mL), NH4HCO3 (1 x 150 mL) and brine (1 x 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 as an off-white solid (13 g, 97.38%). LCMS: (ESI, m / z): [M+H] + = 249.00.

[0829] At 0 °C, t-BuOK (65.24 mL, 65.240 mmol, 1.25 eq) was added dropwise to a stirred solution of methyl 5-chloro-2-(2-chloroethoxy)benzoate (13 g, 52.190 mmol, 1 eq) in THF. The resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with water (200 mL) and extracted with EtOAc (2 x 150 mL). The organic layers were combined, washed with brine (1 x 200 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-(vinyloxy)benzoate as a colorless oil (6.9 g, 51.61%).

[0830] The aqueous layer was acidified to pH 3 with HCl and extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was recovered for reaction with CH3I to give another batch of the product.

[0831] A solution of methyl 5-chloro-2-(vinyloxy)benzoate (6.9 g, 32.451 mmol, 1 equiv) in CH2Cl2 was treated with chloromethyl iodide (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 at room temperature for 3 h under a nitrogen atmosphere. The reaction was quenched with NH4Cl (100 mL) and NH3·H2O (10 mL) at 0 °C. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2 x 100 mL). The organic layers were combined, washed with brine (1 x 200 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 (7:1) to give methyl 5-chloro-2-cyclopropoxybenzoate (6.25 g, 84.97%) as a pale green oil.

[0832] To a stirred solution of methyl 5-chloro-2-cyclopropoxybenzoate (6.25 g, 27.574 mmol, 1 equiv) in toluene (130 mL) at -78 °C under a nitrogen atmosphere was added dropwise DIBAl-H (46.08 mL, 227.124 mmol). The resulting mixture was stirred at room temperature for 2 h, then quenched with NH4Cl at 0 °C and diluted with water (200 mL). The mixture was then acidified to pH 5 with dilute HCl (1 N) and extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (1 x 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 pale brown solid.

[0833] To a stirred solution of (5-chloro-2-cyclopropoxyphenyl)methanol (3.73 g, 18.777 mmol, 1 equiv) in DCM (37 mL) at 0 °C under a N2 atmosphere was added dropwise PBr3 (7.62 g, 28.166 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 2 h, then neutralized to pH = 7 with NaHCO3. The resulting mixture was extracted with EtOAc (4 x 200 mL). The organic layers were combined 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 (80:1) to give 2-(bromomethyl)-4-chloro-1-cyclopropoxybenzene (3.35 g, 68.22%) as a white oil.

[0834] Under a nitrogen atmosphere at -78 °C, 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 and the resulting solution was stirred at -78 °C for 1 h. 2-(Bromomethyl)-4-chloro-1-cyclopropoxybenzene (3.35 g, 12.809 mmol, 1 equiv) was added dropwise to the above solution at -78 °C. The mixture was stirred at -78 °C for 2 h and then quenched with NH4Cl at -78 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined 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 (80:1), to give (2S,5R)-2-[(5-chloro-2-cyclopropoxyphenyl)methyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a white oil (3.06 g, 65.48%). LCMS: (ESI, m / z): [M+H] + = 365.40.

[0835] At room temperature, HCl (2 M) (8.5 mL) was added 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). The mixture was stirred at room temperature for 2 h and then neutralized to pH = 7 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, water / ACN, 0% to 100% gradient over 30 min; detector, UV 254 nm. This gave methyl (2S)-2-amino-3-(5-chloro-2-cyclopropoxyphenyl)propionate as a white oil (1.9 g, 82.91%). LCMS: (ESI, m / z): [M+H] + = 270.10.

[0836] At room temperature, NaOH (682.11 mg, 17.055 mmol, 5 equiv) in H2O (5 mL) was added dropwise to a stirred solution of methyl (2S)-2-amino-3-(5-chloro-2-cyclopropoxyphenyl)propionate (920 mg, 3.411 mmol, 1 equiv) in MeOH (5 mL). The mixture was stirred at room temperature for 1 h and then acidified to pH = 2 with dilute HCl (1 N). The resulting mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 256.20.

[0837] At room temperature, 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (1143.77 mg, 3.390 mmol, 1.02 equiv) and NaHCO3 (1396.27 mg, 16.620 mmol, 5 equiv) were added portionwise 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). The mixture was stirred at room temperature for 2 h and then acidified to pH = 2 with dilute HCl (1 N). The resulting mixture was extracted with EtOAc (5 x 50 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, H2O / ACN, 0% to 100% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This gave (2R)-3-(5-chloro-2-cyclopropoxyphenyl)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid as a white solid (1.1361 g, 71.51%). LCMS: (ESI, m / z): [M+Na] + = 500.10.

[0838] Preparation of Building Block 38: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyridin-2-yl)phenyl)propanoic acid Preparation of Building Block 39: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl)propanoic acid

[0839]

[0840] Under a nitrogen atmosphere at room temperature, (bromomethyl)cyclopropane (3.38 g, 25.054 mmol, 2 equiv) was added dropwise to a stirred mixture of 5-chloro-3-iodopyridin-2-ol (3.2 g, 12.527 mmol, 1 equiv) and Ag2CO3 (4.15 g, 15.032 mmol, 1.2 equiv) in toluene. 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 x mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give 5-chloro-2-(cyclopropylmethoxy)-3-iodopyridine as a colorless oil (3.6 g, 92.84%). LCMS: (ESI, m / z): [M+H] + = 310

[0841] Under a nitrogen atmosphere at room temperature, 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, followed by the dropwise addition at room temperature of methyl 2-[(tert-butoxycarbonyl)amino]-3-zincopropionate (3 mL, 9.692 mmol, 1.5 equiv, prepared from the iodide and Zn powder). 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 x mL). The organic layer was washed with brine, 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]propionate as a crude white solid (6.4 g, 102.95%). LCMS: (ESI, m / z): [M+Na] + = 385.

[0842] Under a nitrogen atmosphere at 0 °C, an aqueous sodium hydroxide solution (NaOH (3.33 g, 83.145 mmol, 5 eq) in 20 mL of water) was added to a stirred solution / mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propionate (6.4 g, 16.629 mmol, 1 eq) in 20 mL of THF. The resulting mixture was stirred at room temperature for an additional 1 - 2 hours. The reaction was acidified to pH = 4 with dilute HCl. The resulting mixture was extracted with EtOAc (50 x 3 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, H2O / ACN, 10% to 50% gradient in 10 minutes; detector, UV 254 nm. This gave (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propionic acid as a yellow solid (4.8 g, 77.84%). LCMS: (ESI, m / z): [M+H] + = 371.

[0843] At 0 °C, trimethylsilyl trifluoromethanesulfonate (2.78 g, 13.5 mmol, 1.5 eq) was added dropwise over 5 minutes to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propionic acid (3.3 g, 8.899 mmol, 1 eq) and 2,6-dimethylpyridine (1.8 g, 18 mmol, 2 eq) in 30 mL of DCM. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water / ACN, 0% to 100% gradient in 40 minutes; detector, UV 254 nm. This gave (2S)-2-amino-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propionic acid as a white solid (1.6 g, 66.42%). LCMS: (ESI, m / z): [M+H] + = 271

[0844] Under a nitrogen atmosphere at 0 °C, (2S)-2-amino-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]propanoic acid (1.5 g, 5.541 mmol, 1 equiv), 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (1.87 g, 5.541 mmol, 1 equiv), and Na2CO3 (2.33 g, 27.705 mmol, 5 equiv) were added to a stirred solution of 1,4-dioxane:H2O (40 mL, v / v = 3 / 1). The resulting mixture was stirred at room temperature for an additional 1 - 2 h. The residue was acidified to pH = 5 and then extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, H2O / ACN, 0% to 100% gradient over 60 min; detector, UV 254 nm, to give (2S)-3-[5-chloro-2-(cyclopropylmethoxy)pyridin-3-yl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid as a white solid (691.5 mg, 25.32%). LCMS: (ESI, m / z): [M-tert-butyl] + = 493

[0845] Preparation of Building Block 40: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(5-fluoropyridin-3-yl)phenyl)propanoic acid Preparation of Building Block 41: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)propanoic acid

[0846]

[0847] Step 1: Synthesis of (2-bromo-5-chlorophenyl)methanol

[0848]

[0849] To a solution of methyl 2-bromo-5-chlorobenzoate (10 g, 40.082 mmol, 1 equiv) in THF at 0 °C under a nitrogen atmosphere, lithium aluminum hydride (1.0 M in THF) (4.56 g, 120.246 mmol, 3 equiv) was added dropwise. The resulting mixture was stirred at room temperature for an additional 2 h. TLC showed normal (PE:EA = 1:1). The reaction was quenched with saturated NH4Cl (aqueous solution) 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 as a pale brown oil (8 g, 90.12%). TLC: Rf = 0.5 (PE / EA = 1:1).

[0850] Step 2: Synthesis of 1-bromo-2-(bromomethyl)-4-chlorobenzene

[0851]

[0852] Under a nitrogen atmosphere at 0 °C, PBr3 (19.55 g, 72.242 mmol, 2 equivalents) was added dropwise to a solution of (2-bromo-5-chlorophenyl)methanol (8.0 g, 36.121 mmol, 1 equivalent) in CH2Cl2. The resulting mixture was stirred at room temperature for an additional 2 hours. TLC (PE / EA = 1:1) indicated completion of the reaction. The reaction was quenched by the addition of saturated NH4Cl (aqueous solution) (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 70 mL). The organic layers were combined, washed with brine (3 x 50 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 (1:1), to give 1-bromo-2-(bromomethyl)-4-chlorobenzene as a brown oil (5.89 g, 57.34%). TLC: Rf = 0.5 (PE / EA = 3:1)

[0853] Step 3: Synthesis of tert-butyl (2S)-3-(2-bromo-5-chlorophenyl)-2-[(diphenylmethylene)amino]propionate

[0854]

[0855] Under a nitrogen atmosphere at 0 °C, a solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (5.89 g, 20.712 mmol, 1 equivalent) in CH2Cl2 (100 mL) was treated with tert-butyl 2-[(diphenylmethylene)amino]acetate (6.12 g, 20.712 mmol, 1 equivalent) and (2R,4R,5S)-1-(anthracen-9-ylmethyl)-5-vinyl-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 equivalent) for 30 minutes, followed by the dropwise addition of KOH (11.62 g, 207.120 mmol, 10 equivalents) in water (100 mL) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 2 hours. The product was detected by TLC (PE / EA = 4:1). The reaction was quenched by the addition of water (30 mL) at room temperature and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (3 x 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-[(diphenylmethylene)amino]propionate as a pale brown oil (1.5 g, 14.52%). LCMS: (ESI, m / z): [M+H] + = 497.60

[0856] Step 4: Synthesis of tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylene)amino]propionate

[0857]

[0858] Under a nitrogen atmosphere at room temperature, Pd(PPh3)4 (1.46 g, 1.263 mmol, 0.3 eq) and CuI (0.80 g, 4.210 mmol, 1 eq) were added portionwise to a stirred mixture of tert-butyl (2S)-3-(2-bromo-5-chlorophenyl)-2-[(diphenylmethylene)amino]propionate (2.1 g, 4.210 mmol, 1 eq) and 2-(tributylstannyl)pyridine (6.20 g, 16.840 mmol, 4 eq) in 1,4-dioxane. The mixture was stirred at 80 °C overnight. The desired product could be detected by LCMS. Water (50 mL) was added to the resulting mixture and the mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 100% gradient in 30 minutes; detector, UV254 nm. This gave tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylene)amino]propionate as a pale yellow oil (1.5 g, 71.69%). LCMS: (ESI, m / z): [M+H] + = 497.20

[0859] Step 5: Synthesis of (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid

[0860]

[0861] A solution of tert-butyl (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-[(diphenylmethylene)amino]propionate (1.5 g, 3.018 mmol, 1 eq) in 1,4-dioxane (30 mL) was treated with HCl (6 M) (20 mL, 658.256 mmol, 218.12 eq) at 50 °C for 2 hours 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.

[0862] Under a nitrogen atmosphere at room temperature, 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (1.61 g, 4.771 mmol, 1.1 eq) was added portionwise to a solution of (2S)-2-amino-3-[5-chloro-2-(pyridin-2-yl)phenyl]propanoic acid (1.2 g, 4.337 mmol, 1 eq) and NaHCO3 (0.52 g, 21.685 mmol, 5 eq) in 1,4-dioxane (50 mL) / water (15 mL). 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 organic layers were combined and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN / water, 10% to 100% gradient in 30 minutes; detector, UV 254 nm. This gave (2S)-3-[5-chloro-2-(pyridin-2-yl)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid as an off-white solid (0.2511 g, 11.60%). LCMS: (ESI, m / z): [M+H] + = 499.1

[0863] Preparation of Building Block 42: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)propanoic acid Preparation of Building Block 43: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoic acid

[0864]

[0865] This compound was prepared in steps 4 to 5 using 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 516.1.

[0866] Preparation of Building Block 44: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl)propanoic acid Preparation of Building Block 45: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyrimidin-2-yl)phenyl)propanoic acid

[0867]

[0868] This compound was prepared in steps 4 to 5 using (5-fluoropyridin-3-yl)boronic acid according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 517.05.

[0869] Preparation of Building Block 46: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(morpholinomethyl)phenyl)propanoic acid Preparation of Building Block 47: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoic acid

[0870]

[0871] This compound was prepared using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 538.1

[0872] Preparation of Building Block 48: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-2-yl)phenyl)propanoic acid Preparation of Building Block 49: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl)propanoic acid

[0873]

[0874] This compound was prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 578.0

[0875] Preparation of Building Block 50: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)propanoic acid ​

[0876]

[0877] This compound was prepared using 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 516.1

[0878] ​ ​

[0879]

[0880] This compound was prepared using 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 516.1

[0881] ​ Preparation of (5-((3-(trifluoromethyl)phenyl)amino)-5-oxopentyl)phenyl)propanoic acid

[0882]

[0883] This compound was prepared using pyrimidin-5-ylboronic acid in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 500.1.

[0884] ​ ​

[0885]

[0886] This compound was prepared using potassium trifluoro(morpholinomethyl)borate in steps 4 to 5 according to the general synthetic sequence described for the preparation of building block 38. LCMS: (ESI, m / z): [M+H] + = 521.09.

[0887] ​ ​

[0888]

[0889] Step 1: Synthesis of 5-chloro-2-(thiazol-5-yl)benzaldehyde

[0890]

[0891] To a 100 ml round-bottom flask, 4-chloro-2-formylphenylboronic acid (4.0 g, 21.73 mmol), 5-bromothiazole (3.0, 18.51 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.5 gr, 1.83 mmol) were added. It was dissolved in dioxane (90 ml) and 2M K2CO3 (22 ml). The mixture was bubbled with nitrogen and the reaction was heated to 60 °C for 3 hours. After completion, the reaction was cooled and quenched with water. The crude product was extracted 3 times with EtOAc, the organic matters were combined, dried over MgSO4, filtered and the solvent was reduced. The crude product was purified using column chromatography (15%) to obtain 5-chloro-2-(thiazol-5-yl)benzaldehyde (4.0 g, 98%) as a white solid. ESI MS m / z 222.1.

[0892] Step 2: Synthesis of (5-chloro-2-(thiazol-5-yl)phenyl)methanol

[0893]

[0894] 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 3 portions, the mixture was warmed to room temperature, and the reaction was allowed to proceed for 1 hour. The solvent was reduced, and 1 N HCl was added. The crude product was then extracted 3 times with DCM. The organic layers were combined, dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography to give the desired product, (5-chloro-2-(thiazol-5-yl)phenyl)methanol, as a clear oil (4.0 g, 98%). ESI MS m / z 225.0

[0895] Step 3: Synthesis of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoate

[0896]

[0897] 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. PBr3 (1.7 ml, 17.77 mmol) was added dropwise, and the mixture was warmed to room temperature. The reaction was allowed to proceed for 5 hours. After completion, the mixture was poured into cold saturated NaHCO3 solution. The crude product was extracted 3 times with DCM, the organic layers were combined, dried over MgSO4, filtered, and the solvent was reduced. The crude product was carried on to the next step without further purification.

[0898] To a 100 ml round-bottom flask, add O-allyl-N-(9-anthrylmethyl)cinchonidinium bromide (574 g, 0.94 mmol) and N-(diphenylmethylene)glycine tert-butyl ester (2.83 g, 9.4 mmol). Dissolve them in DCM (60 ml) and cool the mixture to -20 °C. Add 5-(2-(bromomethyl)-4-chlorophenyl)thiazole (3.3 g, 11.53 mmol) thereto, and then add 45% aqueous KOH solution (5.3 ml). Allow the reaction to proceed at -20 °C for 16 hours. Thereafter, add water and extract the organic matter with DCM three times. Combine the organic matters, dry over MgSO4, filter and concentrate. Then redissolve the crude product in dioxane (100 ml). Add 2N HCl (20 ml) dropwise and allow the reaction to stir at room temperature for 1 hour. After completion, cool the mixture in an ice bath and add saturated NaHCO3 until the pH is 7-9. Then, add the dissolution solution of FmocOSu (3.4 gr, 10.08 mmol) and allow the mixture to react for 12 hours. Quench the solution with water and extract the organic matter with EtOAc three times. Combine the organic matters, dry over MgSO4, filter, and reduce the solvent. The crude product is purified by column chromatography (20% EtOAc / hexane) to obtain the desired product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoic acid tert-butyl ester (6.1 gr, 94%). ESIMS m / z 560.1.

[0899] Step 4: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoic acid tert-butyl ester

[0900]

[0901] Dissolve the starting material in DCM (30 ml), add 50% TFA / DCM (30 ml) thereto and allow the reaction to proceed at room temperature until completion. Thereafter, reduce the solvent and purify the crude product by column chromatography (80% EtOAc / hexane) to obtain the desired product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-5-yl)phenyl)propanoic acid tert-butyl ester as a white solid. (5.0 gr, 91%) ESI MS m / z 504.9.

[0902] ​ ​

[0903]

[0904] This compound was prepared using 2-bromothiazole instead of 5-bromothiazole in steps 1 to 4 according to the general synthetic sequence described for the preparation of building block 47. ESI MS m / z 504.09

[0905] ​ ​

[0906]

[0907] This compound was prepared using 3-bromopyrazole instead of 5-bromothiazole in steps 1 to 4 according to the general synthetic sequence described for the preparation of building block 47. ESI MS m / z 501.15.

[0908] ​ ​

[0909]

[0910] This compound was prepared using 4-bromopyrazole instead of 5-bromothiazole in steps 1 to 4 according to the general synthetic sequence described for the preparation of building block 47. ESI MS m / z 501.15.

[0911] 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

[0912]

[0913] This compound was prepared using 4-fluoro-2-formylphenylboronic acid and 3-bromopyrazole in steps 1 to 4 according to the general synthetic sequence described for the preparation of building block 47. ESI MS m / z485.18.

[0914] Building Block 52: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(thiazol-4-yl) phenyl)propanoic acid

[0915]

[0916] This compound was prepared using 4-bromothiazole instead of 5-bromothiazole in steps 1 to 4 according to the general synthetic sequence described for the preparation of building block 47. ESI MS m / z 504.09.

[0917] Building Block 53: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(4-methylth iazol-5-yl)phenyl)propanoic acid

[0918]

[0919] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 5-bromo-4-methylthiazole in place of 5-bromothiazole. ESI MS m / z 518.11.

[0920] Building Block 54: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2,4-dimethyl thiazol-5-yl)phenyl)propanoic acid

[0921]

[0922] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 5-bromo-2-methylthiazole in place of 5-bromothiazole. ESI MS m / z 532.12.

[0923] Building Block 55: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1,3,4-thiad iazol-2-yl)phenyl)propanoic acid

[0924]

[0925] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 2-bromo-1,3,4-thiadiazole in place of 5-bromothiazole. ESI MS m / z 505.09.

[0926] 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

[0927]

[0928] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 4-bromo-2-methyl-2H-1,2,3-triazole in place of 5-bromothiazole. ESI MS m / z502.14.

[0929] Building Block 57: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(2-methylth iazol-5-yl)phenyl)propanoic acid

[0930]

[0931] This compound was prepared according to the general synthetic sequence described for the preparation of Building Block 47. ESI MS m / z518.11.

[0932] Building Block 58: Preparation of (S)-2((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-2-(thiazol-5-yl) phenylpropanoic acid

[0933]

[0934] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 5-bromothiazole and (4-fluoro-2-formylphenyl)boronic acid in place of 5-bromothiazole and (4-chloro-2-formylphenyl)boronic acid. ESIMS m / z 488.12.

[0935] 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

[0936]

[0937] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 2-bromo-5-methyl-1,3,4-thiadiazole in place of 5-bromothiazole. ESI MS m / z 519.10.

[0938] 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

[0939]

[0940] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 5-bromo-1-methyl-1H-pyrazole in place of 5-bromothiazole. ESI MS m / z 501.15.

[0941] Building Block 61: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(pyridin-3-yl) phenyl)propanoic acid

[0942]

[0943] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 47, using 3-bromopyridine in place of 5-bromothiazole. ESI MS m / z 498.1.

[0944] Building Block 62: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chloro-[1,1'-biphenyl]- 2-yl)propanoic acid

[0945]

[0946] This compound was prepared in Steps 1 to 4 according to the general synthetic sequence described for the preparation of Building Block 38, using bromobenzene in place of 5-bromothiazole. LCMS: (ESI, m / z): [M+H] + = 497.14.

[0947] Building Block 63: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3- thiazol-1-yl)phenyl)propanoic acid

[0948]

[0949] 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 allowed to react for 8 hours, then cooled to room temperature. The reaction mixture was diluted with water and DCM, and then acidified with 1N HCl until the pH reading was 4. The organic matter was extracted 3 times with DCM, dried over MgSO4, filtered, and the solvent was reduced. The crude mixture was purified by column chromatography (15% EtOAc / Hex) to give the desired product (1.0 g, 86%). ESIMS m / z: 181.0.

[0950] 2-Azido-5-chlorobenzaldehyde (1 g, 5.52 mmol), trimethylsilylacetylene (852 μl, 5.79 mmol), CuSO4 (137 mg, 0.55 mmol), and sodium ascorbate (220 mg, 1.11 mmol) were combined in a round-bottom flask. It was dissolved in a 4:1 mixture of tert-butanol (20 ml) and water (5 ml). The reaction was allowed to proceed at 50 °C for 12 hours, then cooled to room temperature. The mixture was washed with water and the organic matter was extracted 3 times with DCM. The combined organic matter was dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (25% EtOAc / hexane) to give the desired product (600 mg, 54%). ESI MS m / z: 207.02

[0951] 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 portions. The compound was warmed to room temperature and the reaction was allowed to proceed for 1 hour. The solvent was reduced and 1N HCl was added. The crude product was extracted 3 times with DCM. The combined organic matter was dried over MgSO4, filtered, and the solvent was reduced. The crude product was purified by column chromatography to give 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.

[0952] (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, the mixture was warmed to room temperature and the reaction was allowed to proceed for 12 hours. Then the reaction was transferred to an ice-cold solution of saturated NaHCO3 until basic. Then the organic matter was extracted 3 times with DCM. The combined organic matter was dried over MgSO4, filtered, and concentrated. The crude material was carried on to the next reaction without further purification.

[0953] Add O-allyl-N-(9-anthrylmethyl)cinchonium bromide (40 mg, 0.06 mmol) and N-(diphenylmethylene)glycine tert-butyl ester (180 mg, 0.61 mmol) to a 100 ml round-bottom flask. Dissolve them in DCM (15 ml) and cool the mixture to -20 °C. Add 1-(2-(bromomethyl)-4-chlorophenyl)-1H-1,2,3-triazole (200 mg, 0.074 mmol) thereto, and then add 45% aqueous KOH solution (340 μl). Allow the reaction to proceed at -20 °C for 16 hours. Thereafter, add water and extract the organic matter with DCM three times. Combine the organic matter, dry over MgSO4, filter and concentrate. Then redissolve the crude product in dioxane. Add 2N HCl (3 ml) dropwise and allow the reaction to stir at room temperature for 1 hour. After completion, cool the mixture in an ice bath and add saturated NaHCO3 until the pH is 7-9. Then, add a solution of FmocOSu (215 mg, 6.37 mmol) and allow the mixture to react for 12 hours. Quench the solution with water and extract the organic matter with EtOAc three times. Combine the organic matter, dry over MgSO4, filter, and reduce the solvent. Purify the crude product by column chromatography to obtain the desired product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)propanoic acid tert-butyl ester (350 mg, 86%). ESI MS m / z 544.19.

[0954] Dissolve the starting material in DCM (10 ml), add 50% TFA / DCM (10 ml) thereto and allow the reaction to proceed at room temperature until completion. Thereafter, reduce the solvent and purify the crude product by column chromatography (60% EtOAc / hexane) to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)propanoic acid as a white solid (300 mg, 95%). ESI MS m / z 488.13.

[0955] Building Block 64: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(dimethylamino phenyl)propanoic acid

[0956]

[0957] 4-Chloro-2-iodoaniline (5 g, 19.726 mmol, 1 equiv) in DMF (20 mL) was placed in a 250 mL round-bottom flask, and NaH (2.37 g, 98.630 mmol, 5.00 equiv) was added at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 minutes. CH3I (14.00 g, 98.630 mmol, 5 equiv) was added dropwise at 0 °C over 10 minutes. 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, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (0 - 50%). This gave 4-chloro-2-iodo-N,N-dimethylaniline (4 g, 72.03%) as a yellow oil. LCMS: (ESI, m / z): [M+H] + = 281.85.

[0958] Under N2, 1,2-dibromoethane (374 mg, 2 mmol, 0.14 equiv) was added in one portion to a mixture of Zn (1.6 g, 24.14 mmol, 1.7 equiv) in DMA (10 mL). Then TMSCl (153.4 mg, 1.42 mmol, 0.1 equiv) was added slowly and the mixture was stirred at 25 °C for 30 minutes. A solution of methyl (R)-2-(tert-butoxycarbonylamino)-3-iodopropionate (7 g, 21.3 mmol, 1.5 equiv) in DMA (10 mL) was added dropwise slowly (30 min) to keep the temperature below 50 °C. The resulting mixture was stirred at room temperature for 2 hours and then added via cannula under N2 to a solution of 4-chloro-2-iodo-N,N-dimethylaniline (4 g, 14.2 mmol, 1 equiv), Pd(dppf)Cl2·CH2Cl2 (2.31 g, 2.842 mmol, 0.2 equiv), and CuI (0.54 g, 2.842 mmol, 0.2 equiv) in DMA (20 mL). The color of the mixture turned brown, and then the mixture was heated and stirred at 80 °C under N2 for 2 hours. The mixture was quenched with ice water (200 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified.

[0959] Place methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propionate (1.88 g, 5.268 mmol, 1 equiv) in THF (20 mL) in a 100 mL round-bottom flask. Add NaOH (1.05 g, 26.340 mmol, 5 equiv) in H2O (4 mL) at 0 °C under an air atmosphere. Stir the resulting mixture at room temperature for 2 h. Acidify the mixture to pH = 6 with 2N HCl(aq.). Extract the resulting mixture with EtOAc (2 x 200 mL). Combine the organic layers, wash with brine, and dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with PE / EA (0–50%), to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propionic acid as a white solid (1.8 g, 99.66%). LCMS: (ESI, m / z): [M+H]+ = 343.05.

[0960] Place (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(dimethylamino)phenyl]propionic acid (1.8 g, 5.251 mmol, 1 equiv) in DCM in a 100 mL round-bottom flask. Add TFA (20 mL, 269.261 mmol, 51.28 equiv) at room temperature under a nitrogen atmosphere. Stir the resulting mixture at room temperature for 2 h. Remove the solvent under reduced pressure. Use the crude product directly in the next step without further purification. LCMS: (ESI, m / z): [M+H]+ = 243.05.

[0961] Into a 100 mL round-bottom flask was placed (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 H2O (10 mL). Under an air atmosphere at room temperature, NaHCO3 (3.13 g, 37.1910 mmol, 5 equiv) and 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (2.01 g, 5.9526 mmol, 0.8 equiv) were added. The resulting mixture was stirred at room temperature for 16 h. The mixture was acidified to pH = 6 with 2N HCl(aq) and extracted with EtOAc (3 x 100 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN / 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 as a white solid (708.6 mg, 20.55%). LCMS: (ESI, m / z): [M+H] + = 464.15.

[0962] Building Block 65: Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-2-(methoxymeth yl)phenyl)propanoic acid

[0963]

[0964] Under an air atmosphere at 0 °C, NaH (0.80 g, 33.522 mmol, 3 equiv) was added portionwise to a stirred solution of (4-chloro-2-iodophenyl)methanol (3 g, 11.174 mmol, 1 equiv) in DMF (60 mL). The resulting mixture was stirred at room temperature for 30 min under an air atmosphere. CH3I (7.93 g, 55.870 mmol, 5 equiv) was added to the solution and stirred at room temperature for 16 h. The reaction was quenched with saturated NH4Cl(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water, 0% to 100% gradient in 40 min; detector, UV254 nm. The pure fractions were evaporated to dryness to give 4-chloro-2-iodo-1-(methoxymethyl)benzene as a pale yellow oil (3.3 g, 104.54%).

[0965] Under nitrogen, 1,2-dibromoethane (0.26 g, 1.345 mmol, 0.1 eq) was added to a solution of Zn (2.11 g, 32.282 mmol, 2.4 eq) in DMA (20 mL) in one portion. Then, TMSCl (97.91 mg, 0.901 mmol, 0.067 eq) was added dropwise at 20 °C and the mixture was stirred at room temperature for 30 minutes. Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionate (8.85 g, 26.902 mmol, 2 eq) in DMA (20 mL) was added to the mixture, the temperature was raised to 50 °C and the mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The above mixture was added to a solution of 4-chloro-2-iodo-1-(methoxymethyl)benzene (3.8 g, 13.451 mmol, 1 eq), CuI (0.51 g, 2.690 mmol, 0.2 eq), Pd(dppf)Cl2 (0.98 g, 1.345 mmol, 0.1 eq) in DMA (30 mL). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with saturated NH4Cl(aq.) at 0 °C and extracted with EtOAc (3 x 200 mL). The organic layers were combined, 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-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (0.1% FA), 0% to 100% gradient in 40 minutes; detector, UV 254 nm. The pure fractions were evaporated to dryness to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propionate (3.8 g, 78.95%) as a light brown solid. LCMS: (ESI, m / z): [M+H] + = 380.15.

[0966] A solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propionate (200 mg, 0.559 mmol, 1 eq) and LiOH (0.67 g, 27.945 mmol, 5 eq) in THF (30 mL) / H2O (10 mL) was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 5 with HCl (1N) and extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (1 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(methoxymethyl)phenyl]propionic acid (1.9 g, 98.88%) as a yellow oil. LCMS: (ESI, m / z): [M+H]+ = 366.10

[0967] 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) / 1,4-dioxane (40 mL) was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo to give the crude product (2S)-2-amino-3-[5-chloro-2-(methoxymethyl)phenyl]propanoic acid as a pale brown oil (1.2 g, 94.05%), which was used in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 244.10

[0968] 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) / H2O (10 mL, 555.093 mmol) was added NaHCO3 (3.88 g, 46.163 mmol, 7.5 equiv) and 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (2.28 g, 6.771 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 16 h. 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 organic layers were combined, washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The crude product (1.8 g) was purified by preparative HPLC using 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 as a white solid (1.8025 g, 62.76%). LCMS: (ESI, m / z): [M+H] + = 488.1

[0969] Building block 66: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-oxo-6-(piperidin-1-yl)hexanoic acid Preparation of Building block 66

[0970]

[0971] To a stirred solution of aminocaproate (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 H2O (300 mL). To the above mixture was added 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (50.24 g, 148.924 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The mixture was cooled to -5 °C and acidified to pH 1-2 with dilute HCl. The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The organic layer was 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}adipic acid as a white solid (35 g, 73.56%). LCMS: (ESI, m / z): [M+Na] + = 406.

[0972] A solution / mixture of (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}adipic acid (5 g, 13.041 mmol, 1.00 equiv), paraformaldehyde (7.5 g, 6.5 equiv) and p-toluenesulfonic acid ester (0.22 g, 1.304 mmol, 0.1 equiv) in toluene (300 mL) was stirred at 120 °C for 16 h 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 filtrates were combined and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 4-[(4S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-5-oxo-1,3-oxazolidin-4-yl]butanoic acid as a white solid (5.1 g). LCMS: (ESI, m / z): [M+H] + = 396.41.

[0973] 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;

[0974] A solution of hexafluoro - 1 - [5] - phosphanuide (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 stirred overnight at 50 °C under a nitrogen atmosphere. 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse - phase flash chromatography under the following conditions (EA:PE, 1:3) to give (4S) - 5 - oxo - 4 - [4 - oxo - 4 - (piperidin - 1 - yl)butyl] - 1,3 - oxazolidine - 3 - carboxylic acid 9H - fluoren - 9 - yl methyl ester as a colorless semi - solid (4.7 g, 83.61%). LCMS: (ESI, m / z): [M + H] + = 463.

[0975] To a stirred solution of (4S) - 5 - oxo - 4 - [4 - oxo - 4 - (piperidin - 1 - yl)butyl] - 1,3 - oxazolidine - 3 - carboxylic acid 9H - fluoren - 9 - yl methyl ester (5.46 g, 11.804 mmol, 1.00 equiv) in THF (100 mL) at 0 °C under a nitrogen atmosphere was added NaOH (1.89 g, 47.216 mmol, 4.0 equiv) and H2O (47 mL). 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

[0976] 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) / dioxane (150 mL) and NaHCO3 (4.01 g, 47.703 mmol, 3 equiv) / H2O (50 mL) at room temperature under a nitrogen atmosphere was added 9H - fluoren - 9 - yl methyl carbonyl 2,5 - dioxopyrrolidin - 1 - yl ester (6.44 g, 19.081 mmol, 1.2 equiv). After stirring overnight, the mixture was acidified to pH 1 - 2 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 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 - yl methoxy)carbonyl]amino} - 6 - oxo - 6 - (piperidin - 1 - yl)hexanoic acid as a white solid (1.38 g, 19.01%). LCMS: (ESI, m / z): [M + H] += 451

[0977] Building block 67: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(4,4-difluoropiperidin-1-yl)hexanoic acid Preparation of Building block 67

[0978]

[0979] Under a nitrogen atmosphere at 15 - 25 °C, KI (0.12 g, 0.737 mmol, 0.05 equivalent) and DIPEA (7.62 g, 58.928 mmol, 4 equivalents) were added dropwise to a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(methanesulfonyloxy)hexanoate (5 g, 14.732 mmol, 1.00 equivalent) and 4,4-difluoropiperidine (1.96 g, 16.205 mmol, 1.1 equivalents) in DMF (100 mL). The resulting mixture was stirred at 55 - 60 °C for 24 hours under a nitrogen atmosphere. After completion of the reaction, 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 as a yellow oil (1.8 g, 33.53%). LCMS: (ESI, m / z): [M+H] + = 365.22

[0980] Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(4,4-difluoropiperidin-1-yl)hexanoate (1.8 g, 4.939 mmol, 1.00 equivalent) and concentrated HCl (36 mL) were added to a 250 mL round-bottom flask 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

[0981] Under an air atmosphere at room temperature, LiOH (0.35 g, 14.754 mmol, 3 equivalents) was added portionwise to a stirred solution of methyl (2S)-2-amino-6-(4,4-difluoropiperidin-1-yl)hexanoate (1.3 g, 4.918 mmol, 1.00 equivalent) in THF (20 mL) and H2O (20 mL). The resulting mixture was stirred at room temperature for 1 hour 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 NaHCO3. The final mixture was used directly in the next step without further purification. LCMS: (ESI, m / z): [M+H] + = 251.15

[0982] At room temperature, 9H-fluoren-9-ylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (2.72 g, 8.064 mmol, 1.1 eq) was added to dioxane (5.00 mL). The above solution was added dropwise to the mixture of the previous batch at room temperature over 5 minutes. The resulting mixture was stirred at room temperature for an additional 14 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water, 45% to 50% gradient over 10 minutes; detector, UV 220 nm. This gave (2S)-6-(4,4-difluoropiperidin-1-yl)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid as a white solid (1.4938 g). LCMS: (ESI, m / z): [M+H] + = 473.22.

[0983] Building block 68: N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2,N6-dimethyl-L-lysine Preparation of Building block 68

[0984]

[0985] At 20 - 25 °C, trifluoroacetic acid (TFA) (34.7 g, 304 mmol, 22.5 mL, 0.05 eq) was added to a mixture of N6-(tert-butoxycarbonyl)-L-lysine (1.50 kg, 6.09 mol, 1.00 eq) and benzaldehyde (646 g, 6.09 mol, 615 mL, 1 eq) in MeOH (15 L). The mixture was stirred at 20 - 25 °C for 2 hours. MeOH (7.5 L) was added to the mixture. Then, sodium triacetoxyborohydride (NaBH(OAc)3) (2.84 kg, 13.4 mol, 2.20 eq) was added in ten portions at 25 - 30 °C over 2 hours. The mixture was stirred at 20 - 25 °C for an additional 10 hours. LCMS showed the detection of the desired mass. A saturated aqueous NH4Cl solution (7.5 L) was added dropwise to the reaction mixture at 25 - 30 °C over 75 minutes. The residue was triturated with H2O (15 L) and MTBE (30 L) at 20 °C for 30 minutes. The mixture was filtered and the cake was dried in an oven to give the product. N2-Benzyl-N6-(tert-butoxycarbonyl)-L-lysine was obtained as a white solid (1.75 kg, 5.16 mol, yield 84.7%, purity 99.0%), which was confirmed by LCMS. LCMS: (ESI, m / z): [M+H] + = 336.22.

[0986] At 25 °C, trifluoroacetic acid (TFA) (28.5 g, 250.13 mmol, 18.52 mL, 0.05 eq) was added to a mixture of N2-benzyl-N6-(tert-butoxycarbonyl)-L-lysine (1.70 kg, 5.00 mol, purity 99.0%, 1.00 eq) and formaldehyde (812 g, 10.0 mol, 745 mL, purity 37%, 2.00 eq) in MeOH (17 L). The mixture was stirred at 25 °C for 0.5 h. Then, sodium triacetoxyborohydride (NaBH(OAc)3) (2.33 kg, 11.01 mol, 2.2 eq) was added in ten portions at 25 - 30 °C over 1 h. The mixture was stirred at 25 °C for 1 h. LCMS showed that the starting material was completely consumed and a major peak with the desired mass was detected. A saturated aqueous NH4Cl solution (3.4 L) was added dropwise to the mixture at 25 - 30 °C over 40 min. The mixture was then concentrated under reduced pressure to 7 L. The residue was extracted with EtOAc (4 L x 3). The organic layers were combined, washed with a saturated aqueous NaCl solution (3 L), dried over Na2SO4 (2.00 kg), filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (11 L) at 25 °C for 30 min, filtered and dried in an oven to give N2-benzyl-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine as a white solid (1.75 kg, crude), which was confirmed by LCMS (EC4247 - 24 - P1A3). LCMS: (ESI, m / z): [M + H] + = 351, RT = 0.517 min

[0987] Under an Ar atmosphere, Pd / C (30.0 g, purity 10%) and Pd(OH)2 (30.0 g, purity 20%) were added to a solution of N2-benzyl-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (600 g, 1.71 mol, 1.00 eq) in MeOH (5.00 L). The suspension was degassed and purged with Ar three times. The mixture was stirred at 60 °C under H2 (3 MPa) for 12 h. LCMS (EC4402 - 59 - P1A2) indicated that the starting material was completely consumed. The reaction was filtered, concentrated in vacuo and the filter cake was combined. The suspension of the crude product N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (~297 g) in H2O (3.00 L) was used in the next step.

[0988] At 0 °C, NaHCO3 (287 g, 3.42 mol, 133 mL, 3.00 eq) and FMOC-OSU (462 g, 1.37 mol, 1.20 eq) were added to a solution of N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (297 g, 1.14 mol, 1.00 eq) in THF (1.50 L) and H2O (1.50 L), and the mixture was 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 organic phases were combined, dried over Na2SO4, filtered and concentrated in vacuo. The combined organic phases were 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 was obtained as a yellow gum (467 g, 0.93 mol, yield 81.37%, purity 96%). LCMS: RT = 0.627 min, MS+23 = 505

[0989] At 0 °C, HCl / dioxane (4 M, 1.04 L, 6.00 eq) was added dropwise to a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-N2-methyl-L-lysine (350 g, 696 mmol, purity 96.0%, 1.00 eq) in dioxane (2 L), and the mixture was stirred at 0 °C for 16 h. LCMS showed complete consumption of the starting material and detection of the desired mass. The reaction was filtered, the cake was washed with MTBE (500 mL × 2) and concentrated to give N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-L-lysine as a white solid (227 g, 541 mmol, yield 88.3%). LCMS: RT = 0.447 min, MS+1 = 383

[0990] At 25 °C, Me3SiCl (216 g, 1.99 mol, 252 mL, 3 eq) and DIEA (343 g, 2.65 mol, 462 mL, 4.00 eq) were added to a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-L-lysine (278 g, 663 mmol, 1.00 eq) in DCM (2250 mL), and the mixture was 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 eq) and TrtCl (222 g, 796 mmol, 1.20 eq) were added. The final reaction was stirred at 40 °C for 28 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated in vacuo to remove DCM, diluted with 2.5 L of EtOAc, washed with saturated NaH2PO4 (1 L) and brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-N6-trityl-L-lysine (423 g, crude) as a yellow gum was obtained and used in the next step without purification. LCMS: RT = 0.635 min, MS+1 = 625

[0991] At 0 °C, NaBH(OAc)3 (246.28 g, 1.16 mol, 2 eq) was added to a mixture of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-methyl-N6-trityl-L-lysine (363 g, 581 mmol, 1.00 eq), NaH2PO4 (139 g, 1.16 mol, 2.00 eq), and HCHO (165 g, 2.03 mol, 151 mL, purity 37%, 3.50 eq) in DCM (3000 mL), and the mixture was stirred at 20 °C for 2 h. LCMS indicated 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) as a yellow gum was obtained and used in the next step without purification.

[0992] At 0 °C, HCl / dioxane (4 M, 618 mL, 4.00 eq) was added to a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-N6-trityl-L-lysine (395 g, 618 mmol, 1.00 eq) in dioxane (2.50 L), and the mixture was stirred at 15 °C for 16 h. LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo, poured into 3 L of MTBE and filtered. The filter cake was dried under reduced pressure to give the product. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-L-lysine hydrochloride was obtained as a yellow gum (318 g, 691.18 mmol, yield 55.9%, purity 94.1%), which was confirmed by LCMS. LCMS: RT = 0.447 min, MS+1 = 397

[0993] At 0 °C, NaHCO3 (172.89 g, 2.06 mol, 80.04 mL, 3 eq) and (Boc)2O (179 g, 823 mmol, 189 mL, 1.20 eq) were added to a solution of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2,N6-dimethyl-L-lysine hydrochloride (297 g, 686 mmol, 1.00 eq) in THF (1000 mL) and H2O (2000 mL), and the mixture was stirred at 15 °C for 12 h. LCMS indicated complete consumption of the starting material. 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 was obtained as a pale yellow solid (147 g, 582 mmol, yield 42.4%, purity 98.7%), which was confirmed by LCMS. LCMS: RT = 0.661 min, MS+23 = 519.

[0994] Building block 69: (2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid Preparation of Building block 69

[0995]

[0996] This compound was prepared using 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylic acid according to the general synthetic sequence described for the preparation of building block 6. ESI MS m / z 319.06.

[0997] Building block 70: (2S,4R)-4-fluoro-1-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-2-carboxylic acid Preparation of Building block 70

[0998]

[0999] 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 at 25 °C under a nitrogen atmosphere for 16 h. The reaction mixture was purified directly by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile / water, 5% to 60% gradient 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.

[1000] 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) / H2O (30 mL) was stirred at 20 °C for 16 h. The organic solvents were evaporated in vacuo and the water was acidified with 1 N 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.

[1001] B. Solid-phase synthesis, cleavage, and cyclization to prepare the compounds of formula I

[1002] The compounds of formula I described herein can be prepared as described herein. Generally, the above monomeric building blocks are covalently linked via solid-phase synthesis to form a linear peptide on a resin, followed by cleavage and cyclization in solution. Other transformations to prepare the compounds of formula I generally include, but are not limited to, alkylation, deprotection, cleavage from the solid-phase resin, and cyclization.

[1003] The following paragraphs and subheadings provide general instructions and procedures on how to prepare the compounds of formula I.

[1004] Tables 2A and B provided below list the building blocks and procedures for preparing the exemplified compounds of Formula I listed. The building blocks in Tables 2A and B are listed using the abbreviated names identified in Table 1. The procedures in Tables 2A and B are listed using the abbreviations identified in the subtitles below.

[1005] Solid-phase linear synthesis of peptides containing N-alkylated amino acid monomers was successfully completed by using pre-N-alkylated amino acid building blocks or by sequential on-resin Mitsunobu alkylation methods (Chatterjee et al., Synthesis of N-methylated cyclic peptides. Nature Protocols, Vol 7, 432-444, 2012).

[1006] Certain compounds of Formula I described herein contain building blocks whose side chains are modified on the resin after being incorporated into the linear peptide. Exemplary methods are described in the following paragraphs. See, for example, Example 3, in which the side chain Res5(KDde) was deprotected and functionalized with a morpholine moiety (building block: B2BE); Example 10, in which the side chain Res4(KDde) was deprotected and functionalized with a morpholine moiety (building block: B2BE); Example 216, in which Res6(KDde) was deprotected and functionalized with a deuterated methyl group (MeOD); and Example 308, in which Res5(ODde) was deprotected and functionalized with an acyl moiety (RA245).

[1007] Proper selection of the functionalized solid support allows for sufficient resin loading and C-terminal carboxylic acid functionality. Generally, the solid supports used herein are derived from polystyrene crosslinked with divinylbenzene and functionalized with a 2-chlorotrityl linker.

[1008] The solid-phase peptide synthesis methods described in this document can be carried out manually or automated using a dedicated liquid handler.

[1009] When carried out in a parallel array synthesis mode on a Biotage Syro II automated peptide synthesizer or manually, the methods of the present disclosure can be advantageously carried out as described herein, but how to modify these procedures to synthesize the individual compounds of the present disclosure on a multi-gram scale will be apparent to those skilled in the art.

[1010] Load 50 - 150 mg of a properly functionalized solid support, preferably polystyrene 2-chlorotrityl chloride resin, into a number of reaction vessels equal to the total number of compounds to be synthesized by the parallel method.

[1011] The solvent to be 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), ethanol (EtOH).

[1012] The linear peptide can be cleaved from the 2-chlorotrityl chloride resin under mild acidic conditions (24% HFIP / DCM) without removing the acid-labile side-chain protecting groups (Pbf, Boc). Alternatively, during resin cleavage, more stringent cleavage conditions (20% TFA / DCM or 95% TFA / 2.5% H20 / 2.5% TIS) can also be applied to remove Boc, Mtt, and Trt or Pbf and tBu, respectively.

[1013] Preferably, 9-fluorenylmethoxycarbonyl (Fmoc)-protected amino acid derivatives are used as building blocks for constructing the compounds of Formula I of the present disclosure. For deprotection, i.e., Fmoc removal, a 20% solution of piperidine in DMF or a 2% solution of DBU / 2% piperidine in DMF can be used. It should be understood that alternative protecting groups can also be used.

[1014] Based on the milliequivalents per gram of functionalized solid support loading (meq / g), which is typically 0.3 to 1.4 meqv / g for 2-chlorotrityl chloride polystyrene resin, the amount of the reactant (i.e., amino acid derivative) is usually 1 to 20 equivalents. It is initially weighed into the reaction vessel. If necessary, additional equivalents of the reactant can be used to drive the reaction to completion within a reasonable time. A preferred workstation (but not limited to) is the Biotage Syro II synthesizer, which is equipped with a transfer unit and a reservoir cassette used during the resin cleavage step. This synthesizer can provide a controlled environment, for example, the reaction can be completed at an elevated temperature and under an inert gas if needed.

[1015] For the acylation step, activation of the α-carboxyl group facilitates the formation of the amide bond. Approximately 2 to 24 molar equivalents of an excess coupling reagent and base can be used to drive the coupling reaction to completion. The coupling of amino acids to non-alkylated or N-methylated amino termini is most often achieved via HATU coupling. The coupling of amino acids to highly sterically hindered N-alkylated amino termini is achieved via DIC-mediated coupling. Since a nearly quantitative coupling reaction is highly preferred, it is best to have experimental evidence to demonstrate the completion of the reaction. The ninhydrin test or periodic checking of the reaction by LCMS is crucial for confirming the presence of uncoupled starting materials on the resin. Alternative methods have been developed to couple highly acidic or difficult-to-activate carboxylic acids to the N-terminus of the growing peptide chain, which utilize K-Oxyma (CAS#158014-03-0) as an activator and / or maintain a narrow pH during the reaction.

[1016] The alkylation of α-amino groups on resin in the solid phase is known in the art. The procedure for introducing a methyl group (described in Chatterjee et al., Synthesis of N-methylated cyclic peptides. Nature Protocols, 2012, Vol 7, 432-444) can be achieved, for example, by 1) protecting the N-terminal amine with a 2-nitrobenzenesulfonyl (nosyl) group, 2) performing Mitsunobu alkylation with methanol, triphenylphosphine and DIAD or related reagents, and 3) removing the protection of the 2-nitrobenzenesulfonyl group with DBU and a thiol such as 2-mercaptoethanol. Some cyclic peptides in the present disclosure are obtained using a variant of the published Mitsunobu method on resin, which attaches a larger primary alcohol to the activated amino group (on the backbone 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).

[1017] After each reaction, the resin-bound intermediate in each reaction vessel is washed with excess or residual reagents, solvents and by-products by repeated exposure to pure solvents (DCM, DMF or MeOH, depending on the reaction). The reaction vessel is filled with solvent (preferably 5 mL), agitated for 1 minute, then drained to remove the solvent, and the process is repeated two more times.

[1018] For each successive transformation, the above procedure of reacting the resin-bound compound with the reagent in the reaction tube, followed by removal of excess reagent, by-products and solvent, is repeated until the desired resin-bound fully protected linear peptide is obtained.

[1019] For modifications along the side chain of the linear peptide, including but not limited to side chain acylation and alkylation, residues with base-stable protecting groups such as Dde or 2-nitrobenzenesulfonyl are used. After the linear synthesis is completed, the orthogonally protected side chains are deprotected and modified with subsequent chemical methods. Dde-protected side chains can be removed on the resin with 10% hydrazine / DMF. The primary amines generated at the branching points serve as substrates for subsequent acylation, reductive amination or alkylation reactions on the resin. 2-Nitrobenzenesulfonyl-protected side chains can be N-alkylated via the Mitsunobu conditions described above, followed by removal of the 2-nitrobenzenesulfonyl group to obtain secondary amines.

[1020] The separation of the fully protected linear peptide from the solid support is achieved by exposing the loaded resin to a reagent solution (preferably 3 to 5 mL) for cleavage. Temperature control, agitation, and reaction monitoring are carried out as described above. Via a transfer unit, the reaction vessel is connected to a reservoir cassette containing reservoir tubes to efficiently collect the cleavage product solution. The remaining resin in the reaction vessel is then washed 2 to 5 times with 3 to 5 mL of a suitable solvent as described above to extract the separated product as much as possible. The product solutions thus obtained are combined, taking care to avoid cross-mixing. The individual solutions / extracts are then manipulated as needed to isolate the final compound. Typical manipulations include, but are not limited to, evaporation, concentration, liquid / liquid extraction, acidification, basification, neutralization, or other reactions in solution.

[1021] The solution containing the fully deprotected linear peptide is then evaporated, resuspended in DMSO, purified via RP-HPLC, and lyophilized.

[1022] The lyophilized linear peptide is cyclized. Cyclization can be carried out at various concentrations in various pure solvents or mixed solvents (e.g., ACN / THF, NMP, DCM, DMF, EtOAc, etc.) using various cyclizing reagents (e.g., PyBop, PyAop, HATU, HBTU, T3P). To facilitate rapid cyclization, low dimer formation, and easy purification of the macrocycles described herein, 3 eq of T3P and 8 eqv of DIEA in 1.5 mL of DCM:NMP are preferred. On a small scale (50 μmol), the reaction is typically complete within 10 minutes. Larger scale reactions can be diluted up to 250 mL and allowed to react for up to 12 hours. The progress of the reaction is followed by monitoring the disappearance of the starting material using LCMS. After completion of the reaction, the excess solvent is removed by evaporation, the compound is purified via RP-HPLC, and lyophilized.

[1023] 1. Solid-phase synthesis - General method

[1024] General methods i - xiv are typically carried out on 50 - 100 mg of 2-chlorotrityl chloride polystyrene resin in a reaction at a scale of 50 μmol.

[1025] i. CTC-resin loading

[1026] Dissolve Fmoc-AA-OH (4 equivalents) in 1.0 mL of anhydrous NMP. Add neat DIEA (8 equivalents) to the Fmoc-AA-OH solution. Aliquot the solution into a peptide reactor vessel containing 100 mg of 2-chlorotrityl chloride (CTC) resin and agitate at room temperature for 2 hours. Drain the Fmoc-AA-OH solution, then wash the resin three times with 1.0 mL of DMF. Cap the unreacted CTC resin with a solution of methanol:DMF (50:50, 1.0 mL) and DIEA (8 equivalents) at room temperature for 10 minutes. Drain the methanol solution, then wash the resin three times with 1.0 mL of DMF.

[1027] After coupling is complete, displace the Fmoc protecting group using Method ii.

[1028] ii. Fmoc Deprotection

[1029] Add a mixture of piperidine:DMF (20:80, 1 mL) to the resin and agitate at room temperature for 10 to 15 minutes. Drain the piperidine solution, then wash the resin three times with 1.0 mL of DMF.

[1030] iii. HATU–Peptide Coupling Followed by Fmoc Deprotection

[1031] Prepare a solution of Fmoc-AA-OH (4 equivalents), HATU (4 equivalents), and DIEA (8 equivalents) in 1.0 mL of anhydrous NMP. Allow the mixture to react at room temperature for 5 minutes, then add it to the resin and agitate at 35 to 45 °C for 10 to 90 minutes. Drain the mixture, then wash the resin three times with 1.0 mL of DMF.

[1032] If the reaction is incomplete (less than 95% coupling, as determined by LCMS), or if the coupling is carried out on an N-methylated amine substrate, repeat the coupling once.

[1033] After coupling is complete (as determined by LCMS), displace the Fmoc protecting group using Method ii.

[1034] iv. HATUnf–Peptide Coupling Without Fmoc Deprotection

[1035] Prepare 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. Allow the mixture to react at room temperature for 5 minutes, then add it to the resin and agitate at 35 to 45 °C for 10 to 90 minutes. Drain the mixture, then wash the resin three times with 1.0 mL of DMF.

[1036] If the reaction is incomplete (as determined by LCMS), or if the coupling is carried out on an N-methylated amine substrate, the coupling is repeated once.

[1037] v. KO–Sterically hindered peptide coupling, followed by Fmoc deprotection

[1038] Dissolve Fmoc-AA-OH or carboxylic acid (4 eq), K-Oxyma (3.8 eq), and DIC (3.8 eq) in 1.0 mL of anhydrous NMP. Allow the mixture to react for 5 minutes at room temperature, then add it to the resin and agitate at 35 to 45 °C for 10 to 90 minutes. Drain the mixture, then wash the resin three times with 1.0 mL of DMF. This method is repeated twice.

[1039] After the coupling is complete (as determined by LCMS), replace the Fmoc protecting group using Method ii.

[1040] vi. EEDQ–Sterically hindered peptide coupling, followed by Fmoc deprotection

[1041] When the N-alkyl group is larger than the N-methyl group, couple on the N-alkylated amine. Dissolve Fmoc-AA-OH (6 eq) and EEDQ (5 eq) in 1.0 mL of anhydrous NMP. Allow the mixture to react for 15 minutes. Then, add the mixture to the resin and agitate at 45 °C for 3 hours. Drain the mixture, then wash the resin three times with 1.0 mL of DMF. This method is repeated twice.

[1042] Replace the Fmoc protecting group using Method ii.

[1043] vii. DIC–Sterically hindered peptide coupling, followed by Fmoc deprotection

[1044] When the N-alkyl group is larger than the N-methyl group, couple on the N-alkylated amine. Dissolve Fmoc-AA-OH (24 eq) in 1.5 mL of anhydrous NMP:DCE (50:50). NMP can be added dropwise to completely dissociate Fmoc-AA-OH. Add DIC (23 eq) to the Fmoc-AA-OH solution. Add this mixture to the resin and agitate at room temperature for 12 to 24 hours. Drain the slurry, then wash the resin four times with 1.0 mL of methanol and three times with 1.0 mL of DMF.

[1045] If the reaction is incomplete (less than 95% coupling, as determined by LCMS), repeat the coupling once.

[1046] After the coupling is complete, replace the Fmoc protecting group using Method ii.

[1047] viii. DIC_KMe2 – Neutral Peptide Coupling for KMe2 Binding

[1048] Dissolve Fmoc-KMe2-OH (4 equivalents) in 1 mL of anhydrous NMP. Add DIC (4 equivalents) to the Fmoc-KMe2-OH solution. Add this mixture to the resin and agitate at room temperature for 2 hours. Drain the slurry, then wash the resin three times with 1.0 mL of methanol and three times with 1.0 mL of DMF.

[1049] Use method ii to displace the Fmoc protecting group.

[1050] ix. Onto_KMe2 – Peptide Coupling for Coupling Amino Acids to KMe2 Residues

[1051] Prepare a solution of Fmoc-AA-OH (4 equivalents), HATU (4 equivalents), and DIEA (8 equivalents) in 1.0 mL of anhydrous NMP. Let the mixture react at room temperature for 5 minutes, then add it to the resin and agitate at 25 °C for 10 to 90 minutes. Drain the mixture, then wash the resin three times with 1.0 mL of DMF.

[1052] After the coupling is complete, use method ii to displace the Fmoc protecting group.

[1053] x. DdeR – Removal of Dde by Hydrazine

[1054] Add 10% hydrazine monohydrate in 1.0 mL of NMP to the resin and agitate at room temperature for 20 minutes. Drain the mixture, then wash the resin three times with 1.0 mL of DMF.

[1055] xi. RA - Reductive Amination

[1056] Dissolve the aldehyde (20 equivalents) in 1.0 mL of anhydrous NMP. Add this mixture to the resin and agitate at room temperature for 30 minutes. Then, drain the mixture and wash the resin three times with 1.0 mL of DMF.

[1057] Add 1.0 mL of DCM:MeOH (3:1) to the resin. Then, add sodium borohydride (NaBH4, 20 equivalents) to the resin. Agitate the slurry at room temperature for 1 hour. Drain the slurry, wash the resin six times with 1.0 mL of methanol, and then three times with 1.0 mL of DMF.

[1058] xii. MITS – Nitrobenzenesulfonylation (nosylation), mitsunobu, Nitrobenzenesulfonyl Deprotection [1...

Claims

1. A compound of formula I wherein R 3 For (a) C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 1-8 haloalkyl, each optionally substituted with 0 to 5 R 3a substituents; (b) C substituted by 0 to 5 Rs 3b cycloalkyl; or 3-12 ​ (c) Heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 5 R 3c substituted; Each R 3a is independently –OH, C 1-3 alkoxy, –O–(CH2CH2O) 1-4 –C 1-4 alkyl, –O–(CH2CH2O) 1-4 –heteroalkyl, C 1-3 haloalkoxy, –NR 3a1 R 3a2 、–O–C(O)C 1-4 alkyl, C 3-6 cycloalkyl, phenyl or heteroaryl, wherein each heteroalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently selected from N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from N, O or S; Each R 3b is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, 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 selected from N, O or S; Each R 3c is independently C 1-4 alkyl, C 1-4 haloalkyl, oxo or C 3-6 cycloalkyl; Each R 3a1 , R 3a2 , R 3b1 , R 3b2 , and R 3b3 is independently H or C 1-4 alkyl; Each R 3b4 is C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H or C 1-4 alkyl; R 4b and R 4c each independently is 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, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S; Alternatively, R 4c and R 4a together with the respective attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently selected from N, O, or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; Each R 4c1 and R 4c2 is independently C 1-4 alkyl or C 2-6 alkoxyalkyl; Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy, halogen or –N(R 4a2 )S(O)2–C 1-4 alkyl; R 4a2 is H or C 1-4 alkyl; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R groups; 4a1 4a3 ​​ Each R 4a3 is independently C 1-4 alkyl, –OH, C 1-4 alkyl–OH, C 1-4 alkoxy or halogen; R 5a is H or C 1-4 alkyl; R 5b and R 5c each independently is 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, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein each cycloalkyl and heteroaryl is substituted with 0 to 3 R 5b5 ; Each R 5b1 and R 5b2 independently is H, C 1-4 alkyl, C 1-4 haloalkyl, –C(O)C 1-4 alkyl or –C(O)C 1-4 haloalkyl; Alternatively, R 5b1 and R 5b2 combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O, or S, wherein said heterocycloalkyl is substituted with 0 to 3 R 5b5 substituents; Each R 5b3 is H or C 1-4 alkyl; Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 0 to 3 R 5b5 substituents; Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl, –NH2, –N(C 1-4 alkyl)2 or NH(C 1-4 alkyl); X 6 is C 2-5 an alkylene group; R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, 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 alkyl; R 6d is H, C 1-4 alkyl, C 1-4 deuterated alkyl, –OH or C 2-6 alkoxyalkyl; R 7a is H or C 1-4 alkyl; R 7b and R 7c each independently is H, C 1-8 alkyl, C 3-6 cycloalkyl or C 1-4 alkyl–C 3-6 cycloalkyl; R 8a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-6 alkoxyalkyl, C 3-6 cycloalkyl or C 1-4 alkyl–C 3-6 cycloalkyl; R 8b , R 8d and R 8e Each independently is H or C 1-4 alkyl; Alternatively, R 8b and R 8d combine with the respective attached carbon to form C 3-6 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 from 0 to 5; Each R 8f is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, 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, –O–C 3-6 cycloalkyl, C 1-4 alkyl–C 3-6 cycloalkyl, –O–C 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 ; Each R 8f1 and R 8f2 is independently H or C 1-4 alkyl; Each R 8f3 independently is C 1-4 alkyl, –OH, C 1-4 alkoxy, –SH, –S–C 1-4 alkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl, –O–C 3-6 cycloalkyl, –O–C 1-4 alkyl–C 3-6 cycloalkyl or a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S; X 9 is C alkylene substituted by R 9b and R 9c ; 1-3 alkylene R 9a is H or C 1-4 alkyl group; R 9b and R 9c each independently is 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 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each cycloalkyl and heteroaryl is independently substituted by 0 to 3 R 9c1 substituents; Alternatively, R 9b and R 9c combine with their respective attached carbons to form a C 9c2 cycloalkyl group which is substituted with from 0 to 2 R 3-4 groups; or Alternatively, R 9c and R 9a together with the respective connected carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 9c2 substituents; Each R 9c1 and R 9c2 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy; and ring A contains 15 to 17 ring atoms; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is (a) C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, each optionally substituted with 0 to 5 R 3a substituents; (b) C substituted by 0 to 5 R 3b cycloalkyl; or 3-12 or (c) Heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 5 R 3c substituted; Each R 3a is independently –OH, C 1-3 alkoxy, –O–(CH2CH2O) 1-3 –C 1-4 alkyl, –O–(CH2CH2O) 1-2 –heteroalkyl, C 1-3 haloalkoxy, –NR 3a1 R 3a2 、–O–C(O)C 1-4 alkyl, C 3-6 cycloalkyl, phenyl or heteroaryl, wherein each heteroalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S; Each R 3b is independently C 1-4 alkyl, C 2-4 alkynyl, halogen, 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 is independently C 1-4 alkyl, C 1-4 haloalkyl, oxo or C 3-6 cycloalkyl; Each R 3a1 , R 3a2 and R 3b3 is independently H or C 1-4 alkyl; and Each R 3b4 is C 1-4 alkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein R 3 is (a) C 1-6 alkyl, C 2-6 alkynyl or C 1-6 haloalkyl, each optionally substituted with 0 to 5 R 3a substituents; (b) C substituted by 0 to 5 Rs 3b cycloalkyl; or 3-12 or (c) Heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 5 R 3c substituted; Each R 3a is independently –OH, C 1-3 alkoxy, –O–(CH2CH2O) 1-3 –C 1-4 alkyl, –O–(CH2CH2O) 1-2 –heteroalkyl, C 1-3 haloalkoxy, –NH2, –O–C(O)C 1-4 alkyl, C 3-6 cycloalkyl or phenyl, wherein each heteroalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S; Each R 3b is independently C 1-4 alkyl, C 2-4 alkynyl, halogen, C 1-4 haloalkyl, cyano or –NHC(O)C 1-4 alkyl; and Each R 3c is independently C 1-4 alkyl, C 1-4 haloalkyl or oxo.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 3 is 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 3 is 6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 4a is H or C 1-4 alkyl; R 4b and R 4c each independently is 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, wherein each heterocycloalkyl has 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S; Alternatively, R 4c and R 4a together with the attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; Each R 4c1 and R 4c2 is independently C 1-4 alkyl or C 2-6 alkoxyalkyl; Each R 4a1 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen or –N(H)S(O)2–C 1-4 alkyl; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 R 4a1 groups; and 4a3 substituents; and Each R 4a3 is independently –OH, C 1-4 alkyl–OH or C 1-4 alkoxy group.

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

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4a is H or methyl; R 4b is H; R 4c is methyl, ethyl, isopropyl, tert-butyl, Alternatively, R 4c and R 4a together with the respective connected carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; and Each R 4a1 is independently methyl, –OH, methoxy, fluoro or –N(H)S(O)2CH3; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 –OH groups. 4a1 ​ 9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 4a is H or methyl; R 4b is H; R 4c is methyl, ethyl, isopropyl, Alternatively, R 4c and R 4a together with the respective attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; and Each R 4a1 is independently –OH or fluorine; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 1 –OH group. 4a1 ​ 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, 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, where each cycloalkyl is substituted with 0 to 3 R 5b5 substituents; 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, provided that no more than one of R 5b1 and R 5b2 is H; Alternatively, R 5b1 and R 5b2 combine to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 R 5b5 substituents; Each R 5b3 is H or C 1-4 alkyl; Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 0 to 1 R 5b5 ; and Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl or NH(CH3).

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, 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, where each cycloalkyl is substituted with 0 to 3 R 5b5 ; and Each R 5b5 is independently C 1-4 alkyl, halogen or C 1-4 haloalkyl.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 5b and R 5c each independently is 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 ; wherein Each R 5b1 and R 5b2 independently is H, C 1-4 alkyl, C 1-4 haloalkyl, –C(O)C 1-4 alkyl, –C(O)C 1-4 haloalkyl, provided that no more than one of R 5b1 and R 5b2 is H; Alternatively, R 5b1 and R 5b2 combine to form a heterocycloalkyl having 6 ring members and 0 to 1 additional oxygen ring members, wherein said heterocycloalkyl is substituted with 0 to 2 R 5b5 substituents; Each R 5b3 is H or C 1-4 alkyl; Each R 5b4 is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, which is substituted with 0 to 1 R 5b5 substituent; and Each R 5b5 is independently C 1-4 alkyl, halogen, C 1-4 haloalkyl or NH(CH3).

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, 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, 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 5a is H; R 5b is H; and R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl or C 1-4 alkyl–heteroalkyl, wherein the heteroalkyl 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 deuterated alkyl, –OH or C 2-6 alkoxyalkyl.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 6a is H, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 alkyl–C 3-6 cycloalkyl; R 6b is H; and R 6d is H, C 1-4 alkyl or C 1-4 deuterated alkyl.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, –CD3, R 6b is H; and R 6d is H, methyl, ethyl, n-propyl, isopropyl, –CD3 or 18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 6a is H, methyl, ethyl, n-propyl, isobutyl, –CD3 or R 6b is H; and R 6d is H, methyl, isopropyl or –CD3.

19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein X 6 is 20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein X 6 is 21. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein X 6 is 22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 7a is H; and R 7b and R 7c each independently is H, C 1-8 alkyl or C 1-4 alkyl–C 3-6 cycloalkyl.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein R 7a is H; R 7b is H; and R 7c is isobutyl, 24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein R 7a is H; R 7b is H; and R 7c is isobutyl.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, which has the structure of formula Ia:

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, which has the structure of formula Ia1:

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

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

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

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

31. The compound according to any one of claims 1 to 28 or 30 or a pharmaceutically acceptable salt thereof, wherein ring B is 32. The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-6 alkoxyalkyl or C 1-4 alkyl–C 3-6 cycloalkyl; R 8b , R 8d and R 8e Each independently is H; Alternatively, R 8b and R 8d combine with their respective attached carbons to form C 3-6 cycloalkyl; subscript m8 is an integer from 0 to 5; Each R 8f is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, 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, –O–C 3-6 cycloalkyl, C 1-4 alkyl–C 3-6 cycloalkyl, –O–C 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted with 0 to 3 R 8f3 substituents; Each R 8f1 and R 8f2 is independently H or C 1-4 alkyl; and Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl or a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S.

33. The compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R 8a is C 1-4 alkyl, C 1-4 deuterated alkyl or C 1-4 alkyl–C 3-6 cycloalkyl; R 8b , R 8d and R 8e Each independently is H; subscript m8 is an integer from 0 to 5; Each R 8f is independently C 1-4 alkyl, C 1-4 alkoxy, C 2-8 alkoxyalkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano, –NR 8f1 R 8f2 , –C 3-6 cycloalkyl, –O–C 3-6 cycloalkyl, –O–C 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 being N, O or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, where each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is substituted by 0 to 3 R 8f3 substituents; Each R 8f1 and R 8f2 is each C 1-4 alkyl; and Each R 8f3 is independently C 1-4 alkyl, –OH, C 1-4 alkoxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, –C(O)C 1-4 alkyl, –O–C 1-4 alkyl–C 3-6 cycloalkyl or a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently selected from N, O, or S.

34. The compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3, and R 8b , R 8d and R 8e Each is H; Alternatively, R 8b and R 8d combine with their respective attached carbons to form a cyclopropyl group.

35. The compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3 or and R 8b 、R 8d and R 8e are each H.

36. The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein m8 is 0, 1, 2 or 3; and Each R 8f independently is methyl, ethynyl, methoxy, fluoro, chloro, bromo, iodo, 37. The compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, wherein m8 is 0, 1, 2 or 3; and Each R 8f independently is methyl, methoxy, fluoro, chloro, bromo, iodo, 38. The compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein subscript m8 is 2.

39. A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein moiety –C(O)–X 9 –NR 9a – is 40. A compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein moiety –C(O)–X 9 –NR 9a – is 41. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein moiety –C(O)–X 9 –NR 9a – is 42. The compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein R 9a is H or C 1-4 alkyl; R 9b and R 9c each independently is 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, where each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S; Alternatively, R 9b and R 9c combine with the respective attached carbon to form a C 9c2 cycloalkyl group which is substituted with from 0 to 2 R 3-4 groups; or Alternatively, R 9c and R 9a together with the attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 or 2 R 9c2 substituents; Each R 9c1 is independently a halogen; and Each R 9c2 is independently –OH or a halogen.

43. The compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, wherein R 9a is H or C 1-4 alkyl; R 9b and R 9c each independently is H, C 1-6 alkyl, C 2-6 alkoxyalkyl or C 3-6 cycloalkyl; Alternatively, R 9b and R 9c combine with their respective attached carbons to form a C 9c2 cycloalkyl group which is substituted with from 0 to 2 R 3-4 groups; or Alternatively, R 9c and R 9a together with the attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 members and 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 or 2 R 9c2 substituents; and Each R 9c2 is independently –OH or a halogen.

44. The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, 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, Alternatively, R 9b and R 9c together with the carbon atoms to which they are attached combine to form a C cycloalkyl group which is substituted with from 0 to 2 fluorine groups; 3-4 cycloalkyl; Alternatively, R 9c and R 9a together with the respective connected carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

45. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein R 9a is H or methyl; R 9b is H or methyl; and R 9c is H, methyl, ethyl, n-propyl, Alternatively, R 9b and R 9c together with the carbon to which they are attached combine to form a C 3-4 cycloalkyl group which is substituted by from 0 to 2 fluorine groups; Alternatively, R 9c and R 9a together with the respective carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

46. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, wherein X 6 For and Part –C(O)–X 9 –NR 9a – is 47. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, wherein X 6 For And Part –C(O)–X 9 –NR 9a – is 48. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, which has the structure of formula Ib:

49. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, which has the structure of formula Ib1:

50. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, wherein X 6 For and Part –C(O)–X 9 –NR 9a – is 51. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, wherein X 6 For And Part –C(O)–X 9 –NR 9a – is 52. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is R 4a is H or methyl; R 4b is H; R 4c is methyl, ethyl, isopropyl, tert-butyl, Or, R 4c and R 4a together with their attached carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 to 1 additional oxygen, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; Each R 4a1 is independently methyl, –OH, methoxy, fluoro or –N(H)S(O)2CH3; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 2 –OH groups; 4a1 ​ R 5a is H; R 5b is H; R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, X 6 For R 6a is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, –CD3, R 6b is H; R 6d is H, methyl, ethyl, n-propyl, isopropyl, –CD3 or R 7a is H; R 7b is H; R 7c is isobutyl, R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3, R 8b , R 8d and R 8e Each is H; Alternatively, R 8b and R 8d combine with the respective attached carbon to form a cyclopropyl group; m8 is 0, 1, 2 or 3; Each R 8f independently is methyl, ethynyl, methoxy, fluorine, chlorine, bromine, iodine, X 9 For R 9a is H or methyl; R 9b is H, methyl or ethyl; and R 9c is H, methyl, ethyl, n-propyl, sec-butyl, Alternatively, R 9b and R 9c combine with the carbon atoms to which they are attached to form a C 3-4 cycloalkyl group which is substituted with from 0 to 2 fluorine groups; Alternatively, R 9c and R 9a together with the respective connected carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

53. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is R 4a is H or methyl; R 4b is H; R 4c is methyl, ethyl, isopropyl, Alternatively, R 4c and R 4a together with the respective connected carbon and nitrogen combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, wherein said heterocycloalkyl is substituted with 0 to 2 R 4a1 substituents; Each R 4a1 is independently –OH or fluorine; Alternatively, two R groups on adjacent ring atoms combine to form a phenyl ring substituted with 0 to 1 –OH; 4a1 ​ R 5a is H; R 5b is H; R 5c is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, X 6 For R 6a is H, methyl, ethyl, n-propyl, isobutyl, –CD3 or R 6b is H; R 6d is H, methyl, isopropyl, or –CD R 7b is isobutyl, R 7a is H; R 7b is H; R 7c is isobutyl, R 8a is methyl, ethyl, n-propyl, n-butyl, –CD3 or R 8b 、R 8d and R 8e are each H; m8 is 0, 1, 2 or 3; and Each R 8f independently is methyl, methoxy, fluoro, chloro, bromo, iodo, X 9 For R 9a is H or methyl; R 9b is H or methyl; and R 9c is H, methyl, ethyl, n-propyl, Alternatively, R 9b and R 9c together with the carbon atoms to which they are attached combine to form a C 3-4 cycloalkyl group which is substituted with from 0 to 2 fluorine groups; Alternatively, R 9c and R 9a together with the carbon and nitrogen to which they are attached combine to form a heterocycloalkyl having 4 to 6 ring members and 0 additional heteroatoms, said heterocycloalkyl being substituted with 0 or 1 fluorine or -OH group.

54. The compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof, which has the structure of formula Ic:

55. The compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof, which has the structure of formula Ic1:

56. The compound according to claim 1, which has the structure of any one of Examples 1 - 693.

57. A pharmaceutical composition, which comprises the compound according to any one of claims 1 to 56 and a pharmaceutically acceptable excipient.

58. A method for treating cancer that is mediated, at least in part, by one or more cyclins, the method 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. 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 that is mediated, at least in part, by one or more cyclins.

60. 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 in the manufacture of a medicament for treating cancer that is mediated, at least in part, by one or more cyclins.

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