ULK complex modulators and uses thereof

Abstract

The present disclosure provides compounds and compositions for binding to a ULK initiation complex, and methods of use thereof.

Description

ULK COMPLEX MODULATORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 605,373, filed December 1, 2023, the entirety of which is incorporated herein by reference.BACKGROUND

[0002] ULK complexes (e.g. ULK1 and ULK2) are important parts of the autophagy pathway. Wong, et al. Autophagy, 9(2): 124-137 (Feb. 1, 2013). The autophagy pathway utilizes lysosomal activity to degrade large objects such as molecular aggregates, organelles, and intracellular pathogens. The autophagy process degrades these materials by forming a membrane structure called the “phagophore,” which encapsulates a target of interest and seals into a double-membrane structure called the “autophagosome”. The autophagosome fuses with lysosomes, resulting in degradation of the encapsulated materials and release of metabolic byproducts such as amino acids.SUMMARY

[0003] The therapeutic potential of harnessing cellular degradation systems to direct removal of specific targets has been well appreciated and extensively investigated for more than a decade. See, for example, Bondeson & Crews Annu Rev Pharmacol Toxicol 57:107-123 (Sept. 6, 2017), and references cited therein. Particular focus has been on development of heterobifunctional small molecule agents that recruit an E3 ligase (e.g., the cereblon protein) to a target of interest. Such recruitment leads to ubiquitination of the target, to promote its degradation via the proteosome.

[0004] The present disclosure provides alternative strategies to achieve targeted degradation. Among other things, the present disclosure provides an insight that recruitment of a ULK initiation complex can be used to induce selective autophagy, a process by which the degradative mechanism is targeted to specific substrates.

[0005] ULK initiation complexes include ULK1 and ULK2, where a ULK initiation complex comprises FIP200, ATG13, and ATG101. These complexes are important parts of the autophagy pathway. Wong, et al. Autophagy, 9(2): 124-137 (Feb. 1, 2013); Turco, etal.,Mol. Cell, 74(2):330- 346. e6 (2019); Hurley J H, et al. Annu Rev Biochem. 2017 Jun 20;86:225-244. Initiation of theautophagy pathway via the ULK initiation complex includes: 1) recognition of cargo (i.e., the target to be degraded), typically by adapter proteins that bind to the target cargo (e.g., to modifications, such as ubiquitin or beta-galactoside, on the cargo); and 2) recruitment of a ULK initiation complex by the cargo adapter proteins. Recruitment of the ULK initiation complex is believed to be driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCOCO2) which binds to cytosolically exposed beta-galactoside via galectin-8. See, for example, Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Ravenhill, et al, Mol. Cell, 74(2): 320-329.e6; Turco, et al., J Mol Biol, 432(1): 123-134 (2020); Johansen & Lamark J Mol Bio 432(1):80-103 (Jan.3, 2020).

[0006] Without being bound by theory, the present disclosure proposes that promoting recruitment and / or assembly of the ULK initiation complex (e.g., a ULK1 initiation complex) represents a particularly useful and / or effective strategy for achieving selective removal of cellular components via the autophagy pathway.

[0007] Recent studies have explored interactions involved in selective autophagy mechanisms by, for example, in vitro binding studies and / or genetic modification (e.g., knock out and / or mutagenesis of interacting components). See, for example, Ravenhill, et al., Mol. Cell, 74(2):320- 329.e6 (2018); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019). Moreover, one report has described artificially linking a peptide derived from ATG16L to a protein (FKBP) or mitochondrial cargo can trigger autophagic degradation of the cargo. See Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019).

[0008] The present disclosure surprisingly demonstrates that small molecule agents can be developed that target the ULK initiation complex and can be used to recruit the complex to cargo, and / or to initiate its assembly thereon. The present disclosure provides ULK initiation complex binding moieties, compounds that comprise them, and various compositions and / or methods relating thereto, including using them to induce targeted autophagy of particular cargo.

[0009] In some embodiments, the present disclosure provides a compound or a moiety that is capable of binding to a ULK complex. In some embodiments, a compound or a moiety that is capable of binding to a ULK complex is a compound of or otherwise comprises a structure of formula I:or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; B is a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is a bond, -NR1a-C(O)-, -C(O)-NR1a-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, or optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2is -N(R2a)(R2b), -O-C0-C6aliphatic-R2b, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 2- to 6 membered heteroaliphatic substituted with one or more R2a, C3-C12cycloaliphatic substituted with one or more R2a, or C6-C12aryl substituted with one or more R2a; each R2ais independently selected from the group consisting of oxo, –OH, halogen, Z, -O-R3a, - C(O)NHR3a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl;R2bis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-OR1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of an optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

[0010] In some embodiments, the present disclosure provides a compound of formula II: A’-B’-C’ II or a pharmaceutically acceptable salt thereof, wherein A’ is a ULK complex binding moiety; B’ is a linker; andC’ is a target binding moiety.

[0011] In certain aspects, compounds provided herein are useful for treating certain diseases, disorders, and conditions described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0012] The present disclosure provides compounds and compositions useful for modulating a ULK initiation complex (e.g., a ULK1 initiation complex and / or ULK2 initiation complex) for selective autophagy. In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. Compounds and Definitions

[0013] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0014] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Tables A-1 and B-1 show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0015] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0016] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0017] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) forat least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.

[0018] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is C1-6alkyl.

[0019] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain or cyclic hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, iso- propyl), butyl (e.g., n-butyl, sec-butyl, iso-butyl, tert-butyl), pentyl, hexyl, and heptyl.

[0020] Alkylene: The term "alkylene" and “alkylenyl” are used interchangeably and refer to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in thespecification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

[0021] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0022] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0023] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include

[0024] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0025] Cycloaliphatic: As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8hydrocarbon and / or a bicyclic C7-14hydrocarbon that is completely saturated or that contains oneor more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule. In some embodiments, a cycloaliphatic can be monocyclic, bicyclic, or spirocyclic C3-C14cycloaliphatic.

[0026] Cycloalkyl: As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] Cycloalkenyl: As used herein, the term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0028] Heteroaliphatic: The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight–chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1–4 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.

[0029] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 π-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen,or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycle rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, benzoisoxazolyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0030] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0031] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic (e.g., tricyclic or spirocyclic) heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structureand any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocycle group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclealkyl” refers to an alkyl group substituted by a heterocycle, wherein the alkyl and heterocycle portions independently are optionally substituted. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl,A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.

[0032] Modulator: The term “modulator,” as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator. For example, a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0033] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0034] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0035] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0036] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0037] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0038] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid fdler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other nontoxic compatible substances employed in pharmaceutical formulations.

[0039] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0040] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0041] Polycyclic: As used herein, the term “polycyclic” refers to a saturated or unsaturated ring system having two or more rings (for example, heterocycle rings, heteroaryl rings, cycloaliphatic rings, or aryl rings), having between 7 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings. For example, in some embodiments, a polycyclic ring system refers to a saturated or unsaturated ring system having three or more rings (for example, heterocycle rings, heteroaryl rings, cycloaliphatic rings, or aryl rings), having between 14 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings. The rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof. A “spirocyclic” ring system, as described herein, refers to a moiety where at least two rings share a single common atom. Examples of polycyclic rings include:

[0042] Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0043] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,refers to at least; andrefers to at least Unlessotherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, morepreferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0044] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O– N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0045] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2, -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●, –(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” issubstituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0046] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] Suitable substituents on the aliphatic group of R*include halogen, –R●, -(haloR●), -OH, – OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0051] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0052] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0053] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0054] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0055] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0056] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36Cl for35Cl or37Cl;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0057] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0058] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of thecompound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0059] Those skilled in the art will appreciate that a bond designated asin a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example, the following structure:is intended to encompass both

[0060] Those skilled in the art will further appreciate that, in small molecule structures, the symbols and — , as used herein, are interchangeable, and each refer to a point of attachment between two atoms.

[0061] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.Compounds for Binding a ULK Initiation Complex

[0062] In certain aspects the present disclosure provides compounds for binding a ULK initiation complex (e.g., a ULK1 initiation complex or a ULK2 initaiton complex). In some embodiments,such compounds comprise a targeting moiety for binding a target, thereby promoting autophagy of said target. In some embodiments, ULK binding is determined according to methods described herein, for example in Example C1. In some embodiments, a compound for binding a ULK initiation complex and a target is a compound of formula II: A’-B’-C’ II or a pharmaceutically acceptable salt thereof, wherein A’ is a ULK complex binding moiety; B’ is a linker; and C’ is a target binding moiety.

[0063] In some embodiments, a ULK complex binding moiety (e.g., moiety A’) is a compound of or comprises a structure of Formula I:or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; B is a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is a bond, -NR1a-C(O)-, -C(O)-NR1a-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprisingone 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2is -N(R2a)(R2b), -O-C0-C6aliphatic-R2b, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 2- to 6 membered heteroaliphatic substituted with one or more R2a, C3-C12cycloaliphatic substituted with one or more R2a, or C6-C12aryl substituted with one or more R2a; each R2ais independently selected from the group consisting of oxo, –OH, halogen, Z, -O-R3a, - C(O)NHR3a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; R2bis H, optionally substituted group selected from C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-OR1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, each Cy is independently an optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S optionally substituted C6-C12aryl; and each RZis independently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic.

[0064] As described generally herein, A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl. In some embodiments, A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is optionally substituted 5- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is optionally substituted 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, A is optionally substituted thiazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, A is thiazolyl. In some embodiments, A is oxazolyl. In some embodiments, A is pyrazolyl. In some embodiments, A is pyridinyl. In some embodiments, A is pyrimidinyl. In some embodiments, A is pyrazinyl.

[0065] In some embodiments, A is optionally substituted C6-C12aryl. In some embodiments, A is optionally substituted phenyl.

[0066] In some embodiments, a moiety:is selected from:

[0067] In some embodiments, a moiety is:

[0068] As described herein, B is a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3- C6cycloaliphatic, or optionally substituted C6-C12aryl. In some embodiments, B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl. In some embodiments, B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl.

[0069] In some embodiments, B is a bond.

[0070] In some embodiments, B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is optionally substituted 5- to 6-membered membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is 5- to 6-membered membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S and substituted with one or more of halogen or C1-C6aliphatic. In some embodiments, B is pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, thiazolyl, indolyl, imidazolyl, pyrrolyl, thiophenyl, oxadiazolyl, or pyrazolyl.

[0071] In some embodiments, B is optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, B is 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and substituted with one or more of halogen, C1-C6aliphatic, or oxo. In some embodiments, B is piperdinyl or piperazinyl.

[0072] In some embodiments, B is optionally substituted C3-C6cycloaliphatic. In some embodiments, B is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0073] In some embodiments, B is optionally substituted C6-C12aryl. In some embodiments, B is optionally substituted phenyl or naphthyl. In some embodiments, B is phenyl.

[0074] In some embodiments, B is selected from the group consisting of:

[0075] As described generally herein, L1is a bond, -NR1a-C(O)-, -C(O)-NR1a-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic. In some embodiments, L1is a bond or optionally substituted C1- C6aliphatic.

[0076] In some embodiments, L1is a bond.

[0077] In some embodiments, L1is -NR1a-C(O)-. In some embodiments, L1is –NH-C(O)-.

[0078] In some embodiments, L1is -C(O)-NR1a-. In some embodiments, L1is –C(O)-NH-.

[0079] In some embodiments, L1is optionally substituted C1-C6aliphatic. In some embodiments, L1is –CH(CH3)-, -C(CH3)2-, or –CH2-. In some embodiments, L1is –(CH2)1-6-. In some embodiments, L1is –CH2-. In some embodiments, L1is –C(CH3)2-. In some embodiments, L1is –CH(CH3)-. In some embodiments, L1is an S enantiomer of –CH(CH3)-. In some embodiments, L1is an R enantiomer of –CH(CH3)-. In some embodiments, L1is

[0080] In some embodiments, L1is optionally substituted C3-C6cycloaliphatic. In some emboddiments, L1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L1is:

[0081] In some embodiments, L1is optionally substituted 3- to 6-membered heterocyclic. In some embodiments, L1is:

[0082] As described generally herein, L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, - C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)-NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic. In some embodiments, L2is –NR1a-C(O)- or -C(O)-NR1a-. In some emboidments, L2is -NH-C(O)- or -C(O)-NH-.

[0083] In some embodiments, L2is –NR1a-. In some embodiments, L2is –NH-. In some embodiments, L2is –N(C1-C6aliphatic)-. In some embodiments, L2is –N(CH3)-.

[0084] In some embodiments, L2is –O-.

[0085] In some embodiments, L2is -C(O)-.

[0086] In some embodiments, L2is -NR1a-C(O)-. In some embodiments, L2is –NH-C(O)-. In some embodiments, L2is –N(C1-C6aliphatic)-C(O)-. In some embodiments, L2is N(CH3)-C(O)- .

[0087] In some embodiments, L2is -NR1a-S(O)2-. In some embodiments, L2is –NH-S(O)2-. In some embodiments, L2is –N(CH3)-S(O)2-.

[0088] In some embodiments, L2is -C(O)-NR1a-. In some embodiments, L2is –C(O)-NH-. In some embodiments, L2is –C(O)-N(C1-C6aliphatic). In som embodiments, L2is –C(O)-N(CH3)-.

[0089] In some embodiments, L2is -S(O)2-NR1a-. In some embodiments, L2is -S(O)2-NH-. In some embodimments, L2is –S(O)2-N(C1-C6aliphatic). In some embodiments, L2is –S(O)2- N(CH3)-.

[0090] In some embodiments, L2is -NR1a-C(O)-NR1a-. In some embodiments, L2is –NH-C(O)- NH-. In some embodiments, L2is –NH-C(O)-N(C1-C6aliphatic)-. In some embodiments, L2is – N(C1-C6alipahtic)-C(O)-NH-. In some embodiments, L2is –N(C1-C6aliphatic)-C(O)-N(C1-C6aliphatic)-. In some embodiments, L2is –NH-C(O)-N(CH3)-. In some embodiments, L2is – N(CH3)-C(O)-NH-. In some embodiments, L2is –N(CH3)-C(O)-N(CH3)-.

[0091] In some embodiments, L2is optionally substituted C1-C6aliphatic. In some embodiments, In some embodiments, L2is –CH(CH3)-, -C(CH3)2-, or –CH2-. In some embodiments, L2is – (CH2)1-6-. In some embodiments, L2is –CH2-. In some embodiments, L2is –C(CH3)2-. In some embodiments, L2is –CH(CH3)-.

[0092] In some embodiments, L2is optionally substituted C3-C6cycloaliphatic. In some embodiments, L2is cyclopropyl, cyclobutyl, cyclopently, or cyclohexyl.

[0093] As described herein, R1is H, Z, halogen, -OR1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic. In some embodiments, R1is Z, halogen, -OR1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic.

[0094] In some embodiments, R1is Z. In some embodiments, R1is –C(O)-NH-CH2-CH2-O-CH3or -CH2-C(O)-NH-CH2-CH2-O-CH3.

[0095] In some embodiments, R1is halogen. In some embodiments, R1is fluoro, bromo, chloro, or iodo.

[0096] In some embodiments, R1is H.

[0097] In some embodiments, R1is -OR1a. In some embodiments, R1is OH. In some embodiments, R1is –O-C1-C6aliphatic.

[0098] In some embodiments, R1is optionally substituted C1-C6aliphatic. In some embodiments, R1is C1-C6aliphatic substituted with one or more of: –(CH2)0–4R°, –(CH2)0–4OR°, -O(CH2)0-4R°,or –(CH2)0–4C(O)NR°2. In some embodiments, R1is C1-C6aliphatic substituted with one or more of: –(CH2)0–4R°, –(CH2)0–4OR°, -O(CH2)0-4R°, or –(CH2)0–4C(O)NR°2, wherein R° is H or C1-C6aliphatic optionally substituted with –(CH2)0–2NR●2, –(CH2)0–2OH, or –(CH2)0–2OR●. In some embodiments, R1is methyl, ethyl, propyl, iso-propyl, n-butyl, or t-butyl-. In some embodiments, R1is –CH3.

[0099] In some embodiments, R1is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, R1is –NH-CH2-CH2-O-CH3or –O-CH2-CH2-O-CH3.

[0100] In some embodiments, R1is optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S.

[0101] In some embodiments, R1is optionally substituted C3-C6cycloaliphatic. R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1is cyclopropyl.

[0102] In some embodiments, R1is optionally substituted C6-C12aryl. In some embodiments, R1is phenyl.

[0103] In some embodiments, R1is selected from:

[0104] As described herein, each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic. In some embodiments, one or more R1ais H.

[0105] In some embodiments, one or more R1ais optionally substituted C1-C6aliphatic. In some embodiments, one or more R1ais independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, optionally substituted with one or more of –(CH2)0–4R°, –(CH2)0–4OR°, or -O(CH2)0-4R°.

[0106] In some embodiments, one or more R1ais optionally substituted C3-C6cyloaliphatic. In some embodiments, one or more R1ais cyclopropyl, cyclobutyl, cyclopently, or cyclohexyl optiuonally substituted with one or more of –(CH2)0–4R°, –(CH2)0–4OR°, or -O(CH2)0-4R°.

[0107] As described herein, R2is -N(R2a)(R2b), -O-C0-C6aliphatic-R2b, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 2- to 6 membered heteroaliphatic substituted with one or more R2a, C3-C12cycloaliphatic substituted with one or more R2a, or C6-C12aryl substituted with one or more R2a.

[0108] In some embodiments, R2is 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a,or 2- to 6 membered heteroaliphatic substituted with one or more R2a.

[0109] In some embodiments, R2is -N(R2a)(R2b). In some embodiments, R2is NHR2b. In some embodiments, R2is –NHR2b, wherein R2bis optionally substituted C1-C6aliphatic. In some embodiments, R2is –NHR2bwherein R2bis C1-C6aliphatic is optionally substituted with one or more of –(CH2)0–4R°, –(CH2)0–4OR°, -O(CH2)0-4R°, or –(CH2)0–4C(O)NR°2. In some embodiments, R2is –NHR2b, wherein R2bis C1-C6aliphatic substituted with one or more of: – (CH2)0–4R°, –(CH2)0–4OR°, -O(CH2)0-4R°, or –(CH2)0–4C(O)NR°2, and wherein R° is H or C1-C6aliphatic optionally substituted with –(CH2)0–2NR●2, –(CH2)0–2OH, or –(CH2)0–2OR●. In some embodiments R2is –NH-CH2-C(O)-NH-CH2-CH2-O-CH3.

[0110] In some embodiments, R2is -O-C0-C6aliphatic-R2b. In some embodiments, R2is –O-C1- C6aliphatic-R2b. In some embodiments, R2is –O-(CH2)1-6-R2b. In some embodiments, R2is -O- CH2-CH2-O-CH3. In some embodiments, R2is –O-CH2-R2b. In some embodiments, R2is:

[0111] In some embodiments, R2is 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and substituted with one or more R2a. In some embodiments, R2is a 4- to 6- membered monocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more R2a. In some embodiments, R2is azetidinyl, pyrrolidinyl, or piperdinyl optionally substituted with one or more R2a. In some embodiments, R2is azetidinyl,pyrrolidinyl, or piperdinyl optionally substituted with one or more R2a,where each R2ais selected from oxo, Z, or –C(O)NHR3a. In some embodiments, R2is azetidinyl optionally substituted with one or more R2a. In some embodiments, R2is pyrrolidinyl optionally substituted with one or more R2a. In some embodiments, R2is piperdinyl optionally substituted with one or more R2a.

[0112] In some embodiments, R2is 6- to 12-membered bicyclic or polycyclic (e.g., spirocyclic) heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and substituted with one or more R2a. In some embodiments, R2is:

[0113] In some embodiments, R2is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and substituted with one or more R2a. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S and substituted with one or more R2a. In some embodiments, R2is 7-to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted with one or more R2a.

[0114] In some embodiments, R2is 2- to 6 membered heteroaliphatic substituted with one or more R2a.

[0115] In some embodiments, R2is C3-C12cycloaliphatic substituted with one or more R2a. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more R2a.

[0116] In some embodiments, R2is C6-C12aryl substituted with one or more R2a. In some embodiments, R2is phenyl, substituted with one or more R2a.

[0117] In some embodiments, R2is selected from:

[0118] In some embodiments, R2is selected from:

[0119] As described herein, each R2ais independently selected from the group consisting of oxo, –OH, halogen, Z, -O-R3a, -C(O)NHR3a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl.

[0120] In some embodiments, one or more R2ais oxo.

[0121] In some embodiments, one or more R2ais –OH.

[0122] In some embodiments, one or more R2ais Z.

[0123] In some embodiments, one or more R2ais –O-R3a. In some embodiments, one or more R2ais –O-C1-C6aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, -O(CH2)0-4R°, or –(CH2)0–4C(O)NR°2.

[0124] In some embodiments, one or more R2ais -C(O)NHR3a. In some embodiments, one or more R2ais –C(O)-NH-C1-C6aliphatic optionally substituted with one or more –(CH2)0–4R° or – (CH2)0–4OR°. In some embodiments, one or more R2ais -C(O)-NH-C1-C6aliphatic optionally substituted with one or more–(CH2)0–4OR°.

[0125] In some embodiments, one or more R2ais –C(O)OH.

[0126] In some embodiments, one or more R2ais -C(O)OR3a. In some embodiments, one or more R2ais –C(O)O-C1-C6aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, – (CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0127] In some embodiments, one or more R2ais -C(O)R3a. In some embodiments, one or more R2ais R2ais –C(O)-C1-C6aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0128] In some embodiments, one or more R2ais optionally substituted C1-C6aliphatic. In some embodimments, one or more R2ais C1-C6aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2. In some embodiments, one or more R2ais C1-C6aliphatic optionally substituted with halogen–(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2, wherein R° is H, C1-C6aliphatic, 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0129] In some embodiments, one or more R2ais optionally substituted C3-C6cycloaliphatic. In some embodiments, one or more R2ais C3-C6cycloaliphatic optionally substituted with one ormore of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2. In some embodiments, one or more R2ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0130] In some embodiments, one or more R2ais optionally substituted C6-C12aryl. In some embodiments, R2ais C6-C12aryl optionally substituted with one or more halogen, –(CH2)0–4R°, – (CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0131] As described herein, R2bis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0132] In some embodiments, R2bis H or optionally substituted C1-C6aliphatic.

[0133] In some embodiments, R2bis H.

[0134] In some embodiments, R2bis optionally substituted C1-C6aliphatic. In some embodiments, R2bis C1-C6aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2. In some embodiments, R2bis C1-C6aliphatic optionally substituted with halogen–(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2, wherein R° is H, C1-C6aliphatic, 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0135] In some embodiments, R2bis optionally substituted C3-C6cycloaliphatic. In some embodiments, R2bis C3-C6cycloaliphatic optionally substituted with one or more of of halogen, – (CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0136] In some embodiments, R2bis optionally substituted C6-C12aryl. In some embodimments, R2bis C6-C12aryl optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0137] In some embodiments, R2bis optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2bis 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0138] In some embodiments, R2bis optionally substituted 4- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2bis 4- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)NR°2.

[0139] As described herein, R3is -O-C0-C6aliphatic-R3a, -S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a.

[0140] In some embodiments, R3is C6-C12aryl optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a.

[0141] In some embodiments, R3is -O-C0-C6aliphatic-R3a. In some embodiments, R3is O-C1-C6aliphatic-R3a. In some embodiments, R3is O-R3a. In some embodiments, R3is O-R3a, wherein R3ais optionally substituted C1-C6aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3is O-C1-C6aliphatic-R3a, wherein R3ais optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0142] In some embodiments, R3is -S(O)2R3a. In some embodiments, R3is –S(O)2R3a, wherein R3ais optionally substituted C1-C6aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0143] In some embodiments, R3is C1-C6aliphatic optionally substituted with one or more R3a. In some embodiments, R3is C1-C6aliphatic optionally substituted with one or more R3a, wherein each R3ais independently halogen, CN, -O-R1a, -C(O)-OR1a,-C(O)N(R1a)2, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatomsselected from N, O, and S, optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0144] In some embodiments, R3is 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a. In some embodiments, R3ir 4- to 6-membered monocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a. In some embodiments, R3ir 4- to 6- membered monocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, where each R3ais independently optionally substituted C1-C6aliphatic, O-R1a, oxo, or halogen. In some embodiments, R3is tetrahydropyranyl, morpholinyl, piperdinyl, piperazinyl, optionally substituted with one or more R3a.

[0145] In some embodiments, R3is 6- to 12-membered bicyclic or polycyclic or spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a. In some embodiments, R3is 6- to 12-membered bicyclic or polycyclic or spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, where each R3ais independently optionally substituted C1-C6aliphatic, O-R1a, oxo, or halogen.

[0146] In some embodiments, R3is C6-C12aryl optionally substituted with one or more R3a. In some embodiments, R3is phenyl or naphthyl optionally substituted with one or more R3a. In some embodiments, R3is phenyl optionally substituted with one or more R3a, wherein each R3ais independently selected from halogen, optionally substituted C1-C6aliphatic, O-R1a, –N(R1a)2, or - C(O)-OR1a.In some embodiments, R3is phenyl optionally substituted with one or more R3a, wherein R3ais –NH2.

[0147] In some embodiments, R3is 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a. In some embodiments, R3is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted with one or more R3a. In some embodiments, R3is 4- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted with one or more R3a, wherein each R3ais independently selected from halogen, optionally substituted C1-C6aliphatic, O-R1a, –N(R1a)2, or -C(O)-OR1a. In some embodiments, R3is 4- to 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionallysubstituted with one or more R3a, wherein each R3ais independently selected from C1-C6alkyl or -NH2.

[0148] In some embodiments, R3is selected from:

[0149] As described herein, each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic- C(O)N(R1a)2, -S(O)2R1a, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3- C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each R3ais independently optionally substituted C1-C6aliphatic, O-R1a, oxo, -NH2, or halogen. In some embodiments, R3ais optionally substituted C1-C6aliphatic. In some embodiments, R3ais O-R1a. In some embodiments, R3ais oxo. In some embodiments, R3ais – NH2. In some embodiments, R3ais halogen.

[0150] As described herein each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, - N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, - C(O)N(RZ)SO2(RZ)-, -SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-.

[0151] As described herein, each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl.

[0152] As described herein, each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

[0153] In some embodiments, a compound or moiety of formula I is a compound or moiety of formula Ia:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH; each R4is independently selected from the group consisting of oxo, –OH, halogen, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; or two R4can be joined together, with the atoms to which they are attached to form a 5- to 6- membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; n is 0, 1, 2, 3, or 4; and L1, L2, B, R1, and R3are as described in classes and subclasses herein, both singly and in combination.

[0154] In some embodiments, the present disclosure provides a compound or moiety of formula Ia:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a, -O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;each R4is independently selected from the group consisting of oxo, –OH, halogen, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, or two R4can be joined together, with the atoms to which they are attached to form a 5- to 6- membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -or SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, or optionally substituted C3-C12cycloaliphatic; and n is 0, 1, 2, 3, or 4.

[0155] In some embodiments, a compound or moiety of formula I is a compound or moiety of formula Ib:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH;R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; and L1, L2, B, R1, and R3are as described in classes and subclasses herein, both singly and in combination.

[0156] In some embodiments, the present disclosure provides a compound or moiety of formula Ib:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -OR1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or moreR3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently an optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituited C3-C12cycloaliphatic.

[0157] In some embodiments, a compound or moiety of formula I is a compound or moiety of formula Ic:or a pharmaceutically acceptable salt thereof, whereinR4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; and L1, L2, R1, and R3are as described in classes and subclasses herein, both singly and in combination.

[0158] In some embodiments, the present disclosure provides a compound or moiety of formula Ic:or a pharmaceutically acceptable salt thereof, wherein L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -NR1a-C(O)-NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a, -O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocyclecomprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently selected from H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

[0159] In some embodiments, a compound or moiety of formula I is selected from Table A-1: Table A-1

[0160] In some embodiments, a compound of formula I is selected from Table A-2:Table A-2

[0161] As described herein, the present disclosure provides compounds of formula II: A’-B’-C’ II or a pharmaceutically acceptable salt thereof, wherein A’ is a ULK complex binding moiety; B’ is a linker; and C’ is a target binding moiety.

[0162] In some embodiments, A’ is a moiety derived from a compound of formula I-Ic, as described herein. A person of skill in the art will appreciate that a position for attachment of a compound of formula I to incorporate it into formula II is at any position that produces achemically stable moiety. In some embodiments, positions R1or R2a, as described in classes and subclasses herein with respect to formula I, serve as a suitable locations for attaching moiety A’ to the rest of the compound of formula II (e.g, to moiety B’). In some embodiments, A’ is a compound of formula I, wherein position R1or R2aare replaced with B’, and is therefore a compound of formula II, for example, of structure:where A, R1, R2, L1, L2, B, R3, B’, and C’ are as defined in classes and subclasses herein, both singly and in combination.

[0163] As defined generally herein, B’ is a linker moiety. For example, B’ is a bivalent moiety covalently bonded to moiety A’ and moiety C’. In some embodiments, B’ is Z, wherein Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(Ra)SO2(RZ)-, -SO2(RZ)N(Ra)C(O)-, -OC(O)O-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each -Cy- is independently selected from the group consisting of optionally substituted 3-12 membered bivalent C3-C6cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

[0164] In some embodiments, B’ is a linker moiety selected from Table B’: Table B’wherein t is an integer between 1and 20.

[0165] As defined generally above, C’ is a target binding moiety. In some embodiments, a target binding moiety binds or associates with a target selected from the group consisting of mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A / B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1 / 2, CISD1, MTARC1, ACSL1, BAK1,BAX, HK1 / 2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32, RAB1B, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, damaged lysosomes, STING, cGAS, and USP30. Those of skill in the art would understand which target binding moieties are suitable for inclusion in compounds described herein.

[0166] For example, in some embodiments, C’ is a moiety that binds or associates with mitochondria. In some embodiments, C’ is a moiety that binds or associates with mitochrondria as described in WO 2008 / 074692, WO 2008 / 145596, WO 2013 / 071169, Griffith, et al., J. Med. Chem., 57:10512-10526 (2014), Madauss, et al., Acta Cryst., D65:449-461 (2009), Yamashita, et al., Bioorganic & Med. Chem. Lett., 21:6314-6318 (2011), Freeman-Cook, et al., J. Med. Chem., 55:935-942 (2012), Takagi, et al., J. Pharmacol. Exp. Ther., 372:256-263 (March 2020), Wu and Huang, Future Med. Chem., 12(6):*1-29 (2020), Harriman, et al., PNAS, E1796-E1805 (Mar.14, 2016), Abu-Elheiga, et al., PNAS, 97(4):1444-1449, Toledo-Sherman, et al., J. Med. Chem., 58:1159-1183 (2015), Walker, et al., J. Med. Chem., 60:3383-3404 (2017), Rover, et al., J. Med. Chem., 40:4378-4385 (1997), Kim, et al., Cell Chemical Biology, 25:425-438 (2018), Osgerby, et al., J. Med. Chem., 60, 3518-3524 (2017), Hertz, et al., Cell, 154:737-747 (2013), Milite, et al., J. Med. Chem., 60:7897-7909 (2017), Damont, et al., J. Med. Chem., 58:7449-7464 (2015), Frantz and Wipf, Environ. Mol. Mutagen., 51(5):462-475(2010), Chaveau, et al., Eur. J. Nucl. Med. Mol. Imaging, 38:509-514 (2011), and Ceccarelli, et al., J. Med. Chem., 54:3109-3152 (2011), each of which is incorporated by reference in its entirety.

[0167] In some embodiments, C’ is a moiety that binds or associates with a bacterium.

[0168] In some embodiments, C’ is a moiety that binds or associates with a lipid droplet.

[0169] In some embodiments, C’ is a moiety that binds or associates with a peroxisome.

[0170] In some embodiments, C’ is a moiety that binds or associates with COP9.

[0171] In some embodiments, C’ is a moiety that binds or associates with MYC.

[0172] In some embodiments, C’ is a moiety that binds or associates with a myddosome. In some embodiments, C’ is a moiety that binds or associates with a myddosome, as described in WO 2019 / 099926, WO 2019 / 133531, WO 2019 / 160915, WO 2015 / 103453, Nunes, etal.,Med. Chem. Lett., 10: 1081-1085 (2019), Zhang, et al., Cell Chem. Biol., 27: 1-10 (2020), McElroy, Expert Opinion on Therapeutic Patents, 29(4):243-259 (2019), Genung and Guckian, Progress in Med. Chem., 56: 117-163 (2017), Seganish, Expert Opinion on Therapeutic Patents, 26(8):917-932 (2016), Chen, et al., J. Med. Chem., 63: 13316-13329 (2020), Kargbo, ACS Med. Chem. Lett., 10: 1251-1252 (2019), and Chen, et al., ACS Med. Chem. Lett., 12:82-87 (2021), each of which is incorporated herein by reference in its entirety.

[0173] In some embodiments, C’ is a moiety that binds or associates with a myddosome, and is a compound, or derived from a compound, of the following structure:

[0174] In some embodiments, C’ is a moiety that binds or associates with myddosome, and is selected from the table below, whererepresents a point of attachment between moiety C’ and and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0175] In some embodiments, C’ is a moiety that binds or associates with inflammasome. In some embodiments, C’ is a moiety that binds or associates with NLRP3 inflammasome. In some embodiments, C’ is a moiety that binds or associates with NLRP3 inflammasome as described in WO 2019 / 092170, which is incorporated herein by reference in its entirety.

[0176] In some embodiments, C’ is a moiety that binds or associates with NLRP3 inflammasome.

[0177] In some embodiments, C’ is a moiety that binds or associates with NLRP3 inflammasome, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0178] In some embodiments, C’ is a moiety that binds or associates with EGFR. In some embodiments, C’ is a moiety that binds or associates with EGFR as described in Burslem et al., Cell Chemical Biology, 25: 67–77 (2018), which is incorporated herein by reference in its entirety. In some embodiments, C’ is a moiety that binds or associates with EGFR, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II:

[0179] In some embodiments, C’ is a moiety that binds or associates with KRAS.

[0180] In some embodiments, C’ is a moiety that binds or associates with α-synuclein. In some embodiments, C’ is a moiety that binds or associates with α-synuclein as described in WO 2020 / 041331, and Josephson, et al., Molecular Imaging, 17:1-6 (2018), each of which is incorporated herein in its entirety.

[0181] In some embodiments, C’ is a moiety that binds or associates with tau. In some embodiments, C’ is a moiety that binds or associates with tau, as described in WO 2021 / 011913, Walji, et al., J. Med. Chem., 59:4778-4789 (2016), Kroth, et al., E. J. of Nuclear Med. And Mol.Imaging, 46:2178-2189 (2019), Rombouts, et al., J. Med. Chem., 62:2974-2987 (2019), Ariza, et al., J. Med. Chem., 58:4365-4382 (2015), Vermeiren, et al., Movement Disorders, 33(2):273-287 (2018), Silva, et al., eLife 8:e45457 (2019), Kolb and Andrés, Cold Spring Harb. Perspect. Biol., 9:a023721 (2017), and US App. Pub. No. US 2018 / 0215731, each of which is incorporated by reference in its entirety.

[0182] In some embodiments, C’ is a moiety that binds or associates with tau and is a compound, or derived from a compound, of the following structure:

[0183] In some embodiments, C’ is a moiety that binds or associates with tau, and is selected from the table below, whererepresents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0184] In some embodiments, C’ is a moiety that binds or associates with estrogen receptor alpha (ER-a).

[0185] In some embodiments, C’ is a moiety that binds or associates with an androgen receptor (AR). In some embodiments, C’ is a moiety that binds or associates with AR as described in Scott, et al., ACS Med. Chem. Lett., 11:1539-1547 (2020). In some embodiments, C’ is a moiety that binds or associates with tau, and is represented by the structure below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0186] In some embodiments, C’ is a moiety that binds or associates with acetyl coenzyme A2 (ACC2). In some embodiments, C’ is a moiety that binds or associates with ACC2 as described in WO2013 / 07169 and Yamashita, et al., Bioorganic & Med. Chem. Lett., 21(21):6314-6318 (2011), each of which is incorporated herein by reference in its entirety.

[0187] In some embodiments, C’ is a moiety that binds or associates with ACC2, and is a compound, or derived from a compound, of the following structure:

[0188] In some embodiments, C’ is a moiety that binds or associates with ACC2, and is selected from the table below, whererepresents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0189] In some embodiments, C’ is a moiety that binds or associates with kynurenine 3- monooxygenase (KMO). In some embodiments, C’ is a moiety that binds or associates with KMO as described in Walker, et al., J. Med. Chem., 60(8):3383-3404 (2017). In some embodiments, C’ is a moiety that binds or associates with KMO and is a compound, or derived from a compound, of the following structure:

[0190] In some embodiments, C’ is a moiety that binds or associates with KMO, and is selected from the table below, whererepresents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0191] In some embodiments, C’ is a moiety that binds or associates with KSR1.

[0192] In some embodiments, C’ is a moiety that binds or associates with IAPP. In some embodiments, C’ is a moiety that binds or associates with IAPP as described in Templin, et al., Diabetologia, 61(10):2215-2224 (2018). In some embodiments, C’ is a moiety that binds or associates with IAPP, and is a compound, or derived from a compound, of the following structure:

[0193] In some embodiments, C’ is a moiety that binds or associates with IAPP, and is selected from the table below, whererepresents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0194] In some embodiments, C’ is a moiety that binds or associates with IRAK1 / 2 / 4. In some embodiments, C’ is a moiety that binds or associates with IRAK4. In some embodiments, C’ is a moiety that binds or associates with IRAK4, as described in WO 2019 / 099926, WO 2019 / 133531, WO 2019 / 160915, WO 2015 / 103453, Nunes, et al., Med. Chem. Lett., 10:1081-1085 (2019), Zhang, et al., Cell Chem. Biol., 27:1-10 (2020), McElroy, Expert Opinion on Therapeutic Patents, 29(4):243-259 (2019), Genung and Guckian, Progress in Med. Chem., 56:117-163 (2017), Seganish, Expert Opinion on Therapeutic Patents, 26(8):917-932 (2016), Chen, et al., J. Med. Chem., 63:13316-13329 (2020), Kargbo, ACS Med. Chem. Lett., 10:1251-1252 (2019), and Chen, et al., ACS Med. Chem. Lett., 12:82-87 (2021), each of which is incorporated herein by reference in its entirety.

[0195] In some embodiments, C’ is a moiety that binds or associates with TSPO. In some embodiments, C’ is a moiety that binds or associates with TSPO as described in Daniele, et al., J. Med. Chem., 59(10):4526-4538 (2016), Le Fur, et al., Life Sciences, 32(16):1849-1856 (1983), Camins, et al., Immunopharmacology, 29(2):159-166 (1995), and Damont, et al., J. Med. Chem., 58(18):7449-7464 (2015), each of which is incorporated herein by reference in its entirety.

[0196] In some embodiments, C’ is a moiety that binds or associates with TSPO, and is a compound, or derived from a compound, from the table below:,.

[0197] In some embodiments, C’ is a moiety that binds or associates with TSPO, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’): ,.

[0198] In some embodiments, C’ is a moiety that binds or associates with rubicon.

[0199] In some embodiments, C’ is a moiety that binds or associates with FKBP12.

[0200] In some embodiments, C’ is a moiety that binds or associates with Fis1.

[0201] In some embodiments, C’ is a moiety that binds or associates with PINK1.

[0202] In some embodiments, C’ is a moiety that binds or associates with huntingtin. In some embodiments, C’ is a moiety that binds or associates with huntingtin as described in WO2020 / 176424, WO 2018 / 118598, WO 2016 / 033445, Tomoshige, et al., Angew. Chem. Int. Ed., 56:11530-11533 (2017), Liu, et al., J. Med. Chem., 63(15):8608-8633 (2020), each of which is incorporated by reference in its entirety.

[0203] In some embodiments, C’ is a moiety that binds or associates with huntington and is a compound, or derived from a compound, of the following structure:

[0204] In some embodiments, C’ is a moiety that binds or associates with huntington, and is selected from the table below, whererepresents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0205] In some embodiments, C’ is a moiety that binds or associates with TDP43.

[0206] In some embodiments, C’ is a moiety that binds or associates with HSP90.

[0207] In some embodiments, C’ is a moiety that binds or associates with Hap40.

[0208] In some embodiments, C’ is a moiety that binds or associates with RNA.

[0209] In some embodiments, C’ is a moiety that binds or associates with NLRP3.

[0210] In some embodiments, C’ is a moiety that binds or associates with MCL1.

[0211] In some embodiments, C’ is a moiety that binds or associates with BCL-XL.

[0212] In some embodiments, C’ is a moiety that binds or associates with BCL2.

[0213] In some embodiments, C’ is a moiety that binds or associates with BAD.

[0214] In some embodiments, C’ is a moiety that binds or associates with PARKIN.

[0215] In some embodiments, C’ is a moiety that binds or associates with CPT1A / B.

[0216] In some embodiments, C’ is a moiety that binds or associates with cardiolipin.

[0217] In some embodiments, C’ is a moiety that binds or associates with Miro-1.

[0218] In some embodiments, C’ is a moiety that binds or associates with MAOA.

[0219] In some embodiments, C’ is a moiety that binds or associates with MAOB.

[0220] In some embodiments, C’ is a moiety that binds or associates with VDAC1 / 2.

[0221] In some embodiments, C’ is a moiety that binds or associates with CISD1.

[0222] In some embodiments, C’ is a moiety that binds or associates with MTARC1.

[0223] In some embodiments, C’ is a moiety that binds or associates with ACSL1.

[0224] In some embodiments, C’ is a moiety that binds or associates with BAK1.

[0225] In some embodiments, C’ is a moiety that binds or associates with BAX.

[0226] In some embodiments, C’ is a moiety that binds or associates with HK1 / 2.

[0227] In some embodiments, C’ is a moiety that binds or associates with GPAM.

[0228] In some embodiments, C’ is a moiety that binds or associates with a virus.

[0229] In some embodiments, C’ is a moiety that binds or associates with PNLPA2.

[0230] In some embodiments, C’ is a moiety that binds or associates with PNPLA3.

[0231] In some embodiments, C’ is a moiety that binds or associates with ABHD5.

[0232] In some embodiments, C’ is a moiety that binds or associates with perilipin 2.

[0233] In some embodiments, C’ is a moiety that binds or associates with perilipin 3.

[0234] In some embodiments, C’ is a moiety that binds or associates with HSD17B13.

[0235] In some embodiments, C’ is a moiety that binds or associates with HSD17B7.

[0236] In some embodiments, C’ is a moiety that binds or associates with HSD17B11.

[0237] In some embodiments, C’ is a moiety that binds or associates with LPCAT1.

[0238] In some embodiments, C’ is a moiety that binds or associates with HSDHL.

[0239] In some embodiments, C’ is a moiety that binds or associates with SQLE.

[0240] In some embodiments, C’ is a moiety that binds or associates with EPHX2.

[0241] In some embodiments, C’ is a moiety that binds or associates with LIPE.

[0242] In some embodiments, C’ is a moiety that binds or associates with VCP.

[0243] In some embodiments, C’ is a moiety that binds or associates with LSS.

[0244] In some embodiments, C’ is a moiety that binds or associates with AIFM2.

[0245] In some embodiments, C’ is a moiety that binds or associates with C18orf32.

[0246] In some embodiments, C’ is a moiety that binds or associates with RAB1B.

[0247] In some embodiments, C’ is a moiety that binds or associates with RAB5A.

[0248] In some embodiments, C’ is a moiety that binds or associates with MYD88.

[0249] In some embodiments, C’ is a moiety that binds or associates with ASC.

[0250] In some embodiments, C’ is a moiety that binds or associates with an endosome.

[0251] In some embodiments, C’ is a moiety that binds or associates with receptor tyrosine kinases.

[0252] In some embodiments, C’ is a moiety that binds or associates with cMet.

[0253] In some embodiments, C’ is a moiety that binds or associates with LRP5 / 6.

[0254] In some embodiments, C’ is a moiety that binds or associates with frizzled.

[0255] In some embodiments, C’ is a moiety that binds or associates with oncogenic signaling complexes.

[0256] In some embodiments, C’ is a moiety that binds or associates with RAF.

[0257] In some embodiments, C’ is a moiety that binds or associates with RAS.

[0258] In some embodiments, C’ is a moiety that binds or associates with polyQ / CAG repeat proteins.

[0259] In some embodiments, C’ is a moiety that binds or associates with autophagy cargo adapter proteins.

[0260] In some embodiments, C’ is a moiety that binds or associates with p62.

[0261] In some embodiments, C’ is a moiety that binds or associates with NBR1.

[0262] In some embodiments, C’ is a moiety that binds or associates with OPTN.

[0263] In some embodiments, C’ is a moiety that binds or associates with TAX1BP1.

[0264] In some embodiments, C’ is a moiety that binds or associates with, NDP52. In some embodiments, C’ is a moiety that binds or associates with liquid-liquid phase separation condensates.

[0265] In some embodiments, C’ is a moiety that binds or associates with Shp2.

[0266] In some embodiments, C’ is a moiety that binds or associates with endoplasmic reticulum.

[0267] In some embodiments, C’ is a moiety that binds or associates with AXTN3.

[0268] In some embodiments, C’ is a moiety that binds or associates with FLCN.

[0269] In some embodiments, C’ is a moiety that binds or associates with FNIP.

[0270] In some embodiments, C’ is a moiety that binds or associates with mTOR.

[0271] In some embodiments, C’ is a moiety that binds or associates with ABHD6.

[0272] In some embodiments, C’ is a moiety that binds or associates with damaged lysosomes.

[0273] In some embodiments, C’ is a moiety that binds or associates with STING. In some embodiments, C’ is a moiety that binds or associates with STING as described in WO 2020 / 132582, ACS Med. Chem. Lett., 10(1):92-97 (2019); Science, 369(6506):eaba6098 (2020), each of which is incorporated herein by reference in its entirety.

[0274] In some embodiments, C’ is a moiety that binds or associates with STING and is a compound, or derived from a compound, of the following structure:

[0275] In some embodiments, C’ is a moiety that binds or associates with STING, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0276] In some embodiments, C’ is a moiety that binds or associates with cGAS. In some embodiments, C’ is a moiety that binds or associates with cGAS as described in Nat. Commun., 10:2261 (2019), J. Org. Chem., 85(3):1579-1600 (2020), each of which is incorporated herein by reference in its entirety.

[0277] In some embodiments, C’ is a moiety that binds or associates with cGAS and is a compound, or derived from a compound, of the following structure:.

[0278] In some embodiments, C’ is a moiety that binds or associates with cGAS, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0279] In some embodiments, C’ is a moiety that binds or associates with USP30. In some embodiments, C’ is a moiety that binds or associates with USP30 as described in WO 2020 / 212350, which is incorporated herein by reference in its entirety.

[0280] In some embodiments, C’ is a moiety that binds or associates with USP30 and is a compound, or derived from a compound, of the following structure:

[0281] In some embodiments, C’ is a moiety that binds or associates with USP30, and is selected from the table below, where represents a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):

[0282] In some embodiments, C’ is a moiety derived from a compound of Table E: Table E

[0283] In some embodiments, C’ is a moiety selected from Table F, whereoreach represent a point of attachment between moiety C’ and the remainder of a compound of formula II (e.g., a point of attachment to moiety B’):Table F

[0284] In some embodiments, A’-B’-C’ is a compound of formula Ila or lib :or a pharmaceutically acceptable salt thereof, wherein Axis optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; Bxis a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1xis a bond, -NR1ax-C(O)-, -C(O)-NR1ax-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2xis –NR1ax-, -O-, -C(O)-, -NR1ax-C(O)-, -NR1ax-S(O)2-, -C(O)-NR1ax-, -S(O)2NR1ax-, -NR1ax- C(O)-NR1ax-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1xis H, halogen, -O-R1ax, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1axis independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2xis -N(R2ax)(R2bx), -O-C0-C6aliphatic-R2bx, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 2- to 6 membered heteroaliphatic substituted with one or more R2ax, C3-C12cycloaliphatic substituted with one or more R2ax, or C6-C12aryl substituted with one or more R2ax;each R2axis independently selected from the group consisting of oxo, –OH, halogen, -O-R3ax, - C(O)NHR3ax, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; R2bxis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3xis-O-C0-C6aliphatic-R3ax, -S(O)2R3ax, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax, C6-C12aryl optionally substituted with one or more R3ax, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax; each R3axis independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1ax, -C(O)-OR1ax,-O-R1ax, –N(R1ax)2, -C0-C6aliphatic-C(O)N(R1ax)2, - S(O)2R1ax, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; and B’ and C’ are as described in classes and subclasses herein, both singly and in combination.

[0285] In some embodiments, a compound of Formula II is selected from Table B-1:Table B-1

[0286] In some embodiments, a compound of Formula II is selected from Table B-2:Table B-2Uses, Formulation, and AdministrationPharmaceutically Acceptable Compositions

[0287] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions described herein is such that it is effective to measurably induce degradation of a target in a biological sample or in a patient. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0288] Compounds and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject tosubject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0289] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intraci st emally or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0290] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in anon-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0291] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0292] Injectable formulations can be sterilized, for example, by fdtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0293] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0294] In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0295] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants suchas talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0296] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0297] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0298] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0299] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0300] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0301] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0302] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0303] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0304] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0305] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0306] Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.Uses of Compounds and Pharmaceutically Acceptable CompositionsA ULK Initiation Complex

[0307] Cellular degradation of large objects such as molecular aggregates, organelles, and intracellular pathogens is accomplished by the autophagy pathway. In this process, the autophagy machinery initiates and grows a double membrane phagophore around a cargo of interest. The double membrane phagophore ultimately fuses with itself to encapsulate the cargo in a double membrane autophagosome. Nakatogawa, Nat. Rev. Mol. Cell. Biology, 21 :439-458 (2020). Theautophagosome membrane, which has encompassed the cargo then fuses with a lysosome to degrade the inner membrane and cargo contents, resulting in degradation of the encapsulated materials and release of metabolic byproducts such as amino acids. See Rabinowitz and White, Science, 330(6009):1344-1348 (2010).

[0308] The present disclosure provides an insight that recruitment of a ULK initiation complex (e.g., a ULK1 initiation complex and / or a ULK2 initiation complex) can be used to induce selective autophagy, a process by which the degradative mechanism is targeted to specific substrates. Initiation of the autophagy pathway via a ULK initiation complex includes: 1) recognition of cargo (i.e., the target to be degraded), typically by adapter proteins that bind to the target cargo (e.g., to modifications, such as ubiquitin or beta galactoside, on the cargo) and, 2) recruitment of a ULK initiation complex by the cargo adapter proteins. Recruitment of a ULK initiation complex is believed to be driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCOCO2) which binds to cytosolically exposed beta-galactoside via galectin-8. See, for example, Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Ravenhill, et al, Mol. Cell, 74(2): 320-329.e6; Turco, et al., J Mol Biol, 432(1): 123-134 (2020); Johansen & Lamark J Mol Bio 432(1):80-103 (Jan.3, 2020).

[0309] Without being bound by theory, the present disclosure proposes that promoting recruitment and / or assembly of a ULK initiation complex (e.g., a ULK1 initiation complex and / or a ULK2 initiation complex) represents a particularly useful and / or effective strategy for achieving selective removal of cellular components via the autophagy pathway.

[0310] The ULK initiation complexes include ULK1 and ULK2. ULK initiation complexes comprise FIP200, ATG13, and ATG101, and are an important part of the autophagy pathway. Wong, et al. Autophagy, 9(2):124-137 (Feb.1, 2013); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Hurley JH, et al. Annu Rev Biochem. 2017 Jun 20;86:225-244. Recruitment a ULK initiation complex is driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62, that localize to the ubiquitinated cargo. This process of recognizing substrates for degradation and recruiting a ULK initiation complex is central to triggering the selective removal of cellular components via the autophagy pathway.

[0311] Recent studies have explored interactions involved in selective autophagy mechanisms by, for example, in vitro binding studies and / or genetic modification (e.g., knock out and / ormutagenesis of interacting components). See, for example, Ravenhill, et al., Mol. Cell, 74(2):320- 329.e6 (2018); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019). Moreover, one report has described artificially linking a peptide derived from ATG16L to a protein (FKBP) or mitochondrial cargo can trigger autophagic degradataion of the cargo. Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019); Turco, et al., Mol. Cell, 74(2):330- 346.e6 (2019); Ravenhill, et al., Mol. Cell, 74(2):320-329.e6 (2018).

[0312] The present disclosure surprisingly demonstrates that small molecule agents described herein can be developed that target a ULK initiation complex and can be used to recruit the complex to cargo, and / or to initiate its assembly thereon. Without being bound by theory, it is understood that small molecule compounds can recruit a ULK initiation complex to the target of interest. The present disclosure provides heterobifunctional compounds and compositions that, as described herein, can target a ULK initiation complex as well as certain target moieties, to thereby activate the autophagy pathway.

[0313] In some embodiments, compounds and compositions described herein target a ULK1 initiation complex. In some embodiments, compounds and compositions described herein target a ULK2 initiation complex. In some embodiments, the present disclosure encompasses an insight that one or more compounds can be advantageously used to treat diseases and disorders described herein. For example, in some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a ULK intiation complex comprising administration of one compound or composition described herein. In some embodiments, two or more compounds or compositions described herein are administered (e.g., simultaneously or sequentially). Diseases, Disorders, and Conditions

[0314] The present disclosure encompasses an insight that compounds and compositions provided herein can be used to direct autophagy to a target. The present disclosure also encompasses an insight that directing autophagy to particular targets can be useful for treating particular diseases, disorders, and conditions. In some embodiments, a disease, disorder, or condition is selected from NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secretinglymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Aicardia-Goutieres syndrome, ataxia, Familial chilblain lupus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.

[0315] In some embodiments, a particular target binding moiety (e.g, moiety C’ in formula II, above) can be selected to modulate (and thereby induce degradation of) a target of choice to to treat a disease, disorder, or condition of choice. A person of skill in the art can identify particular binding moieties based on the desired disease, disorder, or condition to be treated, using known binding moieties. For example:

[0316] In some embodiments, a target is a lipid droplet, and a disease, disorder or condition to be treated is selected from NASH and NAFLD.

[0317] In some embodiments, a target is COP9, and a disease, disorder or condition is cancer.

[0318] In some embodiments, a target is MYC, and a disease, disorder or condition is Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, lung cancer, or stomach cancer.

[0319] In some embodiments, a target is myddosome, and a disease, disorder or condition is active B-cell-like diffuse large B-cell lymphomas (ABC DLBCL), diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, or Waldenstrom macroglobulinemia.

[0320] In some embodiments, a target is inflammasome, and a disease, disorder or condition is gout, atherosclerosis, Alzheimer’s disease, Type-II diabetes, experimental autoimmuneencephalitis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes (CAPS), colon cancer, breast cancer, melanoma, hepatitis C’ virus-associated hepatocellular carcinoma, and gastrointestinal cancers.

[0321] In some embodiments, a target is KRAS, and a disease, disorder or condition is colorectal cancer, lung cancer, leukemia, pancreatic cancer,

[0322] In some embodiments, a target is a-synuclein, and a disease, disorder or condition is Parkinson’s disease, dementia with Lewy bodies, multiple systems atrophy, or neuroaxonal dystrophies.

[0323] In some embodiments, a target is tau, and a disease, disorder or condition is Alzheimer’s disease, Primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, or lipofuscinosis.

[0324] In some embodiments, a target is estrogen receptor-a, and a disease, disorder or condition is breast cancer.

[0325] In some embodiments, a target is an androgen receptor, and a disease, disorder or condition is prostate cancer or spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease.

[0326] In some embodiments, a target is KSR1, and a disease, disorder or condition is cancer.

[0327] In some embodiments, a target is islet amyloid polypeptide (LAPP), and a disease, disorder or condition is type-II diabetes.

[0328] In some embodiments, a target is IRAK4, and a disease, disorder or condition is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or psoriasis.

[0329] In some embodiments, a target is PINK 1, and a disease, disorder or condition is Parkinson’s disease, Huntingtin’s disease, or spinocerebellar ataxia.

[0330] In some embodiments, a target is TDP43, and a disease, disorder or condition is familial amylotrophic lateral sclerosis or frontotemporal dementia (FTLD-TDP).Exemplary Embodiments

[0331] The present disclosure provides the following non-limiting numbered embodiments. Embodiment 1. A compound of formula Ior a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; B is a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is a bond, -NR1a-C(O)-, -C(O)-NR1a-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2is -N(R2a)(R2b), -O-C0-C6aliphatic-R2b, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 2- to 6 membered heteroaliphatic substituted with one or more R2a, or C3-C12cycloaliphatic substituted with one or more R2a, or C6-C12aryl substituted with one or more R2a;each R2ais independently selected from the group consisting of oxo, –OH, halogen, Z, -O-R3a, - C(O)NHR3a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; R2bis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic. Embodiment 2. The compound of Embodiment 1, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.Embodiment 3. The compound of Embodiments 1 or 2, wherein A is optionally substituted pyrimidinyl . Embodiment 4. The compound of Embodiment 1, wherein moiety:is selected from: ,Embodiment 5. The compound of any one of Embodiments 1-4, wherein L1is optionally substituted C1-C6aliphatic. Embodiment 6. The compound of any one of Embodiments 1-5, wherein L1is -CH(CH3)-, -C(CH3)2- or –CH2-. Embodiment 7. The compound of any one of Embodiments 1-6, wherein L1is –C(CH3)-. Embodiment 8. The compound of Embodiment 7, wherein L1isEmbodiment 9. The compound of any one of Embodiments 1-8, wherein L2is -NH-C(O)- or -C(O)-NH-. Embodiment 10. The compound of any one of Embodiments 1-9, wherein L2is NH-C(O)-. Embodiment 11. The compound of Embodiment 1, wherein L1is –CH2-, and L2is –NH- C(O)-. Embodiment 12. The compound of any one of Embodiments 1-11, wherein B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl. Embodiment 13. The compound of any one of Embodiments 1-12 wherein B is optionally substituted C6-C12aryl. Embodiment 14. The compound of any one of Embodiments 1-13, wherein B is optionally substituted phenyl. Embodiment 15. The compound of any one of Embodiments 1-11, wherein B is selected from:Embodiment 16. The compound of any one of Embodiments 1-15, wherein R3is C6-C12aryl optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a. Embodiment 17. The compound of any one of Embodiments 1-16, wherein R3is phenyl substituted with one or more R3a. Embodiment 18. The compound of any one of Embodiments 1-17, wherein each R3ais independently selected from halogen, –N(R1a)2, and optionally substituted C1-C6aliphatic. Embodiment 19. The compound of any one of Embodiments 1-15, wherein R3is selected from:Embodiment 20. The compound of any one of Embodiments 1-19, wherein R1is Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic. Embodiment 21. The compound of any one of Embodiments 1-20, wherein R1is Z or optionally substituted C1-C6aliphatic.Embodiment 22. The compound of any one of Embodiments 1-19, wherein R1is selected from –H, -CH3, -Br,Embodiment 23. The compound of any one of Embodiments 1-22 wherein R2is 4- to 12- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a,,or 2- to 6 membered heteroaliphatic substituted with one or more R2a. Embodiment 24. The compound of any one of Embodiments 1-23, wherein R2is 4- to 12- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a. Embodiment 25. The compound of any one of Embodiments 1-22, wherein R2is selected from the group consisting of:Embodiment 26. The compound of any one of Embodiments 1-22, wherein R2is selected from the group consisting ofEmbodiment 27. The compound of Embodiment 1, wherein the compound is of formula Ia:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl;L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R4is independently selected from the group consisting of oxo, –OH, halogen, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl, or two R4can be joined together, with the atoms to which they are attached to form a 5- to 6- membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic; and n is 0, 1, 2, 3, or 4. Embodiment 28. The compound of Embodiment 1, wherein the compound is of formula Ib:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic;R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently an optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic. Embodiment 29. The compound of Embodiment 1, wherein the compound is of formula Ic:or a pharmaceutically acceptable salt thereof, wherein L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -NR1a-C(O)-NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a, -O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl;each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic. Embodiment 30. The compound of Embodiment 1, wherein the compound is selected from Table A-1. Embodiment 31. A compound of formula II: A’-B’-C’ II or a pharmaceutically acceptable salt thereof, wherein A’ is a ULK complex binding moiety; B’ is a linker; and C’ is a target binding moiety. Embodiment 32. The compound of Embodiment 31, wherein the ULK complex binding moiety is a compound of any one of Embodiments 1-29. Embodiment 33. The compound of Embodiment 31, wherein A’-B’-C’ is a compound of formula IIa or IIb:or a pharmaceutically acceptable salt thereof, wherein Axis optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; Bxis a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1xis a bond, -NR1ax-C(O)-, -C(O)-NR1ax-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2xis –NR1ax-, -O-, -C(O)-, -NR1ax-C(O)-, -NR1ax-S(O)2-, -C(O)-NR1ax-, -S(O)2NR1ax-, -NR1ax- C(O)-NR1ax-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1xis H, halogen, -O-R1ax, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1axis independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2xis -N(R2ax)(R2bx), -O-C0-C6aliphatic-R2bx, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 2- to 6 membered heteroaliphatic substituted with one or more R2ax, C3-C12cycloaliphatic substituted with one or more R2ax, or C6-C12aryl substituted with one or more R2ax;each R2axis independently selected from oxo, –OH, halogen, -O-R3ax, -C(O)NHR3axoptionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl; R2bxis H or an optionally substituted group selected from C1-C6aliphatic, C3-C6cycloaliphatic, C6-C12aryl, 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and 4- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3xis-O-C0-C6aliphatic-R3ax, -S(O)2R3ax, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax, C6-C12aryl optionally substituted with one or more R3ax, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax; each R3axis independently selected from -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1ax, -C(O)- OR1ax,-O-R1ax, –N(R1ax)2, -C0-C6aliphatic-C(O)N(R1ax)2, -S(O)2R1ax, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. Embodiment 34. The compound of any one of Embodiments 31-33, wherein the ULK complex binding moiety is a ULK1 complex binding moiety. Embodiment 35. The compound of any one of Embodiments 31-34, wherein the linker is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered bivalent heterocycle ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each RZisindependently H or an optionally substituted group selected from C1-C20aliphatic, or C3-C12cycloaliphatic. Embodiment 36. The compound of any one of Embodiments 31-35, wherein the target binding moiety binds or associates with a target selected from the group consisting of mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A / B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1 / 2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1 / 2, GPAM, USP30, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32, RAB1B, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, STING, cGAS, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes. Embodiment 37. The compound of Embodiment 31, wherein the linker is selected from Table B’. Embodiment 38. The compound of Embodiment 31, wherein the target binding moiety is selected from Table F. Embodiment 39. The compound of Embodiment 31, wherein the compound is selected from Table B-1. Embodiment 40. A pharmaceutical composition comprising a compound of any one of Embodiments 1-39, and a pharmaceutically acceptable excipient.Embodiment 41 . A method of inducing degradation of a target in a biological sample, comprising contacting the biological sample with a compound of any one of Embodiments 1-38 or a pharmaceutical composition of Embodiment 40.Embodiment 42. The method of Embodiment 41, wherein the biological sample comprises a ULK initiation complex.Embodiment 43. The method of Embodiment 41, wherein the biological sample comprises a ULKl initiation complex.Embodiment 44. A method of treating a disease, disorder, or condition in a patient, comprising administering one or more compounds of any one of Embodiments 1-39, or the pharmaceutical composition of Embodiment 40.Embodiment 45. The method of Embodiment 44, wherein the disease, disorder, or condition is selected from NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM- secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin- associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing pan encephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupuserythematosus, Aicardia-Goutieres syndrome, ataxia, Familial chilblain lupus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.Embodiment 46. A compound of any one of Embodiments 1-39, or a pharmaceutical composition of Embodiment 40, for use as a medicament.Embodiment 47. Use of the compound comprising one or more compounds of any one of Embodiments 1-39, or the pharmaceutical composition of Embodiment 40 in the treatment of a disease, disorder, or condition.Embodiment 48. The use of Embodiment 47, wherein the disease, disorder, or condition is selected from NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Aicardia-Goutieres syndrome, ataxia, Familial chilblain lupus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.EXEMPLIFICATION

[0332] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.Table of AbbreviationsAnalytical Instrumentation and Purification:

[0333] NMR Instrument Details: Varian 400MHz, Probe-1: Auto XID Probe 2: ATB.

[0334] LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400. LCMS Method 1 - Acidic conditions Column: X-Select C18 CSH (3.0*50) mm 2.5µ; Make: Waters Mobile Phase A: 0.05% formic acid in water: Acetonitrile ( 95:5); pH= 3.5 Mobile Phase B: 0.05% formic acid in Acetonitrile Column oven temperature: 50 C Flow rate: 1.2 ml / minute PDA: 210nm Maxplot Gradient program :MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000 LCMS Method 2 - Basic conditions Column: X-Select C18 CSH (3.0*50) mm 2.5µm ; Make: Waters Mobile Phase A : 5mM Ammonium Bicarb; pH= 8.8 Mobile Phase B: Acetonitrile Column oven temperature: 50 C Flow rate: 1.2 ml / minute PDA: 210nm Maxplot Gradient program :MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000 HPLC Method 1 – Acidic Conditions Column : X-Select CSH C18 (4.6*150) mm; 5µ; Make: Waters Mobile Phase: A - 0.1% Formic acid in water : Acetonitrile(95:05) ; pH=3.5B - Acetonitrile Flow Rate: 1.0. mL / minute PDA : 210nm maxplot Gradient program :HPLC Method 2 – Basic Conditions Column : Xbridge C18 (4.6*150) mm, 5µ; Make: Waters Mobile Phase A - 0.1% NH3 in water; pH=9.5 B – Acetonitrile Flow Rate: 1.2. mL / minute PDA : 210nm maxplot Gradient program :Example A1. Synthesis of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide dihydrochloride:Step-1. Synthesis of (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide

[0335] (2S,3aS,7aS)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide hydrochloride (5.57 g, 21.1 mmol) was added to a stirred solution of 6-chloro-2-methylpyrimidine-4-carbonitrile (3.24 g, 21.1 mmol), N,N-dimethylpyridin-4-amine (0.257 g, 2.11 mmol) and ethylbis(propan-2- yl)amine (10.9 g, 84.4 mmol) in dry DMF (30 mL). The mixture was stirred at 70 °C for 18 hours, the resulting mixture was diluted with water (120 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (40 mL x 3), sodium hydrosulfate sat. aq. solution (40 mL x 2) and brine (150 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide (5.27 g, 14.5 mmol, 95% purity, 69% yield). Step-2. Synthesis of tert-butyl N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro- 1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamate

[0336] Sodium boranuide (5.48 g, 145 mmol) was added portionwise at 0 °C for 0.5 hour to the stirred solution of (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide (5.27 g, 14.5 mmol), dichloronickel hexahydrate (3.44 g, 14.5 mmol) and di-tert-butyl dicarbonate (7.90 g, 36.2 mmol) in dry methanol (100 mL). Obtained reaction mixture was stirred at room temperature for 20 hours. After the reaction completion the mixture was poured into NH4Cl sat. aq. solution (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl N-({6-[(2S,3aS,7aS)- 2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamate (6.4 g, 13.5 mmol, 95% purity, 93.8% yield). Step-3. Synthesis of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide dihydrochloride

[0337] Tert-butyl N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1- yl]-2-methylpyrimidin-4-yl}methyl)carbamate (6.4 g, 13.5 mmol) was dissolved in dry methanol (50 mL), treated with 4N HCl solution in dioxane( 50 mL) and stirred at room temperature for 16 hours. The solvent was removed and the residue was dried under high vacuum to give (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide dihydrochloride, Yield: 6.1 g, 100%; Appearance: Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 3H), 8.36 (s, 1H), 7.33 – 7.17 (m, 1H), 4.54 (t, J = 9.1 Hz, 1H), 4.22 – 4.12 (m, 2H), 4.04 – 3.96 (m, 1H), 3.40 – 3.32 (m, 4H), 3.27 (s, 3H), 3.18 – 3.07 (m, 1H), 2.46 (s, 3H), 2.22 – 1.86 (m, 3H), 1.80 – 1.41 (m, 5H), 1.36 – 1.14 (m, 2H). HPLC purity: 95.37%; LCMS Calculated for C18H31Cl2N5O2: 419.19 (347.23_for_base); Observed: 348.1[M+H]+.Example A2. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(1-methyl-1H- pyrazol-4-yl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide, (A-1)

[0338] (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide (1 eq.), 4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (1.eq.), ethylbis(propan-2-yl)amine (9 eq.), and [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1 eq.) were mixed in dry DMF. The reaction mixture was stirred at room temperature for 16 hours. Then the solvent was evaporated under reduced pressure and the residue was dissolved in the DMSO (1 mL). DMSO solution was filtered, analyzed by LCMS, and subjected to HPLC purification (deionized water / HPLC-grade methanol, ammonia) to give (2S,3aS,7aS)-N-(2-methoxyethyl)-1- [2-methyl-6-({[4-(1-methyl-1H-pyrazol-4-yl)phenyl]formamido}methyl)pyrimidin-4-yl]- octahydro-1H-indole-2-carboxamide, (A-1). Yield: 23.7 mg, 22.7%; Appearance: Light- brown oil;1H NMR (600 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 6.20 (s, 1H), 4.43 – 4.03 (m, 4H), 3.86 (s, 3H), 3.23 – 3.06 (m, 5H), 2.32 – 2.19 (m, 4H), 2.02 (s, 1H), 1.89 (q, J = 11.9 Hz, 2H), 1.66 (d, J = 14.3 Hz, 1H), 1.63 – 1.53 (m, 2H), 1.50 – 1.42 (m, 1H), 1.42 – 1.34 (m, 1H), 1.29 – 1.19 (m, 1H), 1.19 – 1.00 (m, 2H); HPLC purity: 100%; LCMS Calculated for C29H37N7O3: 531.3; Observed: 532.0[M+H]+.

[0339] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A3. Synthesis of (2S,3aS,7aS)-1-(6-{[(4-bromophenyl)formamido]methyl}-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide:

[0340] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (3 g, 2.79 mmol), 4- bromobenzoic acid (0.560 g, 2.79 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1.6 g, 4.18 mmol) and ethylbis(propan-2-yl)amine (2.89 mL, 16.7 mmol) in DMF (100 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to flash chromatography (chloroform / MTBE) that afforded (2S,3aS,7aS)-1-(6-{[(4-bromophenyl)formamido]methyl}-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide, . Yield: 0.8 mg, 51.3%; Appearance: Brown solid;1H NMR (400 MHz, DMSO-d6) δ 9.04 (1H), 8.03 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 4.25 (d, J = 5.9 Hz, 3H), 4.12 – 4.00 (m, 1H), 3.21 (s, 3H), 3.18 – 3.07 (m, 3H), 2.36 – 2.20 (m, 4H), 2.13 – 1.98 (m, 1H), 1.97 – 1.81 (m, 2H), 1.75 – 1.53 (m, 3H), 1.51 – 1.36 (m, 2H), 1.34 – 0.95 (m, 2H); HPLC purity: 100%; LCMS Calculated for C25H32BrN5O3: 529.17; Observed: 530.0[M+H]+. Example A4. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-(2-methyl-6-{[(4-{6-oxa-3- azabicyclo[3.1.1]heptan-3-yl}phenyl)formamido]methyl}pyrimidin-4-yl)-octahydro-1H-indole- 2-carboxamide (A-32)(2S,3aS,7aS)-1-(6-{[(4-bromophenyl)formamido]methyl}-2-methylpyrimidin-4-yl)-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide (1 eq.), 6-oxa-3- azabicyclo[3.1.1]heptane; 4-methylbenzene-1-sulfonic acid (1.5 eq.), and dicaesium(1+) carbonate (4 eq.) were mixed in dry Dioxane (appr. 0.7 ml per 100 mg of product). RuPhos Pd G4 (0.1 eq.) (as a stock solution in dioxane appr. 0.05 ml per 100 mg of product), and RuPhos (0.1 eq.) (as a stock solution in dioxane appr. 0.05 ml per 100 mg of product) were added in one portion in an inert atmosphere. The reaction mixture was sealed and heated with shaking for 16 hours at 100 °C. Then the mixture was cooled and Trifluoroacetic acid was added dropwise until neutral pH and the solvent was evaporated under reduced pressure, and the residue was dissolved in the DMSO (appr. 1 ml per 100 mg of product). DMSO solution was treated with Scavenger SiliaMetS DMT and filtered, analyzed by LCMS, and subjected to HPLCpurification (deionized water / HPLC-grade methanol / 0.1%NH4OH) to give (2S,3aS,7aS)-N-(2- methoxyethyl)-1-(2-methyl-6-{[(4-{6-oxa-3-azabicyclo[3.1.1]heptan-3- yl}phenyl)formamido]methyl}pyrimidin-4-yl)-octahydro-1H-indole-2-carboxamide, (A-32). Yield: 12.1 mg, 22.5%; Appearance: white solid;1H NMR (600 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.14 (s, 1H), 4.71 (d, J = 6.5 Hz, 2H), 4.41 – 3.97 (m, 3H), 3.58 (d, J = 11.5 Hz, 2H), 3.45 (d, J = 11.4 Hz, 2H), 3.20 (s, 3H), 3.14 – 3.06 (m, 2H), 2.28 (s, 3H), 2.24 (s, 1H), 2.02 (s, 1H), 1.92 – 1.81 (m, 3H), 1.66 (d, J = 14.0 Hz, 1H), 1.63 – 1.53 (m, 2H), 1.49 – 1.42 (m, 1H), 1.40 (d, J = 13.8 Hz, 1H), 1.23 (q, J = 13.0 Hz, 1H), 1.16 – 1.02 (m, 1H); HPLC purity: 100%; LCMS Calculated for C30H40N6O4: 548.31; Observed: 549.2[M+H]+.

[0341] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A5. Synthesis of tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4- yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamateStep-1. Synthesis of tert-butyl N-[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate

[0342] Ethyl 4-{[(tert-butoxy)carbonyl]amino}-3-oxobutanoate (10 g, 40.7 mmol) was added to the stirred solution of ethanimidamide hydrochloride (3.92 g, 41.5 mmol) and methoxysodium (8.75 g, 162 mmol) in methanol (250 mL). Obtained mixture was stirred at room temperature for 12 hours, then evaporated to dryness in vacuo. The residue was dissolved in water (100 mL), acidified with aq. sat. sodium bisulfate solution to pH=3-4 and evaporated again to dryness. Theresidue was washed with dry tetrahydrofuran (250 mL). Filtrate was evaporated to dryness in vacuo to afford tert-butyl N-[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate (8.39 g, 32.2 mmol, 92% purity, 79.2% yield) that was used in next step without further purification. Step-2. Synthesis of 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride

[0343] 4N HCl aqueous solution (20 mL) was added at room temperature to a solution of tert- butyl N-[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate (8.39 g, 32.2 mmol, 92% purity) in methanol (20 mL). Resulting mixture was stirred at 40°C for 1 hour and evaporated to dryness in vacuo to give 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride (6 g, 30.7 mmol), 90% purity, 95.5% yield) that was used in next step without further purification. Step-3. Synthesis of tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamoyl}- [1,1'-biphenyl]-4-yl)carbamate,

[0344] Solution of 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride (6 g, 30.7 mmol, 90% purity), 4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (9.61 g, 30.7 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (13.4 g, 35.3 mmol) and ethylbis(propan-2-yl)amine (15.7 g, 122 mmol) in DMF (80 mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (450 mL), filtered, washed with water (80 mL) and dried. Crude product was recrystallized from methanol to afford tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4- yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate as beige solid, . Yield: 11.2 g, 84.2%; Appearance: Beige soild;1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.48 (s, 1H), 9.10 – 8.92 (m, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 4.23 (d, J = 6.0 Hz, 2H), 2.28 (s, 3H), 1.48 (s, 9H). HPLC purity: 97.11%; LCMS Calculated for C24H26N4O4:434.2; Observed: 435.2[M+H]+.Example A6. Synthesis of (2S,5R)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-methyl-5-phenylpyrrolidine-2-carboxamide (A-43)

[0345] (2S,5R)-N-methyl-5-phenylpyrrolidine-2-carboxamide hydrochloride (2 eq.), tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'-biphenyl]-4- yl)carbamate (1 eq.), chlorotris(pyrrolidin-1-yl)phosphanium; hexafluoro-λ⁵- phosphanuide (1.5 eq.), and 2H,3H,4H,6H,7H,8H,9H,10H-pyrimido[1,2-a]azepine (5 eq.) were mixed in dry DMA (appr. 0.7 ml per 100 mg of product). The reaction mixture was sealed and heated at 60 °C for 16 hours. Then the cleavage cocktail (СС) (Trifluoroacetic acid, Triisopropylsilane, water (93:5:2; v / v), appr.1 ml per 100 mg of product) was added in one portion. The mixture was stirred for 6 hours at ambient temperature and evaporated under reduced pressure and the residue was dissolved in the DMSO (appr.1 ml up to 300 mg of product). DMSO solution was filtered, analyzed by LCMS, and subjected to HPLC purification (deionized water / HPLC-grade acetonitrile / 0.1% NH4OH) to give (2S,5R)-1-{6-[({4'-amino-[1,1'- biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-methyl-5-phenylpyrrolidine-2- carboxamide (A-43). Yield: 14.4 mg, 27.2%; Appearance: yellow oil;1H NMR (600 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.00 (s, 1H), 7.71 (s, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.08 (s, 3H), 6.71 – 6.56 (m, 2H), 5.88 (s, 1H), 5.33 (s, 2H), 4.73 – 4.40 (m, 2H), 4.19 (dd, J = 16.7, 5.8 Hz, 1H), 4.08 (s, 1H), 3.04 – 2.96 (m, 1H), 2.65 (s, 2H), 2.36 – 2.19 (m, 4H), 2.05 (s, 1H), 2.00 – 1.90 (m, 1H), 1.85 – 1.77 (m, 1H), 1.75 – 1.56 (m, 1H). HPLC purity: 100%; LCMS Calculated for C31H32N6O2:520.26; Observed: 521.4[M+H]+.

[0346] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A7. Synthesis of tert-butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4- yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate)Step-1. Synthesis of 1-(6-chloro-2-methylpyrimidin-4-yl)methanamine hydrochloride

[0347] Triphenylphosphane (21.8 g, 83.4 mmol) was added portionwise to a solution of tetrabromomethane (33.1 g, 100 mmol) and tert-butyl N-[(6-hydroxy-2-methylpyrimidin-4- yl)methyl]carbamate (10 g, 41.7 mmol) in dichloromethane (250 mL) at 0 °C. Resulting mixture was stirred at room temperature for 6 hours, then cooled down and subjected to flash chromatography (dichloromethane). Fractions containing tert-butyl N-[(6-bromo-2-methylpyrimidin-4-yl)methyl]carbamate was combined and evaporated under reduced pressure. The residue was dissolved in dichloromethane (150 mL), then 3N HCl 1,4-dioxane solution (80 mL) was added. Resulting mixture was stirred at room temperature for 6 hours. Precipitate was filtered, washed with dichloromethane (40 mL x 2) and dried in vacuo affording 1-(6-chloro-2- methylpyrimidin-4-yl)methanamine hydrochloride (2 g, 9.79 mmol, 95% purity, 23.4% yield). Step-2. Synthesis of tert-butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'- biphenyl]-4-yl)carbamate,

[0348] Solution of 4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (3.22 g, 10.3 mmol), 1-(6-chloro-2-methylpyrimidin-4-yl)methanamine hydrochloride (2 g, 10.3 mmol), (3-{[(ethylimino)methylidene]amino}propyl)dimethylamine hydrochloride (2.54 g, 13.3 mmol), and ethylbis(propan-2-yl)amine (4.47 mL, 25.7 mmol) in dichloromethane (30 mL) was stirred at room temperature for 4 hours and evaporated to dryness in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with water (30 mL x 2) and brine (30 mL), dried over sodium sulfate, filtered through short pad of silica gel, and evaporated under reduced pressure affording tert-butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'-biphenyl]-4- yl)carbamate), . Yield: 2.4 g, 47.8%; Appearance: Yellow solid;1H NMR (400 MHz, DMSO- d6) δ 9.49 (s, 1H), 9.25 – 9.10 (m, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.35 (s, 1H), 4.52 (d, J = 5.7 Hz, 2H), 2.60 (s, 3H), 1.49 (s, 9H). HPLC purity: 92.8%; LCMS Calculated for C35H45N7O5: 452.16; Observed: 453.0[M+H]+.Example A8. Synthesis of 2-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-4-ethyl-N-(2-methoxyethyl)-2-azabicyclo[2.1.1]hexane-1-carboxamide, (A-47)

[0349] 4-ethyl-N-(2-methoxyethyl)-2-azabicyclo[2.1.1]hexane-1-carboxamide hydrochloride (1.5 eq.), tert-butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4-yl)methyl]carbamoyl}- [1,1'-biphenyl]-4-yl)carbamate (1 eq.), and ethylbis(propan-2-yl)amine (4.5 eq.), were mixed in dry N-Methyl-2-pyrrolidone (appr.0.7 ml per 100 mg of product), and the mixture was sealed, and stirred for 16 hours at 130 °C. The mixture was cooled to the ambient temperature and the solvent was evaporated under reduced pressure. Then the cleavage cocktail (СС) (Trifluoroacetic acid, triisopropylsilane, water (93:5:2; v / v), appr.1 ml per 100 mg of product) was added in one portion. The mixture was stirred for 6 hours at ambient temperature and evaporated under reduced pressure. The residue was dissolved in the DMSO (appr.1 ml up to 300 mg of product). DMSO solution was filtered, analyzed by LCMS, and subjected to HPLC purification (deionized water / HPLC-grade methanol / 0.1% NH4OH) to give 2-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-4-ethyl-N-(2-methoxyethyl)-2- azabicyclo[2.1.1]hexane-1-carboxamide (A-47). Yield: 13.2 mg, 25%; Appearance: yellow solid;1H NMR (600 MHz, DMSO-d6) δ 9.00 – 8.83 (m, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.71 – 7.58 (m, 3H), 7.43 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 6.22 (s, 1H), 5.32 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 3.16 (s, 3H), 3.12 (d, J = 6.3 Hz, 2H), 2.30 (s, 3H), 1.78 (d, J = 4.7 Hz, 2H), 1.63 – 1.55 (m, 4H), 0.86 (t, J = 7.5 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C30H36N6O3: 528.28; Observed: 529.4[M+H]+.

[0350] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A9. Synthesis of tert-butyl N-{4'-[({2-methyl-6-[(4- methylbenzenesulfonyl)oxy]pyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate

[0351] 4-methylbenzene-1-sulfonyl chloride (6.97 g, 36.6 mmol) was added to a suspension of tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'-biphenyl]-4- yl)carbamate (7.97 g, 18.3 mmol), N,N-dimethylpyridin-4-amine (0.111 g, 0.915 mmol) and ethylbis(propan-2-yl)amine (9.55 mL, 54.9 mmol) in tetrahydrofuran (300 mL). The resulting reaction mixture was refluxed for 3 hours and evaporated to dryness in vacuo. The residue was diluted with dichloromethane (100 mL) and was subjected to flash chromatography (100% dichloromethane, then 100% ethyl acetate). The fractions were concentrated under vacuum to afford tert-butyl N-{4'-[({2-methyl-6-[(4-methylbenzenesulfonyl)oxy]pyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate. Yield: 34.7 mg, 29.6%; Appearance: Beige solid;1H NMR (500 MHz, CDCl3) δ 7.96 (dd, J = 8.5, 1.9 Hz, 2H), 7.88 (dd, J = 8.5, 1.9 Hz, 2H), 7.69 – 7.61 (m, 2H), 7.60 – 7.52 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.39 – 7.32 (m, 2H), 7.31 – 7.26 (m, 1H), 6.88 (s, 1H), 6.60 (s, 1H), 4.70 (d, J = 5.0 Hz, 2H), 2.63 (s, 3H), 2.45 (s, 3H), 1.54 (s, 9H); HPLC purity: 100%; LCMS Calculated for C35H45N7O5: 588.2; Observed: 589.2[M+H]+. Example A10. Synthesis of 2-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-2-azaspiro[4.5]decane-3-carboxamide (A-57)

[0352] N-(2-methoxyethyl)-2-azaspiro[4.5]decane-3-carboxamide hydrochloride (1.5 eq.), tert- butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'-biphenyl]-4- yl)carbamate (1 eq.), and ethylbis(propan-2-yl)amine (4.5 eq.), were mixed in dry N-Methyl-2- pyrrolidone (appr.0.7 ml per 100 mg of product), and the mixture was sealed, and stirred for 16hours at 130 °C. The mixture was cooled to the ambient temperature and the solvent was evaporated under reduced pressure. Then the cleavage cocktail (СС) (Trifluoroacetic acid, Triisopropylsilane, water (93:5:2; v / v), appr.1 ml per 100 mg of product) was added in one portion. The mixture was stirred for 6 hours at ambient temperature and evaporated under reduced pressure. The residue was dissolved in the DMSO (appr.1 ml up to 300 mg of product). DMSO solution was filtered, analyzed by LCMS, and subjected to HPLC purification (deionized water / HPLC-grade methanol / 0.1% NH4OH) to give the product 2-{6-[({4'-amino-[1,1'-biphenyl]- 4-yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-2-azaspiro[4.5]decane- 3-carboxamide (A-57). Yield: 10.4 mg, 19.4%; Appearance: Yellow oil;1H NMR (600 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.07 – 7.86 (m, 3H), 7.63 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 6.07 (d, J = 207.7 Hz, 1H), 5.32 (s, 2H), 4.47 – 4.03 (m, 3H), 3.26 – 3.03 (m, 8H), 2.35 – 2.23 (m, 3H), 2.13 (d, J = 56.0 Hz, 1H), 1.63 (dd, J = 12.5, 7.7 Hz, 1H), 1.50 – 1.44 (m, 1H), 1.44 – 1.31 (m, 7H), 1.28 (s, 2H). HPLC purity: 98.35%; LCMS Calculated for C25H32BrN5O3: 556.32; Observed: 557.2[M+H]+.

[0353] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table belowExample A11. Synthesis of (2S,3aS,7aS)-1-{6-[(1R)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-62), and (2S,3aS,7aS)-1-{6-[(1S)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-63)Step-1. Synthesis of tert-butyl (4-bromophenyl)carbamate

[0354] 4-Bromoaniline (10.0 g, 58.1 mmol) and di-tert-butyl dicarbonate (15.2 g, 69.7 mmol) were dissolved in toluene (300 mL) and heated at 70 °C for 12 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (300 mL) and washed successively with 0.1 M HCl (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure that afforded tert-butyl (4- bromophenyl)carbamate as off-white solid (15.1 g, 55.4 mmol, 100% purity, 95.5% yield).Step-2. Synthesis of methyl 4'-((tert-butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylate

[0355] Tetrakis(triphenylphosphine)palladium(0) (3.09 g, 2.68 mmol) was added to a solution of (4-(methoxycarbonyl)phenyl)boronic acid (9.64 g, 53.6 mmol), tert-butyl (4- bromophenyl)carbamate (14.6 g, 53.6 mmol), and potassium carbonate (14.7 g, 107 mmol) in dioxane (300 mL) / water (100 mL) mixture under argon atmosphere and the reaction mixture was stirred at 90 ° C for 12 hours. After it was cooled to room temperature, partitioned between ethyl acetate (300 mL) and water (500 mL) and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, filtered and concentrated under vacuum. FC of residue (hexane / ethyl acetate) afforded methyl 4'-((tert-butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylate as a white solid (11.24 g, 27.9 mmol, 100% purity, 64% yield). Step-3. Synthesis of 4'-((tert-butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylic acid

[0356] Potassiumol (9.59 g, 171 mmol) solution in water (20 mL) was added to the stirred solution of methyl 4'-((tert-butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylate (11.24 g, 34.2 mmol) in methanol (40 mL) at room temperature. Obtained mixture was stirred at 60 °C for 12 hours. After cooling to room temperature this solution was acidified by aqueous sodium bisulfate solution until pH = 5 and extracted with ethyl acetate (150 mL x 3). Combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording 4'-((tert-butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylic acid as a white solid (10.7 g, 34.1 mmol, 100% purity, 100% yield). Step-4. Synthesis of (2S,3aS,7aS)-tert-butyl 2-((2-methoxyethyl)carbamoyl)octahydro-1H-indole- 1-carboxylate

[0357] Solution of (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid (4.1 g, 15.2 mmol), 2-methoxyethanamine (1.97 mL, 22.8 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium hexafluoro-λ⁵- phosphanuide (6.92 g, 18.2 mmol) and ethylbis(propan-2-yl)amine (9.24 mL, 53.1 mmol) in DMF(50 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (2S,3aS,7aS)-tert-butyl 2-((2- methoxyethyl)carbamoyl)octahydro-1H-indole-1-carboxylate as a yellow oil (3.15 g, 9.64 mmol, 100% purity, 63.5% yield). Step-5. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide

[0358] (2S,3aS,7aS)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide (3.15 g, 13.9 mmol) was dissolved in dichloromethane (25 mL) and trifluoroacetic acid (25 mL) was added. The mixture was stirred at room temperature overnight. After completion, it was concentrated under vacuum to afford (2S,3aS,7aS)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide 2,2,2- trifluoroacetate as a viscous oil (4.6 g, 12.6 mmol, 93.86% purity, 91% yield) that was used in next step without further purification. Step-6. Synthesis of 1-(6-chloro-2-methylpyrimidin-4-yl)ethanamine

[0359] 3M methylmagnesium bromide solution in MeTHF (6.66 mL, 20 mmol) was added dropwise at -5 °C to a solution of 6-chloro-2-methylpyrimidine-4-carbonitrile (3.07 g, 20 mmol) in tetrahydrofuran (100 mL). The reaction was stirred 1 hour at 0 °C under argon atmosphere. Methanol (10 mL) was added at -5 °C and sodium borohydride (1.51 g, 40 mmol) was added to a reaction mixture. After it was stirred for 1 hour at room temperature. The organic layer was washed with ammonium chloride sat. aq. solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-(6-chloro-2-methylpyrimidin- 4-yl)ethanamine as a black oil (1.6 g, 8.53 mmol, 91.53% purity, 42.5% yield) that was used in next step without further purification.Step-7. Synthesis of tert-butyl (4'-((1-(6-chloro-2-methylpyrimidin-4-yl)ethyl)carbamoyl)-[1,1'- biphenyl]-4-yl)carbamate

[0360] Solution of 1-(6-chloro-2-methylpyrimidin-4-yl)ethanamine (1.43 g, 8.33 mmol), 4'-((tert- butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylic acid (2.87 g, 9.16 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium hexafluoro-λ⁵-phosphanuide (3.75 g, 9.99 mmol) and ethylbis(propan-2-yl)amine (5.06 mL, 29.1 mmol) in DMF (50 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording crude product. It’s flash chromatographic purification (hexane / ethyl acetate) resulted in tert-butyl (4'-((1-(6-chloro-2-methylpyrimidin-4- yl)ethyl)carbamoyl)-[1,1'-biphenyl]-4-yl)carbamate as a white solid (0.79 g, 1.66 mmol, 98.36% purity, 20% yield). Step-8. Synthesis of tert-butyl N-(4'-{[(1R)-1-{6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}ethyl]carbamoyl}-[1,1'-biphenyl]-4- yl)carbamate (Diastereomer 1) and tert-butyl N-(4'-{[(1S)-1-{6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}ethyl]carbamoyl}- [1,1'-biphenyl]-4-yl)carbamate (Diastereomer 2)

[0361] The mixture of tert-butyl (4'-((1-(6-chloro-2-methylpyrimidin-4-yl)ethyl)carbamoyl)- [1,1'-biphenyl]-4-yl)carbamate (0.79 g, 1.69 mmol), (2S,3aS,7aS)-N-(2-methoxyethyl)octahydro- 1H-indole-2-carboxamide 2,2,2-trifluoroacetate (0.687 g, 2.02 mmol) and potassium carbonate (0.559 g, 4.05 mmol) in DMF (20 mL) was heated at 80 °C for 12 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was separated, washed with water (40 mL), brine (40 mL), and concentrated under reduced pressure. HPLC of residue (deionized water / HPLC-grade acetonitrile) afforded diastereomeric mixture of tert-butyl N-{4'-[(1-{6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}ethyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.534 g, 0.813 mmol, 94% purity, 45.2% yield). Chiral resolution (hexane / isopropanol / methanol) of this mixture (0.3 g,0.457 mmol) with the use of Chirail ART YMC (250*20mm, 5mkm) column afforded 2 single diastereomers: (0.15941 g, 0.242 mmol, 100% purity, 52.9% yield) and (0.126 g, 0.192 mmol, 100% purity, 42.0% yield). Step-9. Synthesis of (2S,3aS,7aS)-1-{6-[(1R)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide, (A-62), and (2S,3aS,7aS)-1-{6-[(1S)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide, (A-63)

[0362] Trifluoroacetic acid (2 mL) was added to the stirred solution of tert-butyl N-(4'-{[(1R*)-1- {6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin- 4-yl}ethyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate (0.12621 g, 0.191 mmol) in dichloromethane (5 mL). Resulting mixture was stirred at room temperature for 12 hours and evaporated to dryness in vacuo. The residue was purified with HPLC (deionized water / HPLC- grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-{6-[(1R)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-62). Yield: 97.3 mg, 68.9%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.05 – 7.99 (m, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 6.32 (s, 1H), 5.32 (s, 2H), 4.90 – 4.81 (m, 1H), 4.43 – 3.53 (m, 2H), 3.25 – 3.02 (m, 5H), 2.29 (s, 3H), 2.27 – 2.19 (m, 1H), 2.05 – 1.95 (m, 2H), 1.95 – 1.85 (m, 1H), 1.70 – 1.56 (m, 3H), 1.54 – 1.45 (m, 1H), 1.41 (d, J = 7.3 Hz, 4H), 1.25 (q, J = 13.3 Hz, 1H), 1.14 (q, J = 13.3 Hz, 1H); HPLС purity: 98.90%; LCMS Calculated for C32H40N6O3: 556.32; Observed: 557.4 [M+H]+.

[0363] The same manipulations for second boc-protected diastereomer afforded (2S,3aS,7aS)-1- {6-[(1S)-1-({4'-amino-[1,1'-biphenyl]-4-yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide, (A-63). Yield: 68 mg, 60.9%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.32 (s, 1H), 5.32 (s, 2H), 4.85 (t, J = 7.3 Hz, 1H), 4.43 – 3.63 (m, 2H), 3.22 (s, 3H), 3.16 – 3.04 (m, 1H), 2.32 – 2.21 (m, 4H), 1.95 – 1.79 (m, 2H), 1.68 (d, J = 14.2 Hz, 1H), 1.65 – 1.53 (m, 2H), 1.50 – 1.43 (m,1H), 1.41 (d, J = 7.1 Hz, 4H), 1.24 (q, J = 13.2 Hz, 1H), 1.15 – 1.05 (m, 1H); HPLС purity: 98.33%; LCMS Calculated for C32H40N6O3: 556.32; Observed: 557.4 [M+H]+. The X-ray structure confirmed A-63 is (2S,3aS,7aS)-1-{6-[(1S)-1-({4'-amino-[1,1'-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide.

[0364] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A12. Synthesis of methyl (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-octahydro-1H-indole-2-carboxylate (A-66)Step-1. Synthesis of methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'- biphenyl]-4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate

[0365] Solution of 4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (0.171 g, 0.548 mmol), ethylbis(propan-2-yl)amine (427 µL, 2.46 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.313 g, 0.822 mmol) and {6-[(2S,3aS,7aS)-2-(methoxycarbonyl)-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}methanaminium acetate (0.2 g, 0.548 mmol) in DMF (50 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'- biphenyl]-4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate (0.9 g, 0.471 mmol, 31.4% purity, 85.9% yield) that was used in next step without further purification. Step-2. Synthesis of methyl (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-octahydro-1H-indole-2-carboxylate

[0366] Methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4- yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate (0.9 g, 0.470 mmol) was treated with 4N HCl solution in dioxane (50 mL) at room temperature for 12 hours. The solvent was removed, and the residue was dried under high vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford methyl (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4- yl}-octahydro-1H-indole-2-carboxylate, (A-66). Yield: 47.6 mg, 19.3%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 9.01 – 8.89 (m, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 6.29 (s, 1H), 5.33 (s, 2H), 4.41 – 4.21 (m, 3H), 3.72 (s, 1H), 3.60 (s, 2H), 2.26 (s, 3H), 2.15 (s, 1H), 1.94 (s, 2H), 1.69 – 1.56 (m, 3H), 1.41 (d, J = 13.3 Hz, 1H), 1.34 – 1.20 (m, 2H), 1.18 – 1.03 (m, 1H); HPLC purity: 100%; LCMS Calculated for C29H33N5O3: 499.26; Observed: 500.4 [M+H]+.Example A13. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-octahydro-1H-indole-2-carboxamide (A-67)Step-1. Synthesis of tert-butyl (2S,3aS,7aS)-2-carbamoyl-octahydro-1H-indole-1-carboxylate

[0367] Ethyl carbonochloridate (1.46 g, 13.5 mmol) was added at 0 °C to a solution of (2S,3aS,7aS)-1-[(tert-butoxy)carbonyl]-octahydro-1H-indole-2-carboxylic acid (3.2 g, 11.8 mmol) and triethylamine (1.36 g, 13.5 mmol) in dry tetrahydrofuran (40 mL). The mixture was stirred at 0 °C for 1 hour. Then ammonia (gas) was added at 0 °C for a 5 min and the mixture was stirred at room temperature for 1.5 hour, then partitioned between dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl (2S,3aS,7aS)-2- carbamoyl-octahydro-1H-indole-1-carboxylate (3 g, 11.1 mmol, 95% purity, 94.9 % yield).Step-2. Synthesis of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid

[0368] Trifluoroacetic acid (5 mL) was added to the stirred solution of tert-butyl (2S,3aS,7aS)-2- carbamoyl-octahydro-1H-indole-1-carboxylate (3 g, 11.1 mmol) in dichloromethane (10 mL). Resulting mixture was stirred at room temperature for 3 hours, and evaporated to dryness in vacuo to give (2S,3aS,7aS)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (3.1 g, 9.88 mmol, 90% purity, 89.1% yield). Step-3. Synthesis of tert-butyl N-[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate

[0369] Ethyl 4-{[(tert-butoxy)carbonyl]amino}-3-oxobutanoate (10 g, 40.7 mmol) was added to the stirred solution of ethanimidamide hydrochloride (3.92 g, 41.5 mmol) and methoxysodium (8.75 g, 162 mmol) in methanol (250 mL). Obtained mixture was stirred at room temperature for 12 hours then evaporated to dryness in vacuo, dissolved in water (200 mL), acidified with sodium bisulfate to pH=3-4 and evaporated to dryness again. The residue was washed with dry tetrahydrofuran (250 mL). Filtrate was evaporated to dryness in vacuo to afford tert-butyl N-[(6- hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate (8.39 g, 32.2 mmol, 92% purity, 79.2% yield) that was used in next step without further purification. Step-4. Synthesis of 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride

[0370] 4N HCl aqueous solution (20 mL) was added at room temperature to a solution of tert- butyl N-[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamate (8.39 g, 32.2 mmol, 92% purity) in methanol (20 mL). Resulting mixture was stirred at 40°C for 1 hour and evaporated to dryness in vacuo to give 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride (6 g, 30.7 mmol, 90% purity, 95.5% yield) that was used in next step without further purification.Step-5. Synthesis of tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4-yl)methyl]carbamoyl}- [1,1'-biphenyl]-4-yl)carbamate

[0371] Solution of 6-(aminomethyl)-2-methylpyrimidin-4-ol hydrochloride (6 g, 30.7 mmol), 4'- {[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (9.61 g, 30.7 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (13.4 g, 35.3 mmol) and ethylbis(propan-2-yl)amine (15.7 g, 122 mmol) in DMF (80 mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (450 mL), filtered, the precipitate was washed with water (80 mL) and dried. Crude product was recrystallized from methanol to afford tert-butyl N-(4'-{[(6-hydroxy-2- methylpyrimidin-4-yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate (12.2 g, 25.8 mmol, 92% purity, 84.2% yield) that was used in next step without further purification. Step-6. Synthesis of tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-carbamoyl-octahydro-1H-indol-1-yl]- 2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate

[0372] Chlorotris(pyrrolidin-1-yl)phosphanium; hexafluoro-λ⁵-phosphanuide (0.172 g, 0.409 mmol) was added at 0°C to the stirred solution of (2S,3aS,7aS)-octahydro-1H-indole-2- carboxamide (0.0459 g, 0.273 mmol), tert-butyl N-(4'-{[(6-hydroxy-2-methylpyrimidin-4- yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate (0.13 g, 0.273 mmol, 92% purity) and 2H,3H,4H,6H,7H,8H,9H,10H-pyrimido[1,2-a]azepine (0.207 g, 1.36 mmol) in tetrahydrofuran (8 mL). Obtained mixture was stirred at reflux for 24 hours and evaporated to dryness in vacuo. The residue was suspended in water (30 mL), acidified with sodium bisulfate and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl N-{4'-[({6- [(2S,3aS,7aS)-2-carbamoyl-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.198 g, 0.203 mmol), 60% purity, 74.2% yield) that was used in next step without further purification.Step-7. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-octahydro-1H-indole-2-carboxamide

[0373] Trifluoroacetic acid (3 mL) was added to the stirred solution of tert-butyl N-{4'-[({6- [(2S,3aS,7aS)-2-carbamoyl-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.198 g, 0.201 mmol, 60% purity) in dichloromethane (5 mL). Resulting mixture was stirred at room temperature for 3 hours and evaporated to dryness in vacuo. The residue was purified with HPLC (deionized water / HPLC- grade methanol, ammonia) to afford (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-octahydro-1H-indole-2-carboxamide, (A-67). Yield: 39.9 mg, 38.9%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.94 – 8.84 (m, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.37 (s, 1H), 6.90 (s, 1H), 6.66 – 6.58 (m, 2H), 6.21 (s, 1H), 5.32 (s, 2H), 4.26 (s, 3H), 2.28 (s, 3H), 2.24 (s, 1H), 2.09 (s, 1H), 2.00 – 1.82 (m, 2H), 1.67 (d, J = 14.2 Hz, 1H), 1.63 – 1.55 (m, 2H), 1.48 – 1.33 (m, 2H), 1.30 – 1.17 (m, 1H), 1.16 – 0.95 (m, 1H); HPLC purity: 100%; LCMS Calculated for C28H32N6O2: 484.26; Observed: 485.2[M+H]+. Example A14. Synthesis of (3aS,7aS)-1-(6-((4'-amino-[1,1'-biphenyl]-4- ylcarboxamido)methyl)-2-methylpyrimidin-4-yl)octahydro-1H-indole-2-carboxylic acid, (A- 68)Step-1. Synthesis of methyl (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-octahydro-1H- indole-2-carboxylate

[0374] A mixture of 6-chloro-2-methylpyrimidine-4-carbonitrile (8 g, 52.0 mmol), (2S,3aS,7aS)- 2-(methoxycarbonyl)-octahydro-1H-indol-1-ium chloride (11.4 g, 52.0 mmol) and ethylbis(propan-2-yl)amine (22.6 mL, 130 mmol) in NMP (150 mL) was stirred at 80 °C for 12 hours. Obtained mixture was cooled down to room temperature, diluted with water (350 mL) and extracted with ethyl acetate (150 mL x 3). Combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording methyl (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate (15 g, 49.9 mmol, 95% purity, 96.1% yield). Step-2. Synthesis of {6-[(2S,3aS,7aS)-2-(methoxycarbonyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}methanaminium acetate

[0375] 10% Pd / C (5 g) was added to methyl (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)- octahydro-1H-indole-2-carboxylate (15 g, 49.9 mmol) solution in ethyl acetate / acetic acid (150 mL) and the resulting mixture was hydrogenated at ambient temperature for 12 hours. The catalyst was filtered off, washed with ethyl acetate (50 mL) and the combined filtrate was evaporated under reduced pressure. The residue was subjected to flash chromatography (MTBE / MeOH) that afforded {6-[(2S,3aS,7aS)-2-(methoxycarbonyl)-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methanaminium acetate (5.4 g, 14 mmol, 95% purity, 28.3% yield). Step-3. Synthesis of methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'- biphenyl]-4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate

[0376] Solution of {6-[(2S,3aS,7aS)-2-(methoxycarbonyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}methanaminium acetate (5.25.2 g, 14.214.2 mmol), 4'-((tert- butoxycarbonyl)amino)-[1,1'-biphenyl]-4-carboxylic acid (4.44 g, 14.2 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (8.12 g, 21.3 mmol) and ethylbis(propan-2-yl)amine (11.1 mL, 63.9mmol) in DMF (150 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (150 mL x 2) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to flash chromatography (chloroform / acetonitrile) that afforded methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert- butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)- octahydro-1H-indole-2-carboxylate (5.53 g, 9.22 mmol, 95% purity, 64.9% yield). Step-4. Synthesis of (3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4- yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylic acid

[0377] Solution of methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'- biphenyl]-4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate (0.5 g, 0.833 mmol), LiOH·H2O (0.1 g, 2.49 mmol) in the mixture of tetrahydrofuran (25 mL) / water (25 mL) was stirred at room temperature for 12 hours. The solution was diluted with brine (25 mL), acidified with aq. solution NaHSO4until pH = 7 and extracted with ethyl acetate (50 mL x 3). Combined organic layers dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]- 4-yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylic acid (0.4 g, 0.635 mmol, 93.1% purity, 76.3% yield). Chiral analysis revealed the mixture of diastereomers (9 / 1) Step-5. Synthesis of (3aS,7aS)-1-(6-((4'-amino-[1,1'-biphenyl]-4-ylcarboxamido)methyl)-2- methylpyrimidin-4-yl)octahydro-1H-indole-2-carboxylic acid

[0378] (3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4- yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylic acid (0.0925 g, 0.157 mmol) was treated with 4N HCl solution in dioxane ( 5 mL,) at room temperature for 12 hours. The solvent was removed and the residue was dried under high vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile (methanol), ammonia) to afford (3aS,7aS)-1-(6-((4'-amino-[1,1'-biphenyl]-4-ylcarboxamido)methyl)-2-methylpyrimidin-4-yl)octahydro-1H-indole-2-carboxylic acid, (A-68). Yield: 34.3 mg, 42.6%; Appearance: Beige solid;1H NMR (600 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.98 – 8.87 (m, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 5.32 (s, 2H), 4.36 – 4.17 (m, 3H), 3.69 (s, 1H), 2.37 – 2.22 (m, 4H), 2.16 (s, 1H), 1.92 (s, 2H), 1.72 – 1.56 (m, 3H), 1.44 – 1.19 (m, 3H), 1.12 – 1.00 (m, 1H); HPLC purity: 100%; LCMS Calculated for C28H31N5O3: 485.24; Observed: 486.2[M+H]+. Example A15. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-methyl-octahydro-1H-indole-2- carboxamide, (A-69)Step-1. Synthesis of tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate

[0379] Methyl (2S,3aS,7aS)-1-(6-{[(4'-{[(tert-butoxy)carbonyl]amino}-[1,1'-biphenyl]-4- yl)formamido]methyl}-2-methylpyrimidin-4-yl)-octahydro-1H-indole-2-carboxylate (0.3 g, 0.5 mmol) was treated with 20% MeNH2solution in methanol ( 40 mL). Obtained solution was stirred at 65 °C for 36 hours. The solvent was removed and the residue was dried under high vacuum to give tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate as a yellow solid (0.3 g, 0.386 mmol, 77.2 % purity, 77.2% yield) that was used in next step without further purification.Step-2. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-methyl-octahydro-1H-indole-2-carboxamide

[0380] tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.3 g, 0.385 mmol) was treated with 4N HCl solution in dioxane (50 mL) at room temperature for 12 hours. The solvent was evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'- biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-methyl-octahydro-1H-indole-2- carboxamide, (A-69). Yield: 20.6 mg, 10.7%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.98 – 8.83 (m, 1H), 7.93 – 7.81 (m, 3H), 7.64 (d, J = 8.4 Hz, 2H), 7.49 – 7.39 (m, 2H), 6.69 – 6.57 (m, 2H), 6.35 – 5.71 (m, 1H), 5.33 (s, 2H), 4.36 – 3.66 (m, 4H), 2.35 – 2.18 (m, 5H), 2.05 – 1.85 (m, 3H), 1.66 (d, J = 14.0 Hz, 1H), 1.63 – 1.55 (m, 2H), 1.45 (s, 1H), 1.40 (d, J = 13.2 Hz, 1H), 1.28 – 1.19 (m, 1H), 1.16 – 1.03 (m, 1H); HPLC purity: 100%; LCMS Calculated for C29H34N6O2: 498.27; Observed: 499.4[M+H]+. Example A16. Synthesis of (2S,3aS,6aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydrocyclopenta[b] pyrrole-2-carboxamide (A-70)Step-1. Synthesis of tert-butyl (2S,3aS,6aS)-2-[(2-methoxyethyl)carbamoyl]- octahydrocyclopenta[b]pyrrole-1-carboxylate

[0381] Mixture of (2S,3aS,6aS)-1-[(tert-butoxy)carbonyl]-octahydrocyclopenta[b]pyrrole-2- carboxylic acid (0.6 g, 2.35 mmol), 2-methoxyethan-1-amine (0.18 g, 2.35 mmol), (3- {[(ethylimino)methylidene]amino}propyl)dimethylamine hydrochloride (0.67 g, 3.52 mmol), 1H- 1,2,3-benzotriazol-1-ol (0.38 g, 2.82 mmol), and ethylbis(propan-2-yl)amine (0.61 g, 4.7 mmol) in dichloromethane (20 mL) was stirred at room temperature for 16 hours. Obtained mixture was washed with citric acid sat. aq. solution (15 mL), water (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl (2S,3aS,6aS)-2-[(2- methoxyethyl)carbamoyl]-octahydrocyclopenta[b]pyrrole-1-carboxylate (0.6 g, 1.61 mmol, 84% purity, 68.8% yield) that was used in next step without further purification. Step-2. Synthesis of N-(2-methoxyethyl)-5-azaspiro[3.4]octane-6-carboxamide

[0382] Solution of tert-butyl (2S,3aS,6aS)-2-[(2-methoxyethyl)carbamoyl]- octahydrocyclopenta[b]pyrrole-1-carboxylate (0.60 g, 1.61mmol) in the mixture of trifluoroacetic acid (5 mL) / dichloromethane (5mL) was stirred at room temperature for 16 hours and evaporated to dryness in vacuo. The residue was dissolved in water (20 mL), basified with aqueous NaOH until pH = 9 and extracted with ethyl acetate (15 mL x 3). Combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording N-(2-methoxyethyl)-5-azaspiro[3.4]octane-6-carboxamide (0.38 g, 0.334 mmol, 18.7% purity, 17.4% yield) that was used in next step without further purification. Step-3. Synthesis of tert-butyl N-{4'-[({6-[(2S,3aS,6aS)-2-[(2-methoxyethyl)carbamoyl]- octahydrocyclopenta[b]pyrrol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]- 4-yl}carbamate

[0383] A mixture of (2S,3aS,6aS)-N-(2-methoxyethyl)-octahydrocyclopenta[b]pyrrole-2- carboxamide (0.3 g, 1.41 mmol), 4'-amino-N-[(6-chloro-2-methylpyrimidin-4-yl)methyl]-[1,1'- biphenyl]-4-carboxamide (0.21 g, 0.47 mmol) and ethylbis(propan-2-yl)amine (0.061 g, 0.47mmol) in 2-propanol (6 mL) was heated at 115 °C in a sealed tube for 16 hours. The solution was cooled to room temperature and diluted with water (10 mL). Formed precipitate was filtered and washed with water (5 mL x 2) affording tert-butyl N-{4'-[({6-[(2S,3aS,6aS)-2-[(2- methoxyethyl)carbamoyl]-octahydrocyclopenta[b]pyrrol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.25 g, 0.223 mmol, 56.3% purity, 47.4% yield) that was used in next step without further purification. Step-4. Synthesis of (2S,3aS,6aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydrocyclopenta[b]pyrrole-2-carboxamide

[0384] Solution of tert-butyl N-{4'-[({6-[(2S,3aS,6aS)-2-[(2-methoxyethyl)carbamoyl]- octahydrocyclopenta[b]pyrrol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]- 4-yl}carbamate (0.25 g, 0.397 mmol) in the mixture of trifluoroacetic acid (5 mL) / dichloromethane (5mL) was stirred at room temperature for 16 hours and evaporated to dryness in vacuo. The residue was dissolved in water (20 mL), basified with aqueous NaOH until pH = 9 and extracted with ethyl acetate (15 mL x 3). Combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford (2S,3aS,6aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4- yl}-N-(2-methoxyethyl)-octahydrocyclopenta[b]pyrrole-2-carboxamide, (A-70). Yield: 80 mg, 36.3%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.28 (s, 1H), 5.37 (s, 1H), 4.50 (s, 1H), 4.33 (d, J = 5.8 Hz, 2H), 4.04 (s, 1H), 3.19 (s, 3H), 3.17 – 3.09 (m, 2H), 2.69 (s, 1H), 2.39 – 2.23 (m, 4H), 1.87 (s, 1H), 1.75 – 1.59 (m, 4H), 1.49 – 1.33 (m, 2H); HPLC purity: 100%; LCMS Calculated for C30H36N6O3: 528.28; Observed: 529.2 [M+H]+.

[0385] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A17. Synthesis of (8S)-7-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide, (A-76)Step-1. Synthesis of tert-butyl (8S)-8-[(2-methoxyethyl)carbamoyl]-1,4-dioxa-7- azaspiro[4.4]nonane-7-carboxylate

[0386] Solution of (8S)-7-[(tert-butoxy)carbonyl]-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid (0.5 g, 1.82 mmol), 2-methoxyethan-1-amine (0.177 g, 2.36 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.794 g, 2.09 mmol) and ethylbis(propan-2-yl)amine (0.704 g, 5.45 mmol) in DMF(10 mL) was stirred at room temperature for 14 hours. Resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (15 mL x 3) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl (8S)-8-[(2-methoxyethyl)carbamoyl]-1,4-dioxa-7- azaspiro[4.4]nonane-7-carboxylate (0.36 g, 0.980 mmol, 90% purity, 46.8% yield) that was used in next step without further purification. Step-2. Synthesis of (8S)-N-(2-methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide

[0387] A solution of trimethylsilyl trifluoromethanesulfonate (0.237 g, 1.07 mmol) in dichloromethane (3 mL) was added dropwise to a stirred solution of tert-butyl (8S)-8-[(2- methoxyethyl)carbamoyl]-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate (0.36 g, 0.980 mmol, 90% purity) in dichloromethane (20 mL) at 5 °C. The reaction mixture was stirred at 5 °C for 3 hours and then poured into sodium bicarbonate sat. aq. solution (20 mL). Organic layer was separated and washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording (8S)-N-(2-methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8- carboxamide (0.25 g, 0.759 mmol, 70% purity, 77.7% yield) that was used in next step without further purification. Step-3. Synthesis of tert-butyl N-{4'-[({6-[(8S)-8-[(2-methoxyethyl)carbamoyl]-1,4-dioxa-7- azaspiro[4.4]nonan-7-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4- yl}carbamate

[0388] Mixture of (8S)-N-(2-methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide (0.25 g, 0.759 mmol, 70% purity), tert-butyl N-(4'-{[(6-chloro-2-methylpyrimidin-4- yl)methyl]carbamoyl}-[1,1'-biphenyl]-4-yl)carbamate (0.343 g, 0.759 mmol), and ethylbis(propan-2-yl)amine (0.195 g, 1.51 mmol) in acetonitrile (10 mL) was stirred under argon atmosphere at 80 °C for 72 hours. Obtained mixture was cooled down to room temperature evaporated to dryness in vacuo then diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3), Combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording tert-butyl N-{4'-[({6-[(8S)-8-[(2-methoxyethyl)carbamoyl]-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.158 g, 0.244 mmol, 66% purity, 32.3% yield) that was used in next step without further purification. Step-4. Synthesis of (8S)-7-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide

[0389] A solution of trimethylsilyl trifluoromethanesulfonate (0.0595 g, 0.268 mmol) in dichloromethane (3 mL) was added dropwise to a stirred solution of tert-butyl N-{4'-[({6-[(8S)-8- [(2-methoxyethyl)carbamoyl]-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.24 g, 244 µmol, 66% purity) in dichloromethane (20 mL) at 5 °C. The reaction mixture was stirred at 5 °C for 5 hours and then poured into sodium bicarbonate sat. aq. solution (20 mL). Organic layer was separated and washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (8S)-7-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-(2- methoxyethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxamide (A-76). Yield: 33 mg, 23.6%; Appearance: Yellow oil;1H NMR (600 MHz, DMSO-d6) δ 8.98 – 8.83 (m, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.49 – 7.38 (m, 2H), 6.70 – 6.60 (m, 2H), 6.30 – 5.88 (m, 1H), 5.33 (s, 2H), 4.50 (s, 1H), 4.31 (s, 2H), 3.97 – 3.80 (m, 4H), 3.47 (d, J = 10.7 Hz, 1H), 3.24 – 2.82 (m, 7H), 2.33 (s, 4H), 2.04 (dd, J = 12.9, 7.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C29H34N6O5: 546.26; Observed: 547.4 [M+H]+.Examle A18. Synthesis of 4'-amino-N-({6-[cyclohexyl({[(2- methoxyethyl)carbamoyl]methyl})amino]-2-methylpyrimidin-4-yl}methyl)-[1,1'-biphenyl]-4- carboxamide, (A-77)Step-1. Synthesis of 2-(cyclohexylamino)-N-(2-methoxyethyl)acetamide

[0390] Cyclohexanone (0.29 g, 2.96 mmol) was added to a mixture of 2-amino-N-(2- methoxyethyl)acetamide hydrochloride (0.5 g, 2.96 mmol) and ethylbis(propan-2-yl)amine (0.4 mg, 3.10 mmol) in dichloromethane (35 mL) and a mixture was stirred at room temperature for 1 hour. After that, acetic acid (0.444 g, 7.40 mmol) and sodium cyanoboranuide (0.334 g, 5.32 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. After it was poured into sat. aq. sodium bicarbonate solution (50 mL), aqueous layer was extracted with ethyl acetate (50 mL x3). Combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(cyclohexylamino)-N-(2-methoxyethyl)acetamide (0.45 g, 1.46 mmol, 70% purity, 49.6% yield) that was used in the next step without further purification.Step-2. Synthesis of tert-butyl N-{4'-[({6-[cyclohexyl({[(2- methoxyethyl)carbamoyl]methyl})amino]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'- biphenyl]-4-yl}carbamate

[0391] 2-(cyclohexylamino)-N-(2-methoxyethyl)acetamide (0.15 g, 0.489 mmol, 70% purity) , tert-butyl N-{4'-[({2-methyl-6-[(4-methylbenzenesulfonyl)oxy]pyrimidin-4- yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.172 g, 0.293 mmol) and ethylbis(propan-2-yl)amine (0.188 g, 1.46 mmol) were mixed in iPrOH (6 mL) and stirred in the sealed tube at 110 °C for 16 hours. After completion of reaction (monitored by LCMS), the solvent was evaporated under reduced pressure to give tert-butyl N-{4'-[({6-[cyclohexyl({[(2- methoxyethyl)carbamoyl]methyl})amino]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'- biphenyl]-4-yl}carbamate (0.3 g, 0.29 mmol, 61% purity, 59.4% yield) that was used in the next step without further purification. Step-3. Synthesis of 4'-amino-N-({6-[cyclohexyl({[(2-methoxyethyl)carbamoyl]methyl})amino]-2- methylpyrimidin-4-yl}methyl)-[1,1'-biphenyl]-4-carboxamide

[0392] Tert-butyl N-{4'-[({6-[cyclohexyl({[(2-methoxyethyl)carbamoyl]methyl})amino]-2- methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.3 g, 0.290 mmol, 61% purity) was dissolved in 4N HCl in dioxane (8 mL) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was subjected to HPLC purification (deionized water / HPLC grade methanol, ammonia) to give 4'-amino-N-({6- [cyclohexyl({[(2-methoxyethyl)carbamoyl]methyl})amino]-2-methylpyrimidin-4-yl}methyl)- [1,1'-biphenyl]-4-carboxamide, (A-77). Yield: 59.3 mg, 36.7%; Appearance: Brown solid;1H NMR (600 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.48 – 7.37 (m, 2H), 6.70 – 6.59 (m, 2H), 5.32 (s, 2H), 4.30 (d, J = 5.8 Hz, 2H), 4.07 – 3.78 (m, 2H), 3.22 (s, 2H), 3.15 (s, 3H), 3.13 (s, 2H), 2.33 (s, 3H), 1.69 (t, J = 15.6 Hz, 4H), 1.54 (d, J = 12.7 Hz, 1H), 1.33 (q, J = 12.0 Hz, 2H), 1.27 – 1.15 (m, 2H), 1.06 (q, J = 13.2 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C30H38N6O3: 530.3; Observed: 531.4[M+H]+.

[0393] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A19. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-80)Step-1. Synthesis of (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide

[0394] Solution of 6-chloro-2-methylpyrimidine-4-carbonitrile (0.1 g, 0.651 mmol), (2S,3aS,7aS)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (0.332 g, 0.976 mmol), N,N-dimethylpyridin-4-amine (0.00795 g, 0.0651 mmol) and ethylbis(propan-2-yl)amine (0.252 g, 1.95 mmol) in DMF (10 mL) was stirred at 70 °C for 18 hours. Resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (15 mL x 3) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (2S,3aS,7aS)-1-(6- cyano-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.24 g, 0.642 mmol, 92% purity, 98.6% yield) that was used in next step without further purification.Step-2. Synthesis of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0395] Sodium boranuide (0.241 g, 6.39 mmol) was added portionwise at 0 °C to the mixture of (2S,3aS,7aS)-1-(6-cyano-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (0.24 g, 0.642 mmol) and dichlorocobalt hexahydrate (0.302 g, 1.27 mmol) in the mixture of tetrahydrofuran (15 mL) / methanol (15 mL). The resulting mixture was stirred at 0 °C for 1 hour and after that was allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (30 mL), acidified with 2N HCl aq. solution until pH = 2, then treated with NaOH sat. aq. solution until pH=10 and extracted with ethyl acetate (15 mL x 3). Combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide (0.3 g, 0.440 mmol, 51% purity, 68.9% yield) that was used in the next step without further purification. Step-3. Synthesis of tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4- yl}carbamate

[0396] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.3 g, 0.440 mmol, 51% purity), 4'-{[(tert- butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (0.137 g, 0.440 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.192 g, 0.505 mmol) and ethylbis(propan-2-yl)amine (0.140 mg, 1.09 mmol) in DMF (15 mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (70 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (20 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.2 g, 0.0902 mmol, 29% purity, 20.5% yield) that was used in next step without further purification. Step-4. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0397] Trifluoroacetic acid (10 mL, 90.0 µmol) was added to the stirred solution of tert-butyl N- {4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.2 g, 0.0902 mmol, 29% purity) in dichloromethane (10 mL). Resulting mixture was stirred at room temperature for 16 hours, and evaporated to dryness in vacuo. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'- biphenyl]-4-yl}formamido)methyl]-2-methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro- 1H-indole-2-carboxamide (A-80). Yield: 19.7 mg, 38.3%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.97 – 8.83 (m, 1H), 8.01 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.33 – 5.85 (m, 1H), 5.32 (s, 2H), 4.26 (d, J = 5.8 Hz, 3H), 3.18 (s, 3H), 3.13 – 3.07 (m, 1H), 2.28 (s, 3H), 2.24 (s, 1H), 2.10 – 1.85 (m, 3H), 1.69 – 1.55 (m, 3H), 1.42 (dd, J = 32.6, 13.3 Hz, 2H), 1.28 – 1.18 (m, 1H), 1.15 – 1.05 (m, 1H); HPLC purity: 100%; LCMS Calculated for C31H38N6O3: 542.3; Observed: 543.2 [M+H]+.

[0398] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A20. Synthesis of (2S,3aS,7aS)-l-[6-({[4-(6-aminopyridin-3- yl)phenyl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-lH- indole-2-carboxamide, (A-90)Step-1. Synthesis of methyl 4-(6-aminopyridin-3-yl)benzoate

[0399] Dichloro[1,11-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.189 g, 0.231 mmol) was added to a solution of 5-bromopyridin-2-amine (2.0 g, 11.56 mmol), 4-vethoxycarbonylphenylboronic acid (2.5 g, 13.87 mmol) and sodium hydrocarbonate (2.91 g, 34.68 mmol) in dioxane (10 mL) / water (10 mL) mixture under argon atmosphere and the reaction mixture was stirred at 80 °C for 4 hours. After it was cooled to room temperature, diluted with water (40 mL), resulting precipitate was filtered and air dried to give methyl 4-(6-aminopyridin- 3-yl)benzoate as light brown solid (2.4 g, 9.13 mmol, 86.9% purity, 79.3% yield) that was used in next step without further purification. Step-2. Synthesis of 4-(6-aminopyridin-3-yl)benzoic acid

[0400] Suspension of methyl 4-(6-aminopyridin-3-yl)benzoate (0.7 g, 3.06 mmol) and sodium hydroxide (0.73 g, 18.3 mmol) in the mixture of methanol (10 mL) / water (10 mL) was stirred at 60 ° for 16 hours. Then solution was cooled to room temperature, acidified with acetic acid (2 mL), resulting precipitate was filtered and air dried affording 4-(6-aminopyridin-3-yl)benzoic acid (0.6 g , 2.38 mmol, 85% purity, 90% yield). Crude product was used in the next step without further purification. Step-3. Synthesis of (2S,3aS,7aS)-1-[6-({[4-(6-aminopyridin-3-yl)phenyl]formamido}methyl)-2- methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0401] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide trifluoroacetate (0.15 g, 0.325 mmol), 4-(6- aminopyridin-3-yl)benzoic acid (0.835 g, 0.39 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.185 g, 0.487 mmol) and ethylbis(propan-2-yl)amine (0.57 mL, 3.25 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. Resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (15 mL x 3) and brine (15 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. Theresidue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-[6-({[4-(6-aminopyridin-3-yl)phenyl]formamido}methyl)-2-methylpyrimidin-4- yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide, (A-90). Yield: 25 mg, 13.4%; Appearance: Light-yellow solid;1H NMR (400 MHz, DMSO-d6) δ 9.00 – 8.86 (m, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.78 (dd, J = 8.6, 2.6 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.6 Hz, 1H), 6.17 (s, 2H), 4.28 (d, J = 5.9 Hz, 2H), 3.28 – 3.02 (m, 6H), 2.36 – 2.20 (m, 5H), 2.12 – 1.99 (m, 1H), 1.99 – 1.84 (m, 2H), 1.72 – 1.56 (m, 3H), 1.52 – 1.36 (m, 2H), 1.33 – 1.00 (m, 2H). HPLC purity: 96.02%; LCMS Calculated for C30H37N7O3: 543.3; Observed: 544.2[M+H]+.

[0402] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A21. Synthesis of N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro- 1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)-2-aminoquinoline-6-carboxamide, (A-97)Step-1. Synthesis of methyl 2-aminoquinoline-6-carboxylate

[0403] 6-bromoquinolin-2-amine (10 g, 44.8 mmol), triethylamine (12.4 mL, 89.6 mmol) and Pd(dppf)Cl2(1.09 g, 1.34 mmol) were dissolved in dry methanol (0.35 L). The reaction mixturewas heated at 125 °C in high pressure vessel at 20 atm CO pressure for 16 hours. The solvent was evaporated and the mixture was poured into water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2), combined organics were dried over sodium sulfate, filtered and evaporated to dryness to give methyl 2-aminoquinoline-6-carboxylate (7.79 g, 38.5 mmol, 92% purity, 86% yield) as a pink solid. Step-2. Synthesis of sodium 2-aminoquinoline-6-carboxylate

[0404] Methyl 2-aminoquinoline-6-carboxylate (1 g, 4.94 mmol) and sodium hydroxide (0.395 g, 9.88 mmol) in methanol / water mixture (1 / 1, 100 mL) was refluxed for 4 hours, evaporated under reduced pressure affording sodium 2-aminoquinoline-6-carboxylate (1.00 g, 4.79 mmol, 97% purity, 97% yield). Step-3. Synthesis of N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1- yl]-2-methylpyrimidin-4-yl}methyl)-2-aminoquinoline-6-carboxamide

[0405] Solution of sodium 2-aminoquinoline-6-carboxylate (0.0541 g, 0.216 mmol), (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide; trifluoroacetic acid (0.1 g, 0.216 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.0942 g, 0.248 mmol) and ethylbis(propan-2-yl)amine (93.9 µL, 0.540 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. Resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over sodium sulfate, filtered, and evaporated under reduced. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford pressure affording N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)-2-aminoquinoline-6-carboxamide (A- 97). Yield: 28.1 mg, 23.9%; Appearance: Yellow solid;1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.6, 2.1 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 5.13 (s, 2H), 4.65 – 4.51 (m, 2H), 4.51 – 4.38 (m, 1H), 3.95 (s, 1H), 3.45 (s, 4H), 3.31 (s, 3H), 2.53 (s, 3H), 2.42 – 2.26 (m, 2H),2.05 (d, J = 13.6 Hz, 2H), 1.87 – 1.64 (m, 3H), 1.60 – 1.48 (m, 2H), 1.48 – 1.33 (m, 1H), 1.33 – 1.22 (m, 1H); HPLC purity: 100%; LCMS Calculated for C28H35N7O3: 517.28; Observed: 518.2 [M+H]+. Example A22. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(piperazin-1- yl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide (A-98)Step-1. Synthesis of tert-butyl 4-[4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate

[0406] A reaction flask was charged with methyl 4-bromobenzoate (1 g, 4.65 mmol), tert-butyl piperazine-1-carboxylate (1.29 g, 6.97 mmol), Pd2(dba)3 (0.425 g, 0.465 mmol), XantPhos (0.269 g, 0.465 mmol), and cesium carbonate (4.52 g, 13.9 mmol). The mixture was stirred at room temperature for 10 min under argon atmosphere, then toluene (25 mL) was added sequentially. The reaction mixture was heated at 100 °C overnight. After it was allowed to cool to room temperature, diluted with water (25 mL) and the product was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 4- [4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (2.4 g, 3.18 mmol, 42.5% purity, 68.9% yield) that was used in next field without further purification.Step-2. Synthesis of 4-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}benzoic acid

[0407] Potassium hydroxide (0.892 g, 15.9 mmol) solution in water (10 mL) was added to the stirred solution of tert-butyl 4-[4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (2.4 g, 3.18 mmol, 42.5% purity) in methanol (20 mL) at room temperature. Obtained mixture was stirred at 60 °C for 12 hours. After cooling to room temperature this solution was acidified by aqueous citric acid solution. The precipitate was filtered off, washed with water (2x10 mL) to obtain 4-{4-[(tert- butoxy)carbonyl]piperazin-1-yl}benzoic acid (0.9 g, 2.93 mmol, 100% purity, 92.4% yield). Step-3. Synthesis of tert-butyl 4-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}piperazine-1- carboxylate

[0408] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide trifluoroacetate (0.486 g, 0.433 mmol, 41.1% purity), 4-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}benzoic acid (0.265 g, 0.866 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium hexafluoro-λ⁵-phosphanuide (0.329 g, 0.866 mmol) and ethylbis(propan-2-yl)amine (0.676 mL, 3.89 mmol) in DMF (15 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 2) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford tert-butyl 4-{4-[({6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]phenyl}piperazine-1-carboxylate (0.68 g, 0.3711 mmol, 34.7% purity, 85.4% yield) that was used in next field without further purification. Step-4. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(piperazin-1- yl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide

[0409] Tert-butyl 4-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol- 1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}piperazine-1-carboxylate (0.68 g,0.3711 mmol, 34.7% purity) was dissolved in dichloromethane (10 mL) and TFA (5 mL) was added. The mixture was stirred at room temperature overnight. After completion, it was concentrated under vacuum. The residue was subjected to HPLC purification (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6- ({[4-(piperazin-1-yl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2- carboxamide, (A-98). Yield: 45.7 mg, 22%; Appearance: Light-brown solid;1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.72 – 8.57 (m, 1H), 8.08 – 7.97 (m, 1H), 7.83 – 7.71 (m, 2H), 7.03 – 6.88 (m, 2H), 6.11 (s, 1H), 4.23 (d, J = 5.8 Hz, 3H), 3.21 (s, 3H), 3.19 – 3.06 (m, 6H), 2.86 – 2.74 (m, 4H), 2.35 – 2.22 (m, 4H), 2.11 – 1.99 (m, 2H), 1.97 – 1.83 (m, 2H), 1.73 – 1.54 (m, 3H), 1.51 – 1.36 (m, 2H), 1.33 – 1.18 (m, 1H), 1.18 – 1.01 (m, 1H); HPLC purity: 95.26%; LCMS Calculated for C29H41N7O3: 535.33; Observed: 536.2[M+H]+. Example A23. Synthesis of (2S,3aS,7aS)-1-[6-({[4-(4-aminophenyl)cyclohex-1-en-1- yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-99)Step-1. Synthesis of tert-butyl N-[4-(4-oxocyclohexyl)phenyl]carbamate

[0410] 4-(4-aminophenyl)cyclohexan-1-one (4 g, 21.1 mmol) and di-tert-butyl dicarbonate (5.52 g, 25.3 mmol) were dissolved in toluene (100 mL) and heated at 70 °C for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (1000 mL) and washed successively with 0.1 M HCl (400 mL) and brine (500 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure that afforded tert-butyl N- [4-(4-oxocyclohexyl)phenyl]carbamate as white solid (4.55 g, 15.7 mmol, 100% purity, 74.5 % yield). Step-2. Synthesis of tert-butyl N-{4-[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1- yl]phenyl}carbamate

[0411] Tert-butyl N-[4-(4-oxocyclohexyl)phenyl]carbamate (5 g, 17.2 mmol) was dissolved in dry THF (250 mL), the solution was cooled to -78 °C and lithiobis(trimethylsilyl)amine (34.4 mL, 34.4 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at -78 °C and a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (7.35 g, 20.6 mmol) in THF (50 mL) was added dropwise to it. The reaction mixture was stirred at -78 °C for 2 hours and allowed to warm up to room temperature and stir overnight. After the reaction mixture was concentrated in vacuo and the residue was dissolved in MTBE (500 mL). This solution was washed with water (250 mL x 2), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography purification (hexane / MTBE) that afforded tert-butyl N-{4-[4- (trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]phenyl}carbamate as white solid (1.75 g, 4.15 mmol, 100% purity, 24.1 % yield). Step-3. Synthesis of methyl 4-(4-{[(tert-butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1- carboxylate

[0412] 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II), complex with dichloromethane (0.110 g, 0.135 mmol) was added to a solution of tert-butyl N-{4-[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]phenyl}carbamate (1.9 g, 4.50 mmol) and triethylamine (735 µL, 5.40 mmol) in methanol (50 mL). The mixture was heated at 70°C under an atmosphere of CO (20 atm) for 16 hours. After it was cooled to room temperature, partitioned between ethyl acetate (200 mL) and water (500 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum affording methyl 4-(4-{[(tert- butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1-carboxylate (1.5 g, 4.29 mmol, 95% purity, 95.3 % yield). Step-4. Synthesis of 4-(4-{[(tert-butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1-carboxylic acid

[0413] Solution of methyl 4-(4-{[(tert-butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1- carboxylate (1.5 g, 4.52 mmol) and lithiumol hydrate (0.566 g, 13.5 mmol) in the mixture of THF (100 mL) / water (50 mL) was stirred at room temperature for 18 hours. The residue was dissolved in water (200 mL), acidified with aqueous sodium bisulfate until pH = 4 and extracted with ethyl acetate (100 mL x 3). Combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford 4-(4-{[(tert- butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1-carboxylic acid (1.1 g, 2.59 mmol, 75% purity, 57.6 % yield). The resulting semisolid was carried forward without further purification. Step-5. Synthesis of tert-butyl N-(4-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]cyclohex-3-en-1- yl}phenyl)carbamate

[0414] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (0.4 g, 0.372 mmol), 4- (4-{[(tert-butoxy)carbonyl]amino}phenyl)cyclohex-1-ene-1-carboxylic acid (0.469 g, 1.11 mmol), hexafluoro-λ⁵-phosphanuide 1-[(dimethylamino)(dimethyliminiumyl)methyl]-1H- [1,2,3]triazolo[4,5-b]pyridin-3-ium-3-olate (0.422 g, 1.11 mmol) and ethylbis(propan-2-yl)amine (0.239 g, 1.85 mmol) in DMF (50 mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). Thecombined organic layers were washed with water (100 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford tert-butyl N-(4-{4-[({6-[(2S,3aS,7aS)- 2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]cyclohex-3-en-1-yl}phenyl)carbamate (0.0961, 0.133 mmol, 90% purity, 36.0 % yield). Step-6. Synthesis of (2S,3aS,7aS)-1-[6-({[4-(4-aminophenyl)cyclohex-1-en-1- yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide

[0415] Tert-butyl N-(4-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]cyclohex-3-en-1-yl}phenyl)carbamate (0.0961 g, 0.133 mmol) was added to trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile ammonia) to afford (2S,3aS,7aS)-1-[6-({[4-(4-aminophenyl)cyclohex-1-en-1-yl]formamido}methyl)-2- methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide, (A-99). Yield: 53.2mg, 69.4%; Appearance: White solid;1H NMR (600 MHz, DMSO-d6) δ 8.20 (s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.61 (s, 1H), 6.49 (d, J = 8.0 Hz, 2H), 6.10 (s, 1H), 4.82 (s, 2H), 4.25 (s, 1H), 4.09 (d, J = 5.8 Hz, 2H), 3.35 – 3.32 (m, 2H), 3.23 (s, 3H), 3.11 (s, 1H), 2.59 – 2.52 (m, 1H), 2.42 – 2.30 (m, 2H), 2.27 (s, 4H), 2.17 – 2.10 (m, 1H), 2.04 (s, 1H), 1.97 – 1.87 (m, 2H), 1.84 (d, J = 12.9 Hz, 1H), 1.72 – 1.54 (m, 4H), 1.52 – 1.38 (m, 2H), 1.25 (q, J = 13.6 Hz, 1H), 1.14 (q, J = 13.4 Hz, 1H); HPLC purity: 99.01%; LCMS Calculated for C31H42N6O3: 546.33; Observed: 547.4[M+H]+.Example A24. Synthesis of (2S,3aS,7aS)-1-[6-({[5-(4-hydroxybutyl)pyridin-2- yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide, (A-100)Step-1. Synthesis of methyl 5-(4-hydroxybut-1-yn-1-yl)pyridine-2-carboxylate

[0416] A 500- mL round-bottom flask with methyl 5-bromopyridine-2-carboxylate (10 g, 46.2 mmol) was purged with nitrogen gas three times, treated with (Ph3P)Pd (0.1 g, 0.0865 mmol) and Cul (0.1 g, 0.525 mmol), and then purged again with nitrogen gas three times. The mixture was treated with anhydrous tetrahydrofuran (200 mL), triethylamine (6.43 mL, 46.2 mmol), and but- 3-yn-1-ol (3.23 g, 46.2 mmol). The resulting solution was heated to 60 °C and stirred at this temperature for 12 hours. Then the reaction mixture was cooled to 24 °C, and a small amount of charcoal was added. The mixture was filtered by gravity through filter paper, and the remaining residue was rinsed with ethyl acetate (100 mL). The combined filtrate was partially concentrated in vacuo and purified directly by flash chromatography (ethyl acetate / hexane) on silica gel to afford methyl 5-(4-hydroxybut-1-yn-1-yl)pyridine-2-carboxylate as a brown oil (7 g, 31.8 mmol, 93.4% purity, 68.8% yield).Step-2. Synthesis of methyl 5-(4-hydroxybutyl)pyridine-2-carboxylate

[0417] Methyl 5-(4-hydroxybut-1-yn-1-yl)pyridine-2-carboxylate (7 g, 31.8 mmol) was dissolved in methanol (100 mL) and treated with 5% Pd / C (0.7 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control). The catalyst was filtered off and the filtrate was evaporated to afford methyl 5-(4- hydroxybutyl)pyridine-2-carboxylate (7 g, 31.7 mmol, 95% purity, 100% yield). Step-3. Synthesis of methyl 5-(4-hydroxybutyl)pyridine-2-carboxylate

[0418] Methyl 5-[(1E)-4-hydroxybut-1-en-1-yl]pyridine-2-carboxylate (7 g, 32.0 mmol) was dissolved in methanol (100 mL) and treated with 5% Pd / C (0.7 g). The resulting mixture was hydrogenated in an autoclave at 15 atmospheres pressure and room temperature until the reaction was completed (LCMS control). The catalyst was filtered off and the filtrate was evaporated to afford methyl 5-(4-hydroxybutyl)pyridine-2-carboxylate (7 g, 28.4 mmol, 85% purity, 88.9% yield) that was used in next step without further purification. Step-4. Synthesis of 5-(4-hydroxybutyl)pyridine-2-carboxylic acid

[0419] A solution of sodium hydroxide (0.381 g, 9.54 mmol) in water (10 mL) was added to solution methyl 5-(4-hydroxybutyl)pyridine-2-carboxylate (1 g, 4.77 mmol) in methanol (50 mL). The solution was stirred for 12 hours at room temperature, acidified with diluted citric acid aq. solution to pH=4 and the product was exctracted with ethyl acetate (50 mL x 2). Combined organic layer was washed with citric acid aq. sat. solution (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 5-(4-hydroxybutyl)pyridine-2-carboxylic acid as blue oil (0.9 g, 4.14 mmol, 90% purity, 87.0% yield).Step-5. Synthesis of (2S,3aS,7aS)-1-[6-({[5-(4-hydroxybutyl)pyridin-2-yl]formamido}methyl)-2- methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0420] 5-(4-hydroxybutyl)pyridine-2-carboxylic acid (0.16 g, 0.737 mmol, 90% purity) was dissolved in DMF (10 mL) and the mixture was cooled to 0 °C. Hexafluoro-λ⁵-phosphanuide 1- [(dimethylamino)(dimethyliminiumyl)methyl]-1H-[1,2,3]triazolo[4,5-b]pyridin-3-ium-3-olate (0.336 g, 0.884 mmol), ethylbis(propan-2-yl)amine (0.319 mL, 1.84 mmol) and {6-[(2S,3aS,7aS)- 2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methanaminium trifluoroacetate (0.34 g, 0.737 mmol) were subsequently added while keeping the temperature at 0 °C, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with citric acid aq. sat. solution (20 mL), sodium hydrogen carbonate sat. aq. solution (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl N-[5-(4-{[1-(6- chloro-2-methylpyrimidin-4-yl)ethyl]carbamoyl}phenyl)pyrazin-2-yl]carbamate as black solid. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-[6-({[5-(4-hydroxybutyl)pyridin-2-yl]formamido}methyl)-2- methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide, (A-100). Yield: 33.1 mg, 8.13%; Appearance: Brown oil;1H NMR (600 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.82 (dd, J = 8.0, 2.2 Hz, 1H), 6.22 (s, 1H), 4.38 (s, 1H), 4.30 (d, J = 6.0 Hz, 3H), 3.66 (s, 1H), 3.40 (t, J = 6.5 Hz, 3H), 3.20 (s, 3H), 3.12 – 3.03 (m, 1H), 2.68 (t, J = 7.7 Hz, 2H), 2.29 (s, 3H), 2.24 (s, 1H), 2.02 (s, 1H), 1.97 – 1.83 (m, 2H), 1.71 – 1.55 (m, 5H), 1.49 – 1.34 (m, 4H), 1.23 (q, J = 10.4, 7.6 Hz, 1H), 1.08 (s, 1H); HPLC purity: 95.44%; LCMS Calculated for C28H40N6O4: 524.3; Observed: 525.2[M+H]+.Example A25. Synthesis of {4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro- 1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}boronic acid (A-101)Step-1. Synthesis of methyl 4'-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4- carboxylate

[0421] Dichloro[1,11-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.565 g, 0.693 mmol) was added to a solution of methyl 4'-(trifluoromethanesulfonyloxy)-[1,1'- biphenyl]-4-carboxylate (2.5 g, 6.93 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.11 g, 8.31 mmol) and potassium acetate (2.03 g, 20.7 mmol) in dioxane (200 mL) under argon atmosphere and the reaction mixture was stirred at 100 ° C for 12 hours. After it was cooled to room temperature, partitioned between ethyl acetate (200 mL) and water (250 mL) and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford methyl 4'-(4,4,5-trimethyl-1,3,2-dioxaborolan- 2-yl)-[1,1'-biphenyl]-4-carboxylate (2.3 g, 6.16 mmol, 95% purity, 88.8% yield). Step-2. Synthesis of [4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl]boronic acid

[0422] Sodium periodate (0.00189 g, 8.85 mmol) was added to a solution of methyl 4'-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-carboxylate (1 g, 2.95 mmol) in THF (40mL) and water (15 mL) and the mixture was stirred at room temperature for 6 hours. HCl (1.2 mL of 2 M) was added and the mixture was stirred for a further 6 hours. Resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording [4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl]boronic acid (0.71 g, 2.66 mmol, 95% purity, 90.4% yield). Step-3. Synthesis of 4'-(dihydroxyboranyl)-[1,1'-biphenyl]-4-carboxylic acid

[0423] Solution of [4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl]boronic acid (0.71 g, 2.77 mmol) and LiOH*H2O (0.348 g, 8.3 mmol) in the mixture of tetrahydrofuran (25 mL) / water (25 mL) was stirred at room temperature for 12 hours. Resulting mixture was acidified with saturated aqueous NaHSO4solution (pH=4-5), diluted with brine (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording 4'- (dihydroxyboranyl)-[1,1'-biphenyl]-4-carboxylic acid (0.55 g, 1.32 mmol, 95% purity, 47.7% yield). Step-4. Synthesis of {4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol- 1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}boronic acid

[0424] Solution of 4'-(dihydroxyboranyl)-[1,1'-biphenyl]-4-carboxylic acid (0.114 g, 470 µmol) , (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide dihydrochloride (0.2 g, 475 µmol) , [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.271 g, 0.712 mmol) and ethylbis(propan-2-yl)amine (0.506 mL, 2.85 mmol) in DMF (50 mL) was stirred for 12 hours. Resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford {4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}boronic acid (A-101). Yield: 8.7 mg, 3.08%; Appearance: White solid;1H NMR (600 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.20 (s, 2H), 8.01 (s, 1H), 7.99 – 7.94 (m, 2H), 7.93 – 7.85 (m, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.74 – 7.64 (m, 2H), 6.22 (s, 1H), 4.38 – 4.05 (m, 3H), 3.22 – 3.07 (m, 5H), 2.34 – 2.18 (m, 4H), 2.03 (s, 1H), 1.89 (q, J = 12.1 Hz, 2H), 1.67 (d, J = 13.9 Hz, 1H), 1.64 – 1.55 (m, 2H), 1.52 – 1.43 (m, 1H), 1.40 (d, J = 12.9 Hz, 1H), 1.29 – 1.18 (m, 1H), 1.16 – 1.00 (m, 1H); HPLC purity: 97.29%; LCMS Calculated for C31H38BN5O5: 571.3; Observed: 572.4[M+H]+Example A26. Synthesis of (2S,3aS,7aS)-1-[6-({[4'-(hydroxymethyl)-[1,1'-biphenyl]-4- yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (A-102)Step-1. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-formyl-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0425] Solution of {6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]- 2-methylpyrimidin-4-yl}methanaminium trifluoroacetate (0.35 g, 0.325 mmol), 4'-formyl-[1,1'-biphenyl]-4-carboxylic acid (0.0735 g, 0.325 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.185 g, 0.487 mmol) and ethylbis(propan-2-yl)amine (0.339 mL, 195 mmol) in DMF (30 mL) was stirred at room temperature for 12 hours. Resulting mixture was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording (2S,3aS,7aS)-1-{6-[({4'-formyl-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.2 g, 0.241 mmol, 67.2% purity, 74.4% yield) that was used in next step without further purification. Step-2. Synthesis of (2S,3aS,7aS)-1-[6-({[4'-(hydroxymethyl)-[1,1'-biphenyl]-4- yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide

[0426] Solution of (2S,3aS,7aS)-1-{6-[({4'-formyl-[1,1'-biphenyl]-4-yl}formamido)methyl]-2- methylpyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.2 g, 241 µmol) and sodium boranuide (3.64 mg, 96.4 µmol) in methanol (10 mL) was stirred at room temperature for 1 hour and evaporated to dryness in vacuo. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford (2S,3aS,7aS)-1-[6-({[4'-(hydroxymethyl)- [1,1'-biphenyl]-4-yl]formamido}methyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide, (A-102). Yield: 30 mg, 21.2%; Appearance: White solid;1H NMR (600 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.02 (s, 1H), 8.00 – 7.95 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 6.40 – 5.76 (m, 1H), 5.23 (t, J = 5.7 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.27 (d, J = 5.8 Hz, 3H), 3.22 – 3.05 (m, 4H), 2.32 – 2.22 (m, 4H), 2.03 (s, 1H), 1.97 – 1.83 (m, 2H), 1.67 (d, J = 14.2 Hz, 1H), 1.63 – 1.55 (m, 2H), 1.51 – 1.42 (m, 1H), 1.40 (d, J = 13.8 Hz, 1H), 1.29 – 1.18 (m, 1H), 1.17 – 1.03 (m, 1H); HPLC purity: 97.32%; LCMS Calculated for C32H39N5O4: 557.3; Observed: 558.0[M+H]+.Example A27. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-(2-methyl-6-{[(4- phenylpiperazine-1-carbonyl)amino]methyl}pyrimidin-4-yl)-octahydro-1H-indole-2- carboxamide, (A-103)Step-1. Synthesis of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0427] Mixture of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (0.65 g, 0.632 mmol) and dipotassium carbonate (1.74 g, 12.6 mmol) in water (100 mL) was stirred at room temperature for 1 hour and extracted with the product was extracted with ethyl acetate (25 mL x 3). Combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4- yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.155 g, 0.258 mmol, 58 % purity, 41.0 % yield). The resulting semisolid was carried forward without further purification. Step-2. Synthesis of 2,2,2-trifluoroethyl N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamate

[0428] Mixture of 2,2,2-trifluoroethyl carbonochloridate (0.094 g, 0.579 mmol), (2S,3aS,7aS)-1- [6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide (0.155 g, 0.446 mmol), and triethylamine (0.0676 g, 0.669 mmol) in acetonitrile (30 mL) was stirred at room temperature for 8 hours. Obtained mixture was cooled down to roomtemperature, diluted with water (100 mL) and extracted with ethyl acetate (25 mL x 3). Combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording 2,2,2-trifluoroethyl N-({6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamate (0.26 g, 0.329 mmol, 60% purity, 73.9% yield) that was used in next field without further purification. Step-3. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-(2-methyl-6-{[(4-phenylpiperazine-1- carbonyl)amino]methyl}pyrimidin-4-yl)-octahydro-1H-indole-2-carboxamide

[0429] Mixture of 2,2,2-trifluoroethyl N-({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamate (0.1 g, 0.126 mmol, 60% purity), 1-phenylpiperazine (0.0204 g, 0.126 mmol), and 2H,3H,4H,6H,7H,8H,9H,10H- pyrimido[1,2-a]azepine (0.0191 g, 0.126 mmol) in acetonitrile (5 mL) was stirred under argon atmosphere at 80 °C for 18 hours. Obtained mixture was concentrated under vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford (2S,3aS,7aS)-N-(2- methoxyethyl)-1-(2-methyl-6-{[(4-phenylpiperazine-1-carbonyl)amino]methyl}pyrimidin-4-yl)- octahydro-1H-indole-2-carboxamide, (A-103). Yield: 19.6 mg, 27.5%; Appearance: Colorless oil;1H NMR (600 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.21 (dd, J = 8.6, 7.1 Hz, 2H), 7.13 (s, 1H), 6.96 (d, J = 8.1 Hz, 2H), 6.83 – 6.70 (m, 1H), 6.06 (s, 1H), 4.27 (s, 1H), 4.10 – 3.98 (m, 2H), 3.56 – 3.43 (m, 4H), 3.22 (s, 3H), 3.09 (q, J = 4.1 Hz, 5H), 2.31 – 2.18 (m, 4H), 2.09 – 1.94 (m, 1H), 1.94 – 1.76 (m, 2H), 1.64 (d, J = 14.2 Hz, 1H), 1.58 – 1.39 (m, 3H), 1.32 (s, 1H), 1.25 – 1.13 (m, 1H), 1.09 – 0.79 (m, 1H); HPLC purity: 100%; LCMS Calculated for C29H41N7O3: 535.3; Observed: 536.4[M+H]+.

[0430] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A28. Synthesis of tert-butyl 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoate (A-105) and 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]- 2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoic acid (A-106) IStep-1. Synthesis of methyl 4-[3-(tert-butoxy)-3-oxoprop-1-yn-1-yl]benzoate

[0431] A mixture of tert-butyl prop-2-ynoate (1.80 g, 14.3 mmol), methyl 4-iodobenzoate (2.5 g, 9.54 mmol), triethylamine (3.98 mL, 28.6 mmol), CuI (0.361 g, 1.9 mmol), and Pd(PPh3)4(0.219 g, 0.19 mmol) in tetrahydrofuran (150 mL) was stirred at room temperature for 12 hours under argon atmosphere. The solution was diluted with water (300 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue wassubjected to flash chromatography (Hexane / MTBE / CHCl3) that afforded methyl 4-[3-(tert- butoxy)-3-oxoprop-1-yn-1-yl]benzoate (2 g, 7.29 mmol, 95% purity, 76.6% yield). Step-2. Synthesis of 4-[3-(tert-butoxy)-3-oxoprop-1-yn-1-yl]benzoic acid

[0432] Solution of methyl 4-[3-(tert-butoxy)-3-oxoprop-1-yn-1-yl]benzoate (1.8 g, 6.91 mmol) and LiOH*H2O (0.304 g, 7.25 mmol) in the mixture of tetrahydrofuran (50 mL) / water (50 mL) was stirred at room temperature for 12 hours and evaporated to dryness in vacuo. The residue was dissolved in water (40 mL), acidified with sodium bisuldate aq. solution until pH = 5-6 and extracted with ethyl acetate (50 mL x 3). Combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording 4-[3- (tert-butoxy)-3-oxoprop-1-yn-1-yl]benzoic acid (1.7 g, 5.64 mmol, 81.8% purity, 81.7% yield) that was used in next step without further purification. Step-3. Synthesis of tert-butyl 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoate, (A- 105).

[0433] Solution of 4-[3-(tert-butoxy)-3-oxoprop-1-yn-1-yl]benzoic acid (0.146 g, 0.594 mmol), (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide dihydrochloride (0.25 g, 0.594 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.339 g, 0.891 mmol) and ethylbis(propan-2-yl)amine (0.691 mL, 3.56 mmol) in DMF (25 mL) was stirred for 12 hours. Resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford tert-butyl 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1- yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoate, (A-105). Yield: 21.4 mg, 5.95%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 9.17 – 9.04 (m, 1H), 8.01 (s, 1H), 7.97 – 7.90 (m, 2H), 7.78 – 7.71 (m, 2H), 6.19 (s, 1H), 4.37 – 4.14 (m, 3H), 3.20 (s, 4H),3.14 – 3.05 (m, 1H), 2.28 (s, 4H), 2.08 – 1.95 (m, 1H), 1.89 (q, J = 11.9 Hz, 2H), 1.67 (d, J = 14.3 Hz, 1H), 1.64 – 1.55 (m, 2H), 1.48 (s, 9H), 1.46 – 1.35 (m, 2H), 1.28 – 1.19 (m, 1H), 1.17 – 1.03 (m, 1H); HPLC purity: 98.39%; LCMS Calculated for C32H41N5O5: 575.31; Observed: 576.2[M+H]+Step-4. Synthesis of 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoic acid (A-106).

[0434] Tert-butyl 3-{4-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol- 1-yl]-2-methylpyrimidin-4-yl}methyl)carbamoyl]phenyl}prop-2-ynoate (0.255 g, 0.286 mmol, 65% purity) was treated with trifluoroacetic acid (5 mL) at room temperature for 2 hours. The solvent was removed and the residue was dried under high vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford 3-{4-[({6-[(2S,3aS,7aS)-2- [(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4- yl}methyl)carbamoyl]phenyl}prop-2-ynoic acid, (A-106). Yield: 37.7 mg, 24.1%; Appearance: Yellow oil;1H NMR (600 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.13 – 7.99 (m, 1H), 7.97 – 7.84 (m, 2H), 7.65 (d, J = 8.3 Hz, 2H), 6.23 (s, 1H), 4.52 – 3.98 (m, 4H), 3.23 – 3.15 (m, 6H), 3.13 – 3.07 (m, 2H), 2.32 – 2.27 (m, 4H), 2.04 (s, 1H), 1.89 (q, J = 12.3 Hz, 2H), 1.67 (d, J = 13.6 Hz, 1H), 1.63 – 1.55 (m, 2H), 1.50 – 1.44 (m, 1H), 1.41 (d, J = 13.3 Hz, 1H), 1.27 – 1.19 (m, 1H), 1.18 – 1.05 (m, 1H); HPLC purity: 99.24%; LCMS Calculated for C28H33N5O5: 519.25; Observed: 520.2 [M+H]+.Example A29. Synthesis of (2S,3aS,7aS)-1-[6-(2-{[4-(dimethylcarbamoyl)phenyl] carbamoyl}ethyl)-2-methylpyrimidin-4-yl]-N-methyl-octahydro-1H-indole-2-carboxamide (A- 107)Step-1. Synthesis of tert-butyl (2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indole-1- carboxylate

[0435] 1-(1H-imidazole-1-carbonyl)-1H-imidazole (0.78 g, 4.82 mmol) was added to a stirred solution of (2S,3aS,7aS)-1-[(tert-butoxy)carbonyl]-octahydro-1H-indole-2-carboxylic acid (1.0 g, 3.71 mmol) in tetrahydrofuran (20 mL) at 60 °C. The resulting reaction mixture was stirred for 1 hour at 60 °C, cooled to room temperature and followed with addition of triethylamine (0.77 mL, 5.56 mmol) and methylamine hydrochloride (0.325 g, 4.82 mmol). The resulting mixture was stirred overnight at room temperature. After the mixture was poured into water (40 mL), acidified to pH = 2 with phosphoric acid and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (30 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl (2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indole-1- carboxylate as white solid (1.0 g, 3.54 mmol, 95% purity, 95% yield). Step-2. Synthesis of (2S,3aS,7aS)-N-methyl-octahydro-1H-indole-2-carboxamide hydrochloride

[0436] Tert-butyl (2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indole-1-carboxylate (1 g, 3.54 mmol) was treated with 4N HCl solution in dioxane (20 mL, 80 mmol) at 60 °C for 4 hours. The solvent was removed and the residue was dried under high vacuum to give (2S,3aS,7aS)-N-methyl-octahydro-1H-indole-2-carboxamide hydrochloride as a white solid (0.8 g, 3.29 mmol, 90% purity, 93% yield) that was used in next step without further purification. Step-3. Synthesis of ethyl 3-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}propanoate

[0437] Mixture of ethyl 3-(6-chloro-2-methylpyrimidin-4-yl)propanoate (0.3 g, 1.31 mmol), (2S,3aS,7aS)-N-methyl-octahydro-1H-indole-2-carboxamide hydrochloride (0.343 g, 1.57 mmol), and triethylamine (0.45 mL, 3.27 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 16 hours. Obtained mixture was cooled down to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). Combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording ethyl 3-{6-[(2S,3aS,7aS)- 2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}propanoate as colorless oil (0.45 g, 1.15 mmol, 96% purity, 88% yield). Step-4. Synthesis of 3-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}propanoic acid

[0438] Sodium hydroxide (0.096 g, 2.4 mmol) solution in water (5 mL) was added to the stirred solution of ethyl 3-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2- methylpyrimidin-4-yl}propanoate (0.45 g, 1.2 mmol) in methanol (5 mL) at room temperature. Obtained mixture was stirred at room temperature for 16 hours and evaporated to dryness in vacuo. The residue was dissolved in water (10 mL), this solution was acidified by aqueous HCl until pH = 2 and evaporated in vacuo to afford 3-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}propanoic acid (0.43 g, 1.12 mmol, 94% purity, 97% yield). Step-5. Synthesis of tert-butyl (2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indole-1- carboxylate

[0439] 1-(1H-imidazole-1-carbonyl)-1H-imidazole (0.109 g, 0.687 mmol) was added to a stirred solution of 3-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}propanoic acid hydrochloride (0.2 g, 0.522 mmol) and triethylamine (0.22 mL, 1.56 mmol) in tetrahydrofuran (7 mL) at 60 °C. The resulting reaction mixture was stirred for 1 hour at 60 °C, cooled to room temperature and then 4-amino-N,N-dimethylbenzamide (0.102 g, 0.626 mmol) was added and resulting mixture was stirred overnight at 60 °C. After the mixture was cooled to room temperature and concentrated under vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford (2S,3aS,7aS)-1-[6-(2-{[4- (dimethylcarbamoyl)phenyl]carbamoyl}ethyl)-2-methylpyrimidin-4-yl]-N-methyl-octahydro- 1H-indole-2-carboxamide, (A-107). Yield: 67 mg, 24.7%; Appearance: Light yellow solid;1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 4.34 – 4.10 (m, 1H), 2.94 (s, 6H), 2.82 – 2.73 (m, 2H), 2.72 – 2.63 (m, 2H), 2.60 (d, J = 4.7 Hz, 3H), 2.26 (s, 3H), 2.07 (s, 3H), 1.99 – 1.83 (m, 2H), 1.75 – 1.52 (m, 3H), 1.52 – 1.33 (m, 2H), 1.33 – 0.96 (m, 2H); HPLC purity: 100%; LCMS Calculated for C27H36N6O3: 492.28; Observed: 493.2 [M+H]+. Example A30. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(oxetane-3- sulfonyl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide, (A- 108)Step-1. Synthesis of ethyl 4-(oxetan-3-ylsulfanyl)benzoate

[0440] Mixture of oxetan-3-yl methanesulfonate (2.49 g, 16.4 mmol), ethyl 4-sulfanylbenzoate (2.5 g, 13.7 mmol), dicaesio carbonate (8.92 g, 27.4 mmol) and iodopotassium (4.54 g, 27.4 mmol) in DMF (100 mL) was stirred at 100 °C for 18 hours. Obtained mixture was cooled down to roomtemperature, diluted with water (250 mL) and extracted with MTBE (150 mL x 3). Combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (hexane / MTBE) to afford ethyl 4-(oxetan-3-ylsulfanyl)benzoate (2.25 g, 8.96 mmol, 95% purity, 65.3% yield). Step-2. Synthesis of ethyl 4-(oxetan-3-ylsulfanyl)benzoate

[0441] 3-chlorobenzene-1-carboperoxoic acid (4.23 g, 20.9 mmol) was added to the stirred solution of ethyl 4-(oxetan-3-ylsulfanyl)benzoate (2 g, 8.39 mmol) in dichloromethane (200 mL) at 15 °C. Obtained mixture was stirred at room temperature for 3 hours. Then mixture was diluted with dichloromethane (200 mL), washed with NaHSO3sat. aq. solution (150 mL), K2CO3sat. aq. solution (150 mL), brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / MTBE) to afford ethyl 4-(oxetan-3-ylsulfanyl)benzoate (1.7 g, 5.97 mmol, 95% purity, 71.2 % yield). Step-3. Synthesis of 4-(oxetane-3-sulfonyl)benzoic acid

[0442] Solution of ethyl 4-(oxetane-3-sulfonyl)benzoate (1.6 g, 5.91 mmol) and lithiumol hydrate (0.742 g, 17.7 mmol) in the mixture of tetrahydrofuran (100 mL) / water (50 mL) was stirred at room temperature for 18 hours. The residue was dissolved in water (200 mL), acidified with aqueous sodium bisulfate solution until pH = 2 and extracted with ethyl acetate (100 mL x 3). Combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford 4-(oxetane-3-sulfonyl)benzoic acid (1.1 g, 4.54 mmol, 100 % purity, 76.9 % yield). The resulting semisolid was carried forward without further purification. Step-4. Synthesis of (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(oxetane-3- sulfonyl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide

[0443] Solution of (2S,3aS,7aS)-1-[6-(aminomethyl)-2-methylpyrimidin-4-yl]-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide dihydrochloride (0.2 g, 475 µmol), 4-(oxetane-3-sulfonyl)benzoic acid (0.230 g, 0.950 mmol), hexafluoro-λ⁵-phosphanuide 1- [(dimethylamino)(dimethyliminiumyl)methyl]-1H-[1,2,3]triazolo[4,5-b]pyridin-3-ium-3-olate (0.361 g, 0.950 mmol) and ethylbis(propan-2-yl)amine (0.306 g, 2.37 mmol) in DMF (50 mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford (2S,3aS,7aS)-N-(2-methoxyethyl)-1-[2-methyl-6-({[4-(oxetane-3- sulfonyl)phenyl]formamido}methyl)pyrimidin-4-yl]-octahydro-1H-indole-2-carboxamide, (A- 108). Yield: 79 mg, 27.6%; Appearance: Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 9.32 – 9.19 (m, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 3H), 6.18 (s, 1H), 5.03 – 4.89 (m, 1H), 4.82 – 4.71 (m, 4H), 4.38 – 4.04 (m, 3H), 3.29 – 3.24 (m, 1H), 3.21 (s, 3H), 3.17 – 3.01 (m, 2H), 2.35 – 2.19 (m, 4H), 2.12 – 2.00 (m, 1H), 1.98 – 1.84 (m, 2H), 1.69 (d, J = 14.2 Hz, 1H), 1.66 – 1.53 (m, 2H), 1.53 – 1.36 (m, 2H), 1.33 – 1.19 (m, 1H), 1.19 – 1.00 (m, 1H); HPLC purity: 98.33%; LCMS Calculated for C28H37N5O6S: 571.25; Observed: 572.0 [M+H]+.Example A31. Synthesis of (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2-yl)benzamido)ethyl)-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide, Diastereomer 1, (A-109) and (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2-yl)benzamido)ethyl)-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide, Diastereomer 2, (A-110)Step-1. Synthesis of tert-butyl N-(6-bromopyridin-3-yl)carbamate

[0444] 1M sodium bis(trimethylsilyl)amide solution in THF (36.3 mL, 36.3 mmol) was added to a solution of 6-bromopyridin-3-amine (3 g, 17.3 mmol) in THF (200 mL) at -30° C. After addition, the reaction was stirred at -30° C. for 60 min, and then di-tert-butyl dicarbonate (4.14 g, 19.0 mmol) was added in several portions. After addition, the reaction was stirred at room temperature for 18 hours, diluted with water (200 mL) and neutralized by adding ice-cold 1N HCl (about 90 mL) to pH=7-8. The resultant mixture was extracted with ethyl acetate (100 mL x 3). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to give tert-butyl N-(6-bromopyridin-3-yl)carbamate (3.1 g, 10.7 mmol, 95% purity, 62.2% yield).Step-2. Synthesis of methyl 4-(5-{[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoate

[0445] 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II), complex with dichloromethane (0.922 g,1.13 mmol) was added to a solution of tert-butyl N-(6-bromopyridin-3- yl)carbamate (3.1 g, 11.3 mmol), [4-(methoxycarbonyl)phenyl]boronic acid (2.42 g, 13.5 mmol), and sodium hydrogen carbonate (1.41 g, 16.9 mmol) in dioxane (100 mL) / water (50 mL) mixture under argon atmosphere and the reaction mixture was stirred at 80 ° C for 4 hours. After it was cooled to room temperature, partitioned between ethyl acetate (200 mL) and water (500 mL) and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give methyl 4-(5-{[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoate (3 g, 8.86 mmol, 97% purity, 78.4 % yield). Step-3. Synthesis of 4-(5-{[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoic acid

[0446] Potassiumol (2.55 g, 45.6 mmol) solution in water (50 mL) was added to the stirred solution of methyl 4-(5-{[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoate (3 g, 9.13 mmol) in methanol (100 mL) at room temperature. Obtained mixture was stirred at 60 °C for 16 hours. After cooling to room temperature this solution was acidified by aqueous sodium bisulfate solution until pH = 5 and extracted with ethyl acetate (150 mL x 3). Combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording 4-(5-{[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoic acid as a beige solid (2.5 g, 7.55 mmol, 95% purity, 82.8% yield). Step-4. Synthesis of tert-butyl N-[6-(4-{[1-(6-chloro-2-methylpyrimidin-4- yl)ethyl]carbamoyl}phenyl)pyridin-3-yl]carbamate

[0447] Solution of 1-(6-chloro-2-methylpyrimidin-4-yl)ethan-1-amine (0.35 g, 2.03 mmol), 4-(5- {[(tert-butoxy)carbonyl]amino}pyridin-2-yl)benzoic acid (0.763 g, 2.43 mmol), hexafluoro-λ⁵- phosphanuide 1-[(dimethylamino)(dimethyliminiumyl)methyl]-1H-[1,2,3]triazolo[4,5-b]pyridin- 3-ium-3-olate (1 g, 2.63 mmol) and ethylbis(propan-2-yl)amine (528 µL, 3.04 mmol) in DMF (25mL) was stirred at room temperature for 18 hours. Resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (chloroform / MTBE) to afford tert-butyl N-[6-(4-{[1-(6-chloro-2-methylpyrimidin-4-yl)ethyl]carbamoyl}phenyl)pyridin-3- yl]carbamate (0.33 g, 0.641 mmol, 91% purity, 31.6% yield). Step-5. Synthesis of tert-butyl N-(5-{4-[(1-{6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]-2-methylpyrimidin-4-yl}ethyl)carbamoyl]phenyl}pyridin-2- yl)carbamate

[0448] Mixture of tert-butyl N-[6-(4-{[1-(6-chloro-2-methylpyrimidin-4- yl)ethyl]carbamoyl}phenyl)pyridin-3-yl]carbamate (0.33 g, 0.641 mmol), (2S,3aS,7aS)-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide; trifluoroacetic acid (0.654 g, 0.961 mmol), and ethylbis(propan-2-yl)amine (556 µL, 3.20 mmol) in NMP (50 mL) was stirred under argon atmosphere at 80 °C for 18 hours. Obtained mixture was cooled down to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). Combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording tert-butyl N-(5-{4-[(1-{6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}ethyl)carbamoyl]phenyl}pyridin-2-yl)carbamate (0.45g, 615 µmol, 90% purity, 96.1 % yield). Step-6. Synthesis of (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2-yl)benzamido)ethyl)-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide, Diastereomer 1, (A-109), and (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2-yl)benzamido)ethyl)-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide, Diastereomer 2, (A-110)

[0449] Tert-butyl N-(6-{4-[(1-{6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H- indol-1-yl]-2-methylpyrimidin-4-yl}ethyl)carbamoyl]phenyl}pyridin-3-yl)carbamate (0.45 g, 0.615 mmol) was added to a stirred solution of hydrogen chloride in dry dioxane (25 mL). Thereaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2-yl)benzamido)ethyl)-2- methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2-carboxamide, Diastereomer 1, (A-109). Yield: 49.1 mg, 17.1%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.05 – 8.01 (m, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.5, 2.7 Hz, 1H), 6.33 (s, 1H), 5.56 (s, 2H), 4.92 – 4.81 (m, 1H), 4.29 (s, 1H), 3.24 – 3.16 (m, 3H), 3.07 (s, 2H), 2.29 (s, 3H), 2.27 – 2.22 (m, 1H), 2.04 – 1.96 (m, 2H), 1.90 (q, J = 11.7 Hz, 1H), 1.69 – 1.56 (m, 3H), 1.53 – 1.45 (m, 1H), 1.41 (d, J = 7.3 Hz, 4H), 1.30 – 1.20 (m, 1H), 1.19 – 1.09 (m, 1H); HPLC purity: 100%; LCMS Calculated for C31H39N7O3: 557.31; Observed: 558.2 [M+H]+and (2S,3aS,7aS)-1-(6-(1-(4-(5-aminopyridin-2- yl)benzamido)ethyl)-2-methylpyrimidin-4-yl)-N-(2-methoxyethyl)octahydro-1H-indole-2- carboxamide, Diastereomer 2, (A-110). Yield: 25 mg, 8.82%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.06 – 7.97 (m, 4H), 7.88 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.6, 2.7 Hz, 1H), 6.31 (s, 1H), 5.56 (s, 2H), 4.93 – 4.80 (m, 1H), 4.30 (s, 1H), 3.72 (s, 1H), 3.28 (s, 1H), 3.22 (s, 3H), 3.13 (s, 1H), 2.29 (s, 4H), 2.09 – 1.95 (m, 1H), 1.94 – 1.85 (m, 1H), 1.68 (d, J = 13.9 Hz, 1H), 1.65 – 1.53 (m, 2H), 1.49 – 1.43 (m, 2H), 1.41 (d, J = 7.1 Hz, 3H), 1.29 – 1.18 (m, 1H), 1.16 – 1.06 (m, 1H); HPLC purity: 100%; LCMS Calculated for C31H39N7O3: 557.31; Observed: 558.2 [M+H]+.

[0450] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.Example A32. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]pyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2- carboxamide, (A-114)Step-1. Synthesis of (2S,3aS,7aS)-1-(6-cyanopyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide

[0451] Mixture of 6-chloropyrimidine-4-carbonitrile (0.5 g, 3.58 mmol), (2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-ium trifluoroacetate (2.89 g, 3.93 mmol), and ethylbis(propan-2-yl)amine (6.22 mL, 35.8 mmol) in NMP (70 mL) was stirred at 80 °C for 12hours. Obtained mixture was cooled down to room temperature, diluted with water (150 mL) and extracted with ethyl acetate (50 mL x 3). Combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum affording (2S,3aS,7aS)- 1-(6-cyanopyrimidin-4-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (1.3 g, 3.43 mmol, 87% purity, 96.5% yield) that was used in next step without further purification. Step-2. Synthesis of {6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1- yl]pyrimidin-4-yl}methanaminium acetate

[0452] 10% Pd / C (0.1 g) was added to (2S,3aS,7aS)-1-(6-cyanopyrimidin-4-yl)-N-(2- methoxyethyl)-octahydro-1H-indole-2-carboxamide (0.5 g, 1.51 mmol) solution in ethyl acetate / acetic acid (1 / 1, 35 mL) and the resulting mixture was hydrogenated at ambient pressure and temperature until the reaction was completed. The catalyst was filtered off, washed with ethyl acetate (50 mL) and the combined filtrate was evaporated to afford {6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]pyrimidin-4-yl}methanaminium acetate (0.64 g, 1.18 mmol, 72.6% purity, 78.1% yield) that was used in next step without further purification. Step-3. Synthesis of tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]- octahydro-1H-indol-1-yl]pyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate

[0453] Solution of {6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol-1- yl]pyrimidin-4-yl}methanaminium acetate (0.29 g, 0.736 mmol, 72.6% purity), 4'-{[(tert- butoxy)carbonyl]amino}-[1,1'-biphenyl]-4-carboxylic acid (0.230 g, 0.736 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.419 g, 1.1 mmol) and ethylbis(propan-2-yl)amine (0.575 mL, 3.31 mmol) in DMF (50 mL) was stirred at room temperature for 16 hours. Resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-yl]pyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.9 g, 0.532 mmol, 37.2% purity, 72.2% yield) that was used in next step without further purification. Step-4. Synthesis of (2S,3aS,7aS)-1-{6-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]pyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide

[0454] Tert-butyl N-{4'-[({6-[(2S,3aS,7aS)-2-[(2-methoxyethyl)carbamoyl]-octahydro-1H-indol- 1-yl]pyrimidin-4-yl}methyl)carbamoyl]-[1,1'-biphenyl]-4-yl}carbamate (0.9 g, 0.531 mmol) was treated with 4N HCl solution in dioxane ( 50 mL) at room temperature for 12 hours. The solvent was removed and the residue was dried under high vacuum. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to afford (2S,3aS,7aS)-1-{6-[({4'-amino- [1,1'-biphenyl]-4-yl}formamido)methyl]pyrimidin-4-yl}-N-(2-methoxyethyl)-octahydro-1H- indole-2-carboxamide, (A-114). Yield: 72 mg, 24.4%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.95 – 8.85 (m, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.91 – 7.85 (m, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.48 – 7.38 (m, 2H), 6.69 – 6.61 (m, 2H), 5.36 (s, 2H), 4.31 (d, J = 5.8 Hz, 2H), 3.29 – 3.08 (m, 7H), 2.26 (s, 1H), 2.08 (s, 1H), 1.99 – 1.84 (m, 2H), 1.67 (d, J = 14.1 Hz, 1H), 1.64 – 1.54 (m, 2H), 1.50 – 1.44 (m, 1H), 1.41 (d, J = 13.8 Hz, 1H), 1.29 – 1.18 (m, 1H), 1.16 – 1.02 (m, 1H); HPLC purity: 100%; LCMS Calculated for C30H36N6O3: 529.33; Observed: 530.6[M+H]+.Example A33. Synthesis of (2S,3aS,7aS)-1-{4-[({4'-amino-[1,1'-biphenyl]-4- yl}formamido)methyl]-6-methyl-1,3,5-triazin-2-yl}-N-(2-methoxyethyl)-octahydro-1H-indole- 2-carboxamide, (A-115)Step-1. Synthesis of (2S,3aS,7aS)-1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide

[0455] Mixture of 2,4-dichloro-6-methyl-1,3,5-triazine (1 g, 6.09 mmol), (2S,3aS,7aS)-2-[(2- methoxyethyl)carbamoyl]-octahydro-1H-indol-1-ium trifluoroacetate (1.65 g, 4.87 mmol), and ethylbis(propan-2-yl)amine (3.76 mL, 22.9 mmol) in acetonitrile (70 mL) was stirred at room temperature overnight. Obtained mixture was concentrated under vacuum and residue was purified by flash chromatography (chloroform / ethyl acetate) to give (2S,3aS,7aS)-1-(4-chloro-6-methyl- 1,3,5-triazin-2-yl)-N-(2-methoxyethyl)-octahydro-1H-indole-2-carboxamide (1 g, 90% purity, 2.54 mmol, 41.8% yield).Step-2. Synthesis of (2S,3aS,7aS)-1-(4-cyano-6-methyl-1,3,5-triazin-2-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide

[0456] Mixture of (2S,3aS,7aS)-1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-(2-methoxyethyl)- octahydro-1H-indole-2-carboxamide (1 g, 2.54 mmol) and sodium cyanide (0.4 g, 8.16 mmol) in DMF (70 mL) was stirred at 50 °C overnight. Resulting mixture was evaporated under reduced pressure. The residue was diluted with MTBE (200 mL). Solids were filtered ...

Claims

CLAIMS 1. A compound of formula Ior a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; B is a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is a bond, -NR1a-C(O)-, -C(O)-NR1a-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -OR1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2is -N(R2a)(R2b), -O-C0-C6aliphatic-R2b, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 2- to 6 membered heteroaliphatic substituted with one or more R2a, or C3-C12cycloaliphatic substituted with one or more R2a, or C6-C12aryl substituted with one or more R2a;each R2ais independently selected from the group consisting of oxo, –OH, halogen, Z, -O-R3a, - C(O)NHR3a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; R2bis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ)-, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

2. The compound of claim 1, wherein A is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

3. The compound of claims 1 or 2, wherein A is optionally substituted pyrimidinyl.

4. The compound of claim 1, wherein moiety:is selected from:

5. The compound of any one of claims 1-4, wherein L1is optionally substituted C1-C6aliphatic.

6. The compound of any one of claims 1-5, wherein L1is -CH(CH3)-, -C(CH3)2-, or –CH2-.

7. The compound of any one of claims 1-6, wherein L1is –C(CH3)-.

8. The compound of claim 7, wherein L1is9. The compound of any one of claims 1-8, wherein L2is -NH-C(O)- or -C(O)-NH-.

10. The compound of any one of claims 1-9, wherein L2is NH-C(O)-.

11. The compound of claim 1, wherein L1is –CH2-, and L2is –NH-C(O)-.

12. The compound of any one of claims 1-11, wherein B is optionally substituted 5- to 12- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl; 13. The compound of any one of claims 1-12 wherein B is optionally substituted C6-C12aryl.

14. The compound of any one of claims 1-13, wherein B is optionally substituted phenyl.

15. The compound of any one of claims 1-11, wherein B is selected from the group consisting of:

16. The compound of any one of claims 1-15, wherein R3is C6-C12aryl optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a.

17. The compound of any one of claims 1-16, wherein R3is phenyl substituted with one or more R3a.

18. The compound of any one of claims 1-17, wherein each R3ais independently selected from the group consisting of halogen, –N(R1a)2, and optionally substituted C1-C6aliphatic.

19. The compound of any one of claims 1-15, wherein R3is selected from the group consisting of:

20. The compound of any one of claims 1-19, wherein R1is Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic.

21. The compound of any one of claims 1-20, wherein R1is Z or optionally substituted C1-C6aliphatic.

22. The compound of any one of claims 1-19, wherein R1is selected from the group consisting of –H, -CH3, -Br,23. The compound of any one of claims 1-22 wherein R2is 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a, or 2- to 6 membered heteroaliphatic substituted with one or more R2a.

24. The compound of any one of claims 1-23, wherein R2is 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2a.

25. The compound of any one of claims 1-22, wherein R2is selected from:

26. The compound of any one of claims 1-22, wherein R2is selected from:

27. The compound of claim 1, wherein the compound is of formula Ia:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic;R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is -O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)- OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R4is independently selected from the group consisting of oxo, –OH, halogen, -O-R4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl, or two R4can be joined together with the atoms to which they are attached to form a 5- to 6- membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S, and optionally substituted C6-C12aryl; each RZis independently selected from the group consisting of H, optionally substituted group selected from C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic; and n is 0, 1, 2, 3, or 4.

28. The compound of claim 1, wherein the compound is of formula Ib:or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are each independently selected from the group consisting of N and CH; B is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -S(O)2NR1a-, -NR1a-C(O)- NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or moreR3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)- OR1a,-O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, and optionally substituted C6-C12aryl; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

29. The compound of claim 1, wherein the compound is of formula Ic:or a pharmaceutically acceptable salt thereof, wherein L1is optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2is –NR1a-, -O-, -C(O)-, -NR1a-C(O)-, -NR1a-S(O)2-, -C(O)-NR1a-, -NR1a-C(O)-NR1a-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1is H, Z, halogen, -O-R1a, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, or optionally substituted C3-C6cycloaliphatic; each R1ais independently selected from H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R3is-O-C0-C6aliphatic-R3a,-S(O)2R3a, C1-C6aliphatic optionally substituted with one or more R3a, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a, C6-C12aryl optionally substituted with one or more R3a, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3a; each R3ais independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1a, -C(O)-OR1a, -O-R1a, –N(R1a)2, -C0-C6aliphatic-C(O)N(R1a)2, -S(O)2R1a, - B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; R4ais H, -NH2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; R5is oxo, –OH, halogen, Z, -O-R4a, -C(O)NHR4a, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl; each Z is independently an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -C(O)N(RZ)SO2(RZ)-, - SO2(RZ)N(RZ)C(O)-, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-; each Cy is independently selected from the group consisting of optionally substituted C3-C14cycloaliphatic, optionally substituted 5- to 12-membered heterocycle ring having 1-3heteroatoms selected from N, O, S, and optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

30. The compound of claim 1, wherein the compound is selected from Table A-1.

31. A compound of formula II: A’-B’-C’ II or a pharmaceutically acceptable salt thereof, wherein A’ is a ULK complex binding moiety; B’ is a linker; and C’ is a target binding moiety.

32. The compound of claim 31, wherein the ULK complex binding moiety is a compound of any one of claims 1-30.

33. The compound of claim 31, wherein A’-B’-C’ is a compound of formula IIa or IIb:or a pharmaceutically acceptable salt thereof, wherein Axis optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted C6-C12aryl; Bxis a bond, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloaliphatic, or optionally substituted C6-C12aryl;L1xis a bond, -NR1ax-C(O)-, -C(O)-NR1ax-, optionally substituted C1-C6aliphatic, optionally substituted 3- to 6-membered heterocyclic, or optionally substituted C3-C6cycloaliphatic; L2xis –NR1ax-, -O-, -C(O)-, -NR1ax-C(O)-, -NR1ax-S(O)2-, -C(O)-NR1ax-, -S(O)2NR1ax-, -NR1ax- C(O)-NR1ax-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6cycloaliphatic; R1xis H, halogen, -O-R1ax, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12aryl, or optionally substituted C3-C6cycloaliphatic; each R1axis independently selected from the group consisting of H, optionally substituted C1-C6aliphatic, and optionally substituted C3-C6cycloaliphatic; R2xis -N(R2ax)(R2bx), -O-C0-C6aliphatic-R2bx, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with one or more R2ax, 2- to 6 membered heteroaliphatic substituted with one or more R2ax, C3-C12cycloaliphatic substituted with one or more R2ax, or C6-C12aryl substituted with one or more R2ax; each R2axis independently selected from the group consisting of oxo, –OH, halogen, -O-R3ax, - C(O)NHR3axoptionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, and optionally substituted C6-C12aryl; R2bxis H, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 4- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R3xis-O-C0-C6aliphatic-R3ax, -S(O)2R3ax, C1-C6aliphatic optionally substituted with one or more R3ax, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax, C6-C12aryl optionally substituted with one or more R3ax, or 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S and optionally substituted with one or more R3ax; each R3axis independently selected from the group consisting of -CN, halogen, oxo, -C0-C6aliphatic-C(O)-R1ax, -C(O)-OR1ax,-O-R1ax, –N(R1ax)2, -C0-C6aliphatic-C(O)N(R1ax)2, -S(O)2R1ax, -B(OH)2, optionally substituted C1-C6aliphatic, optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

34. The compound of any one of claims 31-33, wherein the ULK complex binding moiety is a ULK1 complex binding moiety.

35. The compound of any one of claims 31-34, wherein the linker is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, - N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, or -SO2-, wherein each -Cy- is independently selected from the group consisting of optionally substituted 3- 12 membered bivalent heterocycle ring having 1-3 heteroatoms selected from N, O, and S, optionally substituted 3-8 membered bivalent heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, optionally substituted C3-C6cycloalkyl, or optionally substituted C6-C12aryl, and each RZis independently selected from the group consisting of H, optionally substituted C1-C20aliphatic, and optionally substituted C3-C12cycloaliphatic.

36. The compound of any one of claims 31-35, wherein the target binding moiety binds or associates with a target selected from the group consisting of mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A / B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1 / 2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1 / 2, GPAM, USP30, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32, RAB1B, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin,TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, STING, cGAS, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes.

37. The compound of claim 31, wherein the linker is selected from Table B’.

38. The compound of claim 31, wherein the target binding moiety is selected from Table F.

39. The compound of claim 31, wherein the compound is selected from Table B-1.

40. A pharmaceutical composition comprising a compound of any one of claims 1-39, and a pharmaceutically acceptable excipient.

41. A method of inducing degradation of a target in a biological sample, comprising contacting the biological sample with a compound of any one of claims 1-39 or a pharmaceutical composition of claim 40.

42. The method of claim 41, wherein the biological sample comprises a ULK initiation complex.

43. The method of claim 41, wherein the biological sample comprises a ULK1 initiation complex.

44. A method of treating a disease, disorder, or condition in a patient, comprising administering one or more compounds of any one of claims 1-39, or the pharmaceutical composition of claim 40.

45. The method of claim 44, wherein the disease, disorder, or condition is selected from the group consisting of NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostatecancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson- dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Aicardia-Goutieres syndrome, ataxia, Familial chilblain lupus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.

46. A compound of any one of claims 1-39, or the pharmaceutical composition of claim 40 for use as a medicament.

47. Use of a compound comprising one or more compounds of any one of claims 1-39, or the pharmaceutical composition of claim 40 in the treatment of a disease, disorder, or condition.

48. The use of claim 47, wherein the disease, disorder, or condition is selected from the group consisting of NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B- cell lymphomas, diffuse large B-cell lymphomas, primary central nervous systemlymphomas, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson- dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Aicardia-Goutieres syndrome, ataxia, Familial chilblain lupus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.

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