C5ar1 antagonists and uses thereof

Abstract

Provided herein are compounds that modulate (e.g., antagonize) complement component 5a receptor 1 (C5aR1), a G protein-coupled receptor for C5a that is associated with autoimmune, inflammatory, and neurodegenerative disorders. Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating C5aR1-related diseases and disorders with the compounds in a subject, by administering the compounds and / or compositions described herein.

Description

C5AR1 ANTAGONISTS AND USES THEREOF RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application 63 / 406,501 filed September 14, 2022, the entirety of which is incorporated herein by reference. BACKGROUND

[0002] The C5a receptor, also known as complement component 5a receptor 1 (C5aR1) or CD88 (Cluster of Differentiation 88) is a G protein-coupled receptor for C5a. It functions as a complement receptor.

[0003] C5a is a potent immunomodulator, but also has emerging roles outside of immunity during embryonic development. Its production is tightly controlled in order to produce a rapid response to tissue injury / pathogens yet protect against unwanted activity on host tissue. The disruption of this control can lead to the overproduction of C5a, which can lead to an uncontrolled inflammatory response. C5a has been associated with a number of autoimmune, inflammatory, and neurodegenerative disorders. Thus, targeting C5aR1 with effective small molecule modulators would be useful in the treatment of several types of diseases (e.g., neurodegenerative disorders). SUMMARY

[0004] The present disclosure provides compounds that are modulators of C5AR1 (e.g., antagonists). These compounds provide new compositions and methods for the treatment of diseases associated with C5AR1 activity.

[0005] In one aspect, provided are compounds of Formula (I):(I), and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein:R1is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R2is an optionally substituted carbocyclyl or optionally substituted heterocyclyl; A1, A2, A3, and A4are each independently =C(R3)– or =N–; B1is –C(R4)t– or –N–, wherein t is 0 or 1 as valency permits; B2is =C(R4)–, –N–, or –C(O)–; Y is –C(R5)2– or a bond; each R3is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, – NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; each R4is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –ORA, –N(RA)2, –SRA, or –CN; each R5is independently hydrogen, halogen, or optionally substituted alkyl; and each RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0006] In certain embodiments, the compounds of Formula (I) are compounds of Formula (I-a), (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5), (I-a-6), (I-a-7), (I-a-8), (I-a-9), (I-a-10), (I-a- 11), (I-b), (I-c), (I-d), (I-e), (I-e-1), (I-e-2), (I-e-3), (I-e-4), (I-e-5), (I-e-6), (I-e-7), (I-e-8), (I-f), (I-f-1), (I-f-2), (I-g), (I-g-1), (I-g-2), (I-h), (I-h-1), (I-h-2), (I-h-7), (I-h-8), or (I-h-9):or pharmaceutically acceptable salts thereof.

[0007] In another aspect, provided are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0008] In another aspect, provided are methods of treating a disease or disorder in a subject in need thereof, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) to the subject.

[0009] In certain embodiments, the disease or disorder is associated with C5aR1 (e.g., C5aR1 activity). In certain embodiments, the disease or disorder is cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder . In certain embodiments, the disease or disorder is a neurological disease or disorder.

[0010] In another aspect, provided are methods of antagonizing C5aR1, the method comprising contacting C5aR1 with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) to the subject.

[0011] In another aspect, provided are kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the kits further comprise instructions for administration (e.g., human administration).

[0012] The details of certain embodiments of the disclosure are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the disclosure will be apparent from the Definitions, Examples, and Claims. DEFINITIONS Chemical definitions

[0013] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0014] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. While compounds may be depicted as racemic or as one or more diastereoisomers, enantiomers, or other isomers, all such racemic, diastereoisomer, enantiomer, or other isomer forms of that depicted are included in the present disclosure.

[0015] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.

[0016] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0017] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0018] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0019] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“ C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“ C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“ C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr),unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6alkyl, e.g., −CF3, Bn).

[0020] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0021] The term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms (“C1-8alkoxy”). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (“C1-6alkoxy”). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (“C1-4alkoxy”). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (“C1-3alkoxy”). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (“C1-2alkoxy”). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0022] The term “alkoxyalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms (“C1-8alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C1-6alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C1-4alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms (“C1-3alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (“C1-2alkoxyalkyl”).

[0023] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-20alkyl”). In some embodiments, a heteroalkyl group is a saturatedgroup having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-18alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-14alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl.

[0024] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”).In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or) may be an (E)- or (Z)- double bond.

[0025] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2heteroatoms within the parent chain (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0026] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0027] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl grouphas 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0028] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8),cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0029] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0030] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0031] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0032] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0033] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0034] “Arylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0037] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] “Heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0039] The term “unsaturated bond” refers to a double or triple bond.

[0040] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0041] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0042] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0043] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. Forpurposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not intended to be limited in any manner by the exemplary substituents described herein.

[0044] When substituted, exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, -SF5, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)3, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), −Raa, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa,−C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6alkyl, −ON(C1-6alkyl)2, −N(C1-6alkyl)2, −N(C1-6alkyl)3+X−, −NH(C1-6alkyl)2+X−, −NH2(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6alkyl), −C(=O)NH2, −C(=O)N(C1-6alkyl)2, −OC(=O)NH(C1-6alkyl), −NHC(=O)(C1-6alkyl), −N(C1-6alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6alkyl), −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(=NH)NH(C1-6alkyl), −OC(=NH)NH2, −NHC(=NH)N(C1-6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6alkyl), −SO2N(C1-6alkyl)2, −SO2NH(C1-6alkyl), −SO2NH2, −SO2(C1-6alkyl), −SO2O(C1-6alkyl), −OSO2(C1-6alkyl), −SO(C1-6alkyl), −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, −C(=O)S(C1-6alkyl), −C(=S)SC1-6alkyl, −SC(=S)SC1-6alkyl, −P(=O)(OC1-6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0045] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0046] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −OC(=NRbb)Raa, −OC(=NRbb)ORaa,−OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0047] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0048] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0049] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0050] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0051] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and –SO2ORaa, wherein Raaand Rbbare as defined herein.

[0052] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0053] The term “acyl” refers to a group having the general formula: −C(=O)RX1, −C(=O)ORX1, −C(=O)−O−C(=O)RX1, −C(=O)SRX1, −C(=O)N(RX1)2, −C(=S)RX1, −C(=S)N(RX1)2, −C(=S)O(RX1), −C(=S)S(RX1), −C(=NRX1)RX1, −C(=NRX1)ORX1, −C(=NRX1)SRX1, or −C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted orunsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0054] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0055] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein.

[0056] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2,−SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0057] For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0058] Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz),p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m- chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0059] Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0060] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2- picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0061] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygenprotecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0062] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0063] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa,−C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0064] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid– 2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5- (CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0065] A “leaving group” (LG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., –OC(=O)SRaa, –OC(=O)Raa, –OCO2Raa, –OC(=O)N(Rbb)2, –OC(=NRbb)Raa, – OC(=NRbb)ORaa, –OC(=NRbb)N(Rbb)2, –OS(=O)Raa, –OSO2Raa, –OP(Rcc)2, –OP(Rcc)3, – OP(=O)2Raa, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –OP(=O)2N(Rbb)2, and –OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, – OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), – OS(=O)2(CF2)3CF3(nonaflate, –ONf), or trifluoromethanesulfonate (triflate, –OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0066] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other definitions

[0067] The term “antagonist” refers to an agent that (i) decreases or suppresses one or more effects of another agent; and / or (ii) decreases or suppresses one or more biological events. In some embodiments, an antagonist may reduce level and / or activity or one or more agents that it targets. An antagonist may be direct (in which case it exerts its influence directly upon its target) or indirect (in which case it exerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, for example so that level or activity of the target is altered). In some embodiments, an antagonist may be a receptor antagonist, e.g., a receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. In certain embodiments, compounds of Formula (I) are antagonists of C5aR1.

[0068] The term “agonist” refers to an agent that (i) increases or induces one or more effects of another agent; and / or (ii) increases or induces one or more biological events. In some embodiments, an agonist may increase level and / or activity or one or more agents that it targets. In various embodiments, agonists may be or include agents of various chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or other entity that shows the relevant agonistic activity. An agonist may be direct (in which case it exerts its influence directly upon its target) or indirect (in which case itexerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, for example so that level or activity of the target is altered). A partial agonist can act as a competitive antagonist in the presence of a full agonist, as it competes with the full agonist to interact with its target and / or a regulator thereof, thereby producing (i) a decrease in one or more effects of another agent, and / or (ii) a decrease in one or more biological events, as compared to that observed with the full agonist alone.

[0069] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0070] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or 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, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts 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, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, 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. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and aminecations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0071] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0072] The term “hydrate” refers to a compound that is associated with water molecules. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)).

[0073] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0074] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0075] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0076] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). Many compounds can adopt a variety of different crystal forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or can vary in some or all properties such as melting points, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0077] The term “co-crystal” refers to a crystalline structure composed of at least two components. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more other component(s), including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co- crystal contains a compound of the present disclosure and one or more acid or base. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more components related to said compound, including, but not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment, or impurity of said compound.

[0078] The term “prodrugs” refers to compounds that have cleavable groups that are removed, by solvolysis or under physiological conditions, to provide the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of theparent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12arylalkyl esters of the compounds described herein may be preferred.

[0079] The terms “composition” and “formulation” are used interchangeably.

[0080] The term “modulate” means decreasing or inhibiting activity and / or increasing or augmenting activity. For example, modulating C5aR1 activity means decreasing or inhibiting C5aR1 activity and / or increasing or augmenting C5aR1 activity. The compounds disclosed herein may be administered to modulate C5aR1 for example, as an antagonist.

[0081] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non- vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.

[0082] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles(such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0083] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0084] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0085] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0086] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.

[0087] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for C5aR1 deactivation (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, or at least 500% decrease in the activity of C5aR1). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder (e.g., neurological disorder). In certain embodiments, a therapeutically effective amount is an amount sufficient for C5aR1 deactivation and treating a disease or disorder (e.g., neurological disorder).

[0088] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for C5aR1 deactivation. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a disease or disorder (e.g., neurological disorder). In certain embodiments, a prophylactically effective amount is an amount sufficient for C5aR1 deactivation and treating a disease or disorder (e.g., neurological disorder).

[0089] As used herein, the term “activate” or “activation” in the context of proteins, for example, in the context of C5aR1, refers to an increase in the activity of the protein. In some embodiments, the term refers to an increase of the level of activity to a level that is statistically significantly higher than an initial level, which may, for example, be a baseline level of activity (e.g., of wild-type C5aR1). In some embodiments, the term refers to an increase in the level of activity to a level that is greater than 1%, greater than 5%, greater than 10%, greater than 25%, greater than 50%, greater than 75%, greater than 100%, greater than 150%, greater than 200%, greater than 300%, greater than 400%, greater than 500%, or greater than 1000% of an initial level, which may, for example, be a baseline level of activity.

[0090] The term “immunotherapy” refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapies are typically, but not always, biotherapeutic agents. Numerous immunotherapies are used to treat cancer. These include, but are notlimited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.

[0091] The terms “biologic,” “biologic drug,” and “biological product” refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologics may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologics may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.

[0092] The term “small molecule” or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0093] The term “therapeutic agent” refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect. For example, therapeutic agents may treat, ameliorate, and / or prevent disease. Therapeutic agents, as disclosed herein, may be biologics or small molecule therapeutics, or combinations thereof.

[0094] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0095] Provided herein are compounds (e.g., a compound of any of the formulae herein) that are modulators of C5aR1 (e.g., C5aR1 antagonists). In one aspect, the provided C5aR1 modulators are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. Accordingly, the compounds are useful for the treatment and / or prevention of diseases and disorders associated with C5aR1 (e.g., neurological diseases and disorders) in a subject in need thereof.

[0096] The compounds described herein interact with C5aR1. As described herein, the therapeutic effect may be a result of modulation (e.g., antagonism), binding, and / or modification of C5aR1 by the compounds described herein. The compounds may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. Compounds of Formula (I)

[0097] In one aspect, disclosed is a compound of Formula (I):(I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R1is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R2is an optionally substituted carbocyclyl or optionally substituted heterocyclyl; A1, A2, A3, and A4are each independently =C(R3)– or =N–; B1is –C(R4)t– or –N–, wherein t is 0 or 1 as valency permits; B2is =C(R4)–, –N–, or –C(O)–; Y is –C(R5)2– or a bond; each R3is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, – NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; each R4is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –ORA, –N(RA)2, –SRA, or –CN; each R5is independently hydrogen, halogen, or optionally substituted alkyl; and each RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. Y

[0098] As described herein, Y is –C(R5)2– or a bond; and each R5is independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, Y is –C(R5)2–. In certain embodiments, Y is –C(R5)2–; and each R5is independently hydrogen or optionally substituted alkyl. In certain embodiments, Y is –CH2–. In certain embodiments, Y is a bond. R1

[0099] As described herein, R1is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In certain embodiments, R1is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted carbocyclyl. In certain embodiments, R1is optionally substituted aryl or optionally substituted heteroaryl.

[0100] In certain embodiments, R1is optionally substituted aryl. In certain embodiments, R1is optionally substituted phenyl.

[0101] In certain embodiments, R1is optionally substituted heteroaryl. In certain embodiments, R1is optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyridazinyl. In certain embodiments, R1is optionally substituted pyridinyl or optionally substituted pyrazinyl. In certain embodiments, R1is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl. In certain embodiments, R1is optionally substituted pyridinyl. In certain embodiments, R1is optionally substituted pyrazinyl.

[0102] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, -SF5, or –ORA; and x is 0, 1, 2, or 3.

[0103] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, -SF5, or –ORA; and x is 0, 1, 2, or 3.

[0104] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, -SF5, or –ORA; and x is 0 or 1.

[0105] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, -SF5, or –ORA; and x is 0 or 1.

[0106] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, -SF5, or –ORA; RAis alkyl or haloalkyl; and x is 0 or 1.

[0107] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, alkyl, haloalkyl, -SF5, or – ORA; RAis alkyl or haloalkyl; and x is 0 or 1.

[0108] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, - CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, –OCH3, –OCH2CH3, –OCH2CF3, – OCH2CHF2, –OCF3, or –OCHF2; and x is 0 or 1.

[0109] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, -SF5, -CH3, -CF3, -CHF2, – OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0 or 1.

[0110] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, – OCH3, –OCH2CH3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2; and x is 0 or 1.

[0111] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, -CH3, -CF3, -CHF2, –OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0 or 1.

[0112] In certain embodiments, R1is, wherein each R6is independently haloalkyl or optionally substituted cycloalkyl; and x is 0 or 1.

[0113] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, – OCH3, –OCH2CH3, –OCH2CF3, –OCF3, –OCH2CHF2, or –OCHF2; and x is 0 or 1.

[0114] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, -CH3, -CF3, -CHF2, –OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0 or 1.

[0115] In certain embodiments,, wherein each R6is independently halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, -SF5, or –ORA; and RAis alkyl or haloalkyl.

[0116] In certain embodiments,, wherein each R6is independently haloalkyl or optionally substituted cycloalkyl.

[0117] In certain embodiments,, wherein each R6is independently -F, - SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, – OCH3, –OCH2CH3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2.

[0118] In certain embodiments,, wherein each R6is independently cyclopropyl, -CF3, –CF2CH3, or –CH2CF3.

[0119] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, – OCH3, –OCH2CH3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2; and x is 0 or 1.

[0120] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, -CH3, -CF3, -CHF2, –OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0 or 1.

[0121] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, – OCH3, –OCH2CH3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2; and x is 0 or 1.

[0122] In certain embodiments, R1is, wherein each R6is independently -F, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, –OCH3, – OCH2CH3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2; and x is 0 or 1.

[0123] In certain embodiments, R1is, wherein each R6is independently -F, -SF5, -CH3, -CF3, -CHF2, –OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0 or 1.

[0124] In certain embodiments, R1is, wherein each R6is independently cyclopropyl, -CF3, –CF2CH3, or –CH2CF3; and x is 0 or 1.

[0125] In certain embodiments, R1is or

[0126] In certain embodiments, R1is, , ,,, , , , ,

[0127] In certain embodiments, R1is, , ,, , o .

[0128] In certain embodiments, R1is, , ,

[0129] In certain embodiments, R1is.

[0130] In certain embodiments, R1is, , ,, , , or .

[0131] In certain embodiments, R1is or

[0132] In certain embodiments, R1is In certain embodimen1ts, R is In certain embodiments, R1is In certain embodiments, R1is

[0133] In certain embodiments, R1is optionally substituted carbocyclyl. In certain embodiments, R1is optionally substituted carbocyclyl, wherein the carbocyclyl is fused with a heteroaryl ring. In certain embodiments, R1is optionally substituted C8-14carbocyclyl, wherein the carbocyclyl is fused with a heteroaryl ring. In certain embodiments, R1is In certain embodiments, R1is

[0134] In certain embodiments, R1is, , ,, , , , , ,

[0135] In certain embodiments, R1is, , ,R2

[0136] As described herein, R2is an optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, R2is optionally substituted carbocyclyl. In certain embodiments, R2is optionally substituted cycloalkyl. In certain embodiments, R2is optionally substituted C3-8cycloalkyl. In certain embodiments, R2is optionally substituted C3-6 cycloalkyl. In certain embodiments, R2is optionally substituted C4-6cycloalkyl. In certain embodiments, R2is optionally substituted C5-6cycloalkyl. In certain embodiments, R2is optionally substituted cyclopentyl. In certain embodiments, R2is optionally substituted cyclobutyl. In certain embodiments, R2is optionally substituted cyclohexyl.

[0137] In certain embodiments, R2is, wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0138] In certain embodiments, R2is, wherein each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0139] In certain embodiments, R2is,wherein each R7is independently optionally substituted aryl or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0140] In certain embodiments, R2is, wherein each R7is independently optionally substituted aryl or optionally substituted heteroaryl; and y is 1.

[0141] In certain embodiments, R2is, wherein each R7is independently optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0142] In certain embodiments, R2is, wherein each R7is independently optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 1 or 2.

[0143] In certain embodiments, R2is, wherein each R7is independently optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 1 or 2.

[0144] In certain embodiments, R2is, wherein R7is optionally substituted aryl; and y is 1.

[0145] In certain embodiments, R2is, wherein R7is substituted aryl; and y is 1.

[0146] In certain embodiments, R2is, wherein R7is substituted phenyl; and y is 1.

[0147] In certain embodiments, R2is, wherein R7is optionally substituted heteroaryl; and y is 1.

[0148] In certain embodiments, R2is, wherein R7is substituted heteroaryl; and y is 1.

[0149] In certain embodiments, R2is, wherein R7is substituted pyridine, substituted thiazole, substituted isothiazole, substituted substituted pyrazole, or substituted indazole; and y is 1.

[0150] In certain embodiments, R2is. In certain embodiments, R2is

[0151] In certain embodiments, R2is

[0152] In certain embodiments, R2is,wherein two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 2.

[0153] In certain embodiments, R2is, wherein two instances of R7together with the atoms to which they are attached form a substituted heterocyclyl; and y is 2.

[0154] In certain embodiments, R2is, wherein two instances of R7together with the atoms to which they are attached form a substituted 4-6 membered heterocyclyl; and y is 2.

[0155] In certain embodiments, R2is, wherein two instances of R7together with the atoms to which they are attached form a substituted azetidine; and y is 2.

[0156] In certain embodiments, R2iswherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0157] In certain embodiments, R2iswherein R7is optionally substituted aryl; and y is 1.

[0158] In certain embodiments, R2is, wherein R7is substituted aryl; and y is 1.

[0159] In certain embodiments, R2is, wherein R7is substituted phenyl; and y is 1.

[0160] In certain embodiments, . certain embodiments, R2is In certain embodiments, R2is . In certain embodiments, R2is

[0161] In certain embodiments, R2is, wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0162] In certain embodiments, R2is, wherein R7is optionally substituted aryl; and y is 1.

[0163] In certain embodiments, R2is,wherein R7is substituted aryl; and y is 1.

[0164] In certain embodiments, R2is, wherein R7is substituted phenyl; and y is 1.

[0165] In certain embodiments, R2is. In certain embodiments, R2is

[0166] In certain embodiments, R2is, or .

[0167] In certain embodiments, R2is

[0168] In certain embodiments, R2is

[0169] In certain embodiments,. certain embodiments, R2isIn certain embodiments, R2is

[0170] In certain embodiments, R2is optionally substituted heterocyclyl. In certain embodiments, R2is optionally substituted 4-7 membered heterocyclyl comprising 1 or 2 nitrogen atoms in the ring. In certain embodiments, R2is optionally substituted azetidine, pyrrolidine, piperidine, or piperazine. In certain embodiments, R2is optionally substituted azetidine. In certain embodiments, R2is optionally substituted pyrrolidine. In certain embodiments, R2is optionally substituted piperidine. In certain embodiments, R2is optionally substituted piperazine.

[0171] In certain embodiments, R2is, wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

[0172] In certain embodiments, R2is, wherein R8is a nitrogen protecting group (e.g., BOC).

[0173] In certain embodiments, R2is, wherein R8is optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of - Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl, heteroaryl substituted with at least one instance of -Ohaloalkyl, alkyl, halogen, or haloalkyl, or a nitrogen protecting group. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2, heteroaryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2, or a nitrogen protecting group.

[0174] In certain embodiments, R2is, wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

[0175] In certain embodiments, R2is, wherein R8is a nitrogen protecting group (e.g., BOC).

[0176] In certain embodiments, R2is, wherein R8is optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group. In certainembodiments, R2is, wherein R8is aryl substituted with at least one instance of - Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl, heteroaryl substituted with at least one instance of -Ohaloalkyl, alkyl, halogen, or haloalkyl, or a nitrogen protecting group. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2, heteroaryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2, or a nitrogen protecting group.

[0177] In certain embodiments, R2is, wherein R8is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl; or heteroaryl substituted with at least one instance of -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2; or heteroaryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2.

[0178] In certain embodiments, R2is, wherein R8is optionally substituted aryl. In certain embodiments, R2is, wherein R8is aryl substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2, wherein R8is aryl substituted with at least one instance of -F, -CH3, CF3, - CHF2, –OCH3, –OCF3, or –OCHF2.

[0179] In certain embodiments, R2is, wherein R8is optionally substituted phenyl. In certain embodiments, R2is, wherein R8is substituted phenyl. In certain embodiments, R2is, wherein R8is phenyl substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2is, wherein R8is phenyl substituted with at least one instance of -F, -CH3, CF3, - CHF2, –OCH3, –OCF3, or –OCHF2.

[0180] In certain embodiments, R2is, wherein R8is optionally substituted heteroaryl. In certain embodiments, R2is, wherein R8is heteroaryl substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2is, wherein R8is heteroaryl substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2.

[0181] In certain embodiments, R2is, wherein R8is optionally substituted pyrazine, optionally substituted pyridine, optionally substituted pyridazine, optionally substituted pyrimidine, optionally substituted thiazole, optionally substituted thiadiazole, or optionally substituted indazole. In certain embodiments, R2is, wherein R8is substituted pyrazine, substituted pyridine, substituted pyridazine, substituted pyrimidine, substituted thiazole, unsubstituted thiadiazole, or substituted indazole. In certain embodiments, R2is, wherein R8is pyrazine, pyridine, pyridazine, pyrimidine,thiazole, thiadiazole, or indazole, each of which is optionally substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2is, wherein R8is pyrazine, pyridine, pyridazine, pyrimidine, thiazole, thiadiazole, or indazole, each of which is optionally substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2.

[0182] In certain embodiments, R2is, wherein R8is optionally substituted pyrazine, optionally substituted pyridine, optionally substituted pyridazine, or optionally substituted pyrimidine. In certain embodiments, R2is, wherein R8is substituted pyrazine, substituted pyridine, substituted pyridazine, or substituted pyrimidine. In certain embodiments, R2is, wherein R8is pyrazine, pyridine, pyridazine, or pyrimidine, each of which is substituted with at least one instance of -Oalkyl, -Ohaloalkyl, alkyl, halogen, or haloalkyl. In certain embodiments, R2is, wherein R8is pyrazine, pyridine, pyridazine, or pyrimidine, each of which is substituted with at least one instance of -F, -CH3, CF3, -CHF2, –OCH3, –OCF3, or –OCHF2.

[0183] In certain embodiments, R2isIn certain embodiments, R2is, ,

[0184] In certain embodiments, R2is, , ,

[0185] In certain embodiments, R2is, , ,, , o .

[0186] In certain embodiments, R2is

[0187] In certain embodiments, R2is

[0188] In certain embodiments, R2is,

[0189] In certain embodiments, R2is, , ,

[0190] In certain embodiments, R2is, ,

[0191] In certain embodiments, R2is, , ,

[0192] In certain embodiments, R2is, , ,B1and B2

[0193] As described herein, B1is –C(R4)t– or –N–, wherein t is 0 or 1 as valency permits; and B2is =C(R4)–, –N–, or –C(O)–. In certain embodiments, t is 0. In certain embodiments, t is 1.

[0194] In certain embodiments, B1is –CR4–. In certain embodiments, B1is =C– or –N–. In certain embodiments, B1is =C–. In certain embodiments, B1is –N–.

[0195] In certain embodiments, B2is =C(R4)–, –N–, or –C(O)–. In certain embodiments, B2is –N–. In certain embodiments, B2is –C(O)–. In certain embodiments, B2is =C(R4)–. In certain embodiments, B2is =C(H)–. In certain embodiments, B2is =C(CH3)–.

[0196] As described herein, each R4is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –ORA, – N(RA)2, –SRA, or –CN. In certain embodiments, each R4is independently hydrogen or optionally substituted alkyl. In certain embodiments, each R4is hydrogen. In certain embodiments, each R4is independently optionally substituted alkyl. In certain embodiments, each R4is independently unsubstituted alkyl. In certain embodiments, each R4is independently unsubstituted C1-4alkyl. In certain embodiments, each R4is independently - CH3.A1, A2, A3, and A4

[0197] As described herein, A1, A2, A3, and A4are each independently =C(R3)– or =N–; and each R3is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, – NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA. In certain embodiments, each R3is independently hydrogen, optionally substituted alkyl, or – ORA. In certain embodiments, each R3is independently hydrogen, unsubstituted alkyl, or – ORA. In certain embodiments, each R3is independently hydrogen, unsubstituted alkyl, or – ORA; and RAis unsubstituted alkyl. In certain embodiments, each R3is independently hydrogen, -CH3, –OCH3, or –OCH2CH3. In certain embodiments, each R3is hydrogen. In certain embodiments, each R3is independently hydrogen or unsubstituted alkyl. In certain embodiments, each R3is independently hydrogen or –ORA. In certain embodiments, each R3is independently hydrogen or –ORA; and RAis unsubstituted alkyl. In certain embodiments, each R3is independently hydrogen, –OCH3, or –OCH2CH3. In certain embodiments, each R3is independently hydrogen or –OCH3. In certain embodiments, each R3is independently hydrogen or -CH3. In certain embodiments, each R3is independently hydrogen, -CH3, – CH2CH3, or –CH2CH2CH3. In certain embodiments, each R3is independently hydrogen, or – CH2CH3. In certain embodiments, each R3is independently hydrogen or –CH2CH2CH3.

[0198] In certain embodiments, each R3is independently hydrogen or optionally substituted alkyl. In certain embodiments, each R3is independently hydrogen or substituted alkyl. In certain embodiments, each R3is independently hydrogen or haloalkyl. In certain embodiments, each R3is independently hydrogen, -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H. In certain embodiments, each R3is independently hydrogen or -CHF2. In certain embodiments, each R3is independently hydrogen or -CF3. In certain embodiments, each R3is independently hydrogen or –CH2CF3. In certain embodiments, each R3is independently hydrogen or –CF2CH3. In certain embodiments, each R3is independently hydrogen or – CH2CF2H.

[0199] In certain embodiments, each R3is independently hydrogen, –OCH3, –OCH2CH3, - CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or –CH2CF2H.

[0200] In certain embodiments, A1is =N–. In certain embodiments, A1is =C(R3)–. In certain embodiments, A1is =C(R3)–; wherein R3is independently hydrogen, optionally substituted alkyl, or –ORA. In certain embodiments, A1is =C(R3)–; wherein R3is independently hydrogen, unsubstituted alkyl, or –ORA; and RAis unsubstituted alkyl. In certain embodiments, A1is =C(R3)–; wherein R3is independently hydrogen, -CH3, –OCH3, or –OCH2CH3. In certain embodiments, A1is =C(R3)–; wherein R3is hydrogen, –OCH3, – OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H.

[0201] In certain embodiments, A2is =N–. In certain embodiments, A2is =C(R3)–. In certain embodiments, A2is =C(R3)–; wherein R3is independently hydrogen, optionally substituted alkyl, or –ORA. In certain embodiments, A2is =C(R3)–; wherein R3is independently hydrogen, unsubstituted alkyl, or –ORA; and RAis unsubstituted alkyl. In certain embodiments, A2is =C(R3)–; wherein R3is independently hydrogen, -CH3, –OCH3, or –OCH2CH3. In certain embodiments, A2is =C(R3)–; wherein R3is hydrogen, –OCH3, – OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H.

[0202] In certain embodiments, A3is =N–. In certain embodiments, A3is =C(R3)–. In certain embodiments, A3is =C(R3)–; wherein R3is independently hydrogen, optionally substituted alkyl, or –ORA. In certain embodiments, A3is =C(R3)–; wherein R3is independently hydrogen, unsubstituted alkyl, or –ORA; and RAis unsubstituted alkyl. In certain embodiments, A3is =C(R3)–; wherein R3is independently hydrogen, -CH3, –OCH3, or –OCH2CH3. In certain embodiments, A3is =C(R3)–; wherein R3is hydrogen, –OCH3, – OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H.

[0203] In certain embodiments, A4is =N–. In certain embodiments, A4is =C(R3)–. In certain embodiments, A4is =C(R3)–; wherein R3is independently hydrogen, optionally substituted alkyl, or –ORA. In certain embodiments, A4is =C(R3)–; wherein R3is independently hydrogen, unsubstituted alkyl, or –ORA; and RAis unsubstituted alkyl. In certain embodiments, A4is =C(R3)–; wherein R3is independently hydrogen, -CH3, –OCH3, or –OCH2CH3. In certain embodiments, A4is =C(R3)–; wherein R3is hydrogen, –OCH3, – OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H.

[0204] In certain embodiments, no more than two of A1, A2, A3, and A4are =N–. In certain embodiments, no more than one of A1, A2, A3, and A4is =N–. In certainembodiments, A1and A4are =N–; and A2and A3are =C(R3)–. In certain embodiments, A1and A3are =N–; and A2and A4are =C(R3)–. In certain embodiments, A2and A4are =N–; and A1and A3are =C(R3)–. In certain embodiments, A1, A2, and A3are =C(R3)–; and A4is =N–. In certain embodiments, A2, A3, and A4are =C(R3)–; and A1is =N–. In certain embodiments, A1, A2, A3, and A4are =C(R3)–.

[0205] In certain embodiments, A1and A4are =N–; and A2and A3are =C(R3)–, wherein each R3is independently hydrogen, –OCH3, –OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. - CHF2, -CF3, –CH2CF3, –CF2CH3, or –CH2CF2H. In certain embodiments, A1and A3are =N–; and A2and A4are =C(R3)–, wherein each R3is independently hydrogen, –OCH3, – OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or – CH2CF2H. In certain embodiments, A2and A4are =N–; and A1and A3are =C(R3)–, wherein each R3is independently hydrogen, –OCH3, –OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. - CHF2, -CF3, –CH2CF3, –CF2CH3, or –CH2CF2H. In certain embodiments, A1, A2, and A3are =C(R3)–; and A4is =N–, wherein each R3is independently hydrogen, –OCH3, –OCH2CH3, - CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, –CF2CH3, or –CH2CF2H. In certain embodiments, A2, A3, and A4are =C(R3)–; and A1is =N–, wherein each R3is independently hydrogen, –OCH3, –OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. -CHF2, -CF3, –CH2CF3, – CF2CH3, or –CH2CF2H. In certain embodiments, A1, A2, A3, and A4are =C(R3)–, wherein each R3is independently hydrogen, –OCH3, –OCH2CH3, -CH3, –CH2CH3, –CH2CH2CH3. - CHF2, -CF3, –CH2CF3, –CF2CH3, or –CH2CF2H. m and n

[0206] As described herein, each occurrence of RAis, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

[0207] In certain embodiments, each occurrence of RAis, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom.

[0208] In certain embodiments, each occurrence of RAis, independently, hydrogen, or optionally substituted alkyl. In certain embodiments, each occurrence of RAis, independently, hydrogen or unsubstituted alkyl. In certain embodiments, RAis hydrogen.

[0209] In certain embodiments, each occurrence of RAis, independently, haloalkyl or unsubstituted alkyl. In certain embodiments, each occurrence of RAis, independently, haloalkyl. In certain embodiments, each occurrence of RAis, independently, unsubstituted alkyl. In certain embodiments, each RAis independently C1-4haloalkyl or unsubstituted C1-4alkyl. In certain embodiments, each RAis independently C1-4haloalkyl. In certain embodiments, each RAis independently unsubstituted C1-4alkyl. In certain embodiments, each RAis independently -CHF2, -CF3, -CH2CF3, -CH2CH3, or -CH3. In certain embodiments, each RAis independently -CF3. In certain embodiments, each RAis independently -CH3. Certain Embodiments

[0210] In certain embodiments, the compound of Formula (I) is of Formula (I-a):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, R3, and R4are as defined herein.

[0211] In certain embodiments, the compound of Formula (I) is of Formula (I-a-1):(I-a-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0212] In certain embodiments, the compound of Formula (I) is of Formula (I-a-2):(I-a-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0213] In certain embodiments, the compound of Formula (I) is of Formula (I-a-3):(I-a-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0214] In certain embodiments, the compound of Formula (I) is of Formula (I-a-4):(I-a-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0215] In certain embodiments, the compound of Formula (I) is of Formula (I-a-5):(I-a-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0216] In certain embodiments, the compound of Formula (I) is of Formula (I-a-6):(I-a-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and Y, R1, R3, and R4are as defined herein.

[0217] In certain embodiments, the compound of Formula (I) is of Formula (I-a-7):(I-a-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are eachindependently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and R3and R4are as defined herein.

[0218] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; x is 0, 1, 2, or 3; and R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

[0219] In certain embodiments, the compound of Formula (I) is of Formula (I-a-8):(I-a-8), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0220] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; and x is 0, 1, 2, or 3.

[0221] In certain embodiments, the compound of Formula (I) is of Formula (I-a-9):(I-a-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0222] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; and x is 0, 1, 2, or 3.

[0223] In certain embodiments, the compound of Formula (I) is of Formula (I-a-10):(I-a-10), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2; and Y, R1, R3, and R4are as defined herein.

[0224] In certain embodiments, each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0225] In certain embodiments, the compound of Formula (I) is of Formula (I-a-11):(I-a-11), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R3and R4are as defined herein.

[0226] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0227] In certain embodiments, the compound of Formula (I) is of Formula (I-a-12):(I-a-12), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are eachindependently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0228] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0229] In certain embodiments, the compound of Formula (I) is of Formula (I-b):(I-b), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0230] In certain embodiments, the compound of Formula (I) is of Formula (I-c):(I-c), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0231] In certain embodiments, the compound of Formula (I) is of Formula (I-d):(I-d),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0232] In certain embodiments, the compound of Formula (I) is of Formula (I-e):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, R3, and R4are as defined herein.

[0233] In certain embodiments, the compound of Formula (I) is of Formula (I-e-1):(I-e-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0234] In certain embodiments, the compound of Formula (I) is of Formula (I-e-2):(I-e-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0235] In certain embodiments, the compound of Formula (I) is of Formula (I-e-3):(I-e-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and Y, R1, R3, and R4are as defined herein.

[0236] In certain embodiments, the compound of Formula (I) is of Formula (I-e-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and R3and R4are as defined herein.

[0237] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; x is 0, 1, 2, or 3; and R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

[0238] In certain embodiments, the compound of Formula (I) is of Formula (I-e-5):(I-e-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0239] In certain embodiments, the compound of Formula (I) is of Formula (I-e-6):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and Y, R1, R3, and R4are as defined herein.

[0240] In certain embodiments, each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0241] In certain embodiments, the compound of Formula (I) is of Formula (I-e-7):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R3and R4are as defined herein.

[0242] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0243] In certain embodiments, the compound of Formula (I) is of Formula (I-e-8):(I-e-8),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R3and R4are as defined herein.

[0244] In certain embodiments, Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or – ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

[0245] In certain embodiments, the compound of Formula (I) is of Formula (I-f):(I-f), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, R3, and R4are as defined herein.

[0246] In certain embodiments, the compound of Formula (I) is of Formula (I-f-1):(I-f-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0247] In certain embodiments, the compound of Formula (I) is of Formula (I-f-2):(I-f-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0248] In certain embodiments, the compound of Formula (I) is of Formula (I-g):(I-g), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, R3, and R4are as defined herein.

[0249] In certain embodiments, the compound of Formula (I) is of Formula (I-g-1):(I-g-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0250] In certain embodiments, the compound of Formula (I) is of Formula (I-g-2):(I-g-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0251] In certain embodiments, the compound of Formula (I) is of Formula (I-h):(I-h), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, R3, and R4are as defined herein.

[0252] In certain embodiments, the compound of Formula (I) is of Formula (I-h-1):(I-h-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, Y, R2, and R3are as defined herein.

[0253] In certain embodiments, the compound of Formula (I) is of Formula (I-h-2):(I-h-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R3are as defined herein.

[0254] In certain embodiments, the compound of Formula (I) is of Formula (I-a-3):(I-a-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and Y, R1, R3, and R4are as defined herein.

[0255] In certain embodiments, the compound of Formula (I) is of Formula (I-a-4):(I-a-4),or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; and R3and R4are as defined herein.

[0256] In certain embodiments, the compound of Formula (I) is of Formula (I-a-5):(I-a-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0257] In certain embodiments, the compound of Formula (I) is of Formula (I-a-6):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are eachindependently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0258] In certain embodiments, the compound of Formula (I) is of Formula (I-a-7):(I-a-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2; and Y, R1, R3, and R4are as defined herein.

[0259] In certain embodiments, the compound of Formula (I) is of Formula (I-a-8):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form asubstituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; y is 0, 1, or 2; and R3and R4are as defined herein.

[0260] In certain embodiments, the compound of Formula (I) is of Formula (I-a-9):(I-a-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R3and R4are as defined herein.

[0261] In certain embodiments, the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:9 956

[0262] In certain embodiments, the provided compounds (e.g., compounds of Formula (I)), antagonize C5aR1 with an IC50of less than 100,000 nM, less than 50,000 nM, less than20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0263] In certain embodiments, the provided compounds (e.g., compounds of Formula (I)), inhibit C5aR1 with an IC50of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. Pharmaceutical Compositions, Kits, and Administration

[0264] The present disclosure provides pharmaceutical compositions comprising a disclosed compound (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0265] In certain embodiments, the compound of any of the formulae herein (e.g., Formula (I) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder. In certain embodiments, the effectiveamount is an amount effective for treating an autoimmune, inflammatory, or neurological disease or disorder. In certain embodiments, the effective amount is an amount effective for treating a neurological disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder. In certain embodiments, the effective amount is an amount effective for preventing an autoimmune, inflammatory, or neurological disease or disorder. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease or disorder in a subject in need thereof.

[0266] In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof.

[0267] In certain embodiments, the effective amount is an amount effective for antagonizing C5aR1 in a subject, tissue, biological sample, or cell.

[0268] In certain embodiments, the subject being treated or administered a compound described herein is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0269] In certain embodiments, the effective amount is an amount effective for decreasing the activity of C5aR1 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 400%, at least about 500%, or at least about 1000%. In certain embodiments, the effective amount is an amount effective fordecreasing the activity of C5aR1 by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0270] The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) C5aR1 for use in treating a C5aR1-related disease or disorder in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., antagonizes) C5aR1 for use in treating a disease or disorder associated with aberrant activity of C5aR1 in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., antagonizes) C5aR1 for use in treating a disease or disorder associated with mutated C5aR1 in a subject in need thereof.

[0271] In certain embodiments, the composition is for use in treating a disease or disorder. In certain embodiments, the composition is for use in treating an autoimmune, inflammatory, or neurological disease or disorder. In certain embodiments, the composition is for use in treating a neurological disease or disorder.

[0272] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0273] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Codeof Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., neurological disease or disorder). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0274] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.

[0275] After formulation with an appropriate pharmaceutically acceptable excipient in a desired dosage, the pharmaceutical compositions of the present disclosure can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, topically, bucally, or the like, depending on the disease or condition being treated.

[0276] In certain embodiments, a pharmaceutical composition comprising a compound of any of the formulae herein (e.g., Formula (I) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, orprodrug thereof) is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg, from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, the composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects.

[0277] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0278] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps ofbringing the composition comprising a compound of Formula (I) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0279] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0280] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0281] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0282] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0283] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0284] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0285] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0286] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0287] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0288] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0289] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0290] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0291] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0292] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0293] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate,potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0294] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0295] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0296] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agents, 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, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, agents of the disclosure are mixed with solubilizing agents such CREMOPHOR EL®(polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0297] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic 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, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0298] Injectable formulations can be sterilized, for example, by filtration 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.

[0299] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent 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 i) lubricants such as 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.

[0300] 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 which 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 polyethylene glycols and the like.

[0301] The active agents 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 agent 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 which can be used include polymeric substances and waxes.

[0302] Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment, or soap. Useful carriers are capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen / thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used. 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 an agent to the body. Such dosage forms can be made by dissolving or dispensing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the agent across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the agent in a polymer matrix or gel.

[0303] Additionally, the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g., liquids and gels), an anhydrous oil or silicone-based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in- water, and oil-in-water-in-silicone emulsions. The emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. The emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems.

[0304] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0305] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kits are useful for decreasing the activity of C5aR1 in a subject or cell. In certain embodiments, the kits are useful for antagonizing C5aR1 in a subject or cell.

[0306] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof. In certainembodiments, the kits and instructions provide for decreasing the activity of C5aR1 in a subject or cell. In certain embodiments, the kits and instructions provide for antagonizing C5aR1 in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment

[0307] The present disclosure provides methods for treating a disease or disorder in a subject in need thereof. In certain embodiments, the present disclosure provides methods for treating a disease or disorder associated with C5aR1 (e.g., C5aR1 activity).

[0308] In certain embodiments, the disease or disorder is any of the following:

[0309] Autoimmune disorders (e.g., Rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, aHUS (Atypical Hemolytic Uremic Syndrome), Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection, hyperacute rejection of transplanted organs).

[0310] Inflammatory disorders and related conditions (e.g., Neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), age-related macular degeneration (AMD, both wet and dry forms), inflammation associated with severe burns, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as acute (adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disorder (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria and multiple organ dysfunction syndrome (MODS). Also included are pathologic sequellae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, IGA nephropathy, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via a heart-lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement), or in association with contact with other artificial vessel or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like), diseases related to ischemia / reperfusion injury, such as those resulting fromtransplants, including solid organ transplant, and syndromes such as ischemic reperfusion injury, ischemic colitis and cardiac ischemia. Compounds of the instant disclosure may also be useful in the treatment of age-related macular degeneration (Hageman et al, P.N.A.S.102: 7227-7232, 2005).

[0311] Cardiovascular and cerebrovascular disorders (e.g., myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of a compound of the disclosure may be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient who has one or more recognized risk factor for myocardial infarction or thrombosis, such as, but not limited to, obesity, smoking, high blood pressure, hypercholesterolemia, previous or genetic history of myocardial infarction or thrombosis) in order reduce the risk of myocardial infarction or thrombosis).

[0312] Diseases of vasculitis: vasculitic diseases are characterized by inflammation of the vessels. Infiltration of leukocytes leads to destruction of the vessel walls, and the complement pathway is believed to play a major role in initiating leukocyte migration as well as the resultant damage manifested at the site of inflammation (Vasculitis, Second Edition, Edited by Ball and Bridges, Oxford University Press, pp 47-53, 2008). The compounds provided in the present disclosure can be used to treat ANCA vasculitis (anti-neutrophil cytoplasmic autoantibody vasculitis). The compounds provided in the present disclosure can be used to treat leukoclastic vasculitis, urticarial vasculitis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schonlein purpura, polyateritis nodosa, Rapidly Progressive Glomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis (GCA), Behcet's disease and Takayasu's arteritis (TAK).

[0313] HIV infection and AIDS (e.g., C5a receptor modulators provided herein may be used to inhibit HIV infection, delay AIDS progression or decrease the severity of symptoms or HIV infection and AIDS).

[0314] Neurodegenerative disorders and related diseases (e.g., Alzheimer's disease, multiple sclerosis, and cognitive function decline associated with cardiopulmonary bypass surgery and related procedures).

[0315] Cancer and precancerous conditions (e.g., melanomas, lung cancer, lymphomas, sarcomas, carcinomas, and mixed tumors. Exemplary conditions that may be treated according to the present disclosure include fibrosarcomas, liposarcomas, chondrosarcomas, osteogenic sarcomas, angiosarcomas, lymphangiosarcomas, synoviomas, mesotheliomas, meningiomas, leukemias, lymphomas, leiomyosarcomas, rhabdomyosarcomas, squamous cellcarcinomas, basal cell carcinomas, adenocarcinomas, papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas, melanomas, renal cell carcinomas, hepatocellular carcinomas, transitional cell carcinomas, choriocarcinomas, seminomas, embryonal carcinomas, Wilm's tumors, pleomorphic adenomas, liver cell papillomas, renal tubular adenomas, cystadenomas, papillomas, adenomas, leiomyomas, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomas and fibromas. In some embodiments, the disease or disorder is selected from the group consisting of glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non- Hodgkin's lymphoma, leukemia, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, gastrointestinal tract, stomach cancer, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, asbestosis, and carcinoma).

[0316] In one embodiment, an effective amount of a compound of the disclosure may be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient who has one or more recognized risk factor for myocardial infarction or thrombosis, such as, butnot limited to, obesity, smoking, high blood pressure, hypercholesterolemia, previous or genetic history of myocardial infarction or thrombosis) in order reduce the risk of myocardial infarction or thrombosis.

[0317] In another embodiment, the compounds of the present disclosure are useful in the treatment of cisplatin induced nephrotoxicity. In this embodiment, compound treatment can alleviate the nephrotoxicity induced by cisplatin chemotherapy of malignancies (Hao Pan et al, Am J Physiol Renal Physiol, 296, F496-504, 2009).

[0318] In one embodiment, the compounds of the disclosure can be used for the treatment of diseases selected from the group consisting of sepsis (and associated disorders), COPD, rheumatoid arthritis, lupus nephritis and multiple sclerosis.

[0319] Provided herein is a method of treating a human suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutical composition thereof.

[0320] Provided herein is a method of inhibiting C5a receptor-mediated cellular chemotaxis comprising contacting mammalian white blood cells with a C5a receptor modulatory amount of an active metabolite of a compound of the disclosure.

[0321] In some embodiments, the disease or disorder is an inflammatory disease or disorder, a cardiovascular or cerebrovascular disorder, an autoimmune disease, or an oncologic disease or disorder.

[0322] In some embodiments, the disease or disorder is selected from the group consisting of neutropenia, neutrophilia, C3-glomerulopathy, C3-glomerulonephritis, dense deposit disease, membranoproliferative glomerulonephritis, Kawasaki disease, sepsis, septic shock, Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS), Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, Uveitis, tissue graft rejection, hyperacute rejection of transplanted organs, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, polypoidal choroidal vasculopathy, traumatic central nervous system injury, ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis, ANCA vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchialasthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, immuno vasculitis, Graft versus host disease, Paroxysmal nocturnal hemoglobinuria, Sjoegrens syndrome, insulin-dependent diabetes, mellitus, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, IGA nephropathy, Membranoproliferative glomerulonephritis, Antiphospholipid syndrome, Age related macular degeneration; Dry age related macular degeneration, Wet age related macular degeneration, Motor neurone disease, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces.

[0323] In some embodiments, the disease or disorder is selected from the group consisting of neutropenia, neutrophilia, C3-glomerulopathy, C3-glomerulonephritis, dense deposit disease, membranoproliferative glomerulonephritis, Kawasaki disease, Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS), tissue graft rejection, hyperacute rejection of transplanted organs, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, lupus glomerulonephritis, vasculitis, ANCA vasculitis, autoimmune hemolytic and thrombocytopenic states, immuno vasculitis, Graft versus host disease, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, IGA nephropathy, Membranoproliferative and glomerulonephritis.

[0324] In some embodiments, the disease or disorder is selected from the group consisting of melanoma, lung cancer, lymphoma, sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma. In some embodiments, the disease or disorder is selected from the group consisting of glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma,rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroid gland, cancer of the parathyroid gland, uterine cancer, cancer of the adrenal gland, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, gastrointestinal tract, stomach cancer, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, asbestosis, and carcinoma.

[0325] In certain embodiments, the autoimmune disease or disorder is acquired aplastic anemia, acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHLE) / Hurst’s disease, gammaglobulinemia, (primary), alopecia areata, ankylosing spondylitis (AS), anti-NMDA receptor encephalitis, antiphospholipid syndrome (APS), arteriosclerosis, autism spectrum disorders (ASD), autoimmune Addison’s disease (AAD), autoimmune dysautonomia / Autoimmune autonomic ganglionopathy (AAG), autoimmune encephalitis, autoimmune gastritis, autoimmune hemolytic anemia (AIHA), autoimmune hepatitis (AIH), autoimmune hyperlipidemia, autoimmune hypophysitis / lymphocytic hypophysitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis (AIP) / Immunoglobulin G4- Related Disease (IgG4-RD), autoimmune polyglandular syndromes (Types I, II, & III), autoimmune progesterone dermatitis, autoimmune sudden sensorineural hearing loss (SNHL), balo disease, Behcet's disease, birdshot chorioretinopathy / birdshot uveitis, bullous pemphigoid, castleman disease, celiac disease, chagas disease, chronic fatigue syndrome (CFS) / myalgic encephalomyelitis(ME), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic Lyme disease / post-treatment Lyme disease syndrome (PTLDS), chronic urticaria (CU), churg-Strauss syndrome / eosinophilic granulomatosis with polyangiitis (EGPA), cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, CREST syndrome / limited cutaneous systemic sclerosis, Crohn’s disease (CD), cronkhite- Canada syndrome (CSS), cryptogenic organizing pneumonia (COP), dermatitis herpetiformis, dermatomyositis, type 1 diabetes, discoid lupus, Dressler’s syndrome / postmyocardial infarction / postpericardiotomy syndrome, endometriosis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibrosing alveolitis, giant cell arteritis / temporal arteritis / Horton’s disease, glomerulonephritis, Goodpasture’s syndrome / anti-GBM / anti-TBM disease, granulomatosis with polyangiitis (GPA) / Wegener’s granulomatosis, Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s thyroiditis / chronic lymphocytic thyroiditis / autoimmune thyroiditis, Henoch-Schonlein purpura / IgA vasculitis, herpes gestationis / pemphigoid gestationis, hypogammaglobulinemia, IgA nephropathy / Berger’s disease, immune thrombocytopenia (ITP) / autoimmune thrombocytopenic purpura, interstitial cystitis juvenile idiopathic arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome (LEMS), leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD) / linear IgA bullous dermatosis (LABD), lupus nephritis, Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis (MG), neuromyelitis optica (NMO) / Devic’s disease, narcolepsy, non-length-dependent small fiber sensory neuropathy (SFSN), ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome (OMS), palindromic rheumatism, palmoplantar pustulosis (type of psoriasis), paraneoplastic cerebellar degeneration, paraneoplastic pemphigus, paroxysmal nocturnal hemoglobinuria (PNH), peripheral uveitis / pars planitis, parsonage turner syndrome, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postural orthostatic tachychardia syndrome (POTS), primary biliary cholangitis (PBC) / primary biliary cirrhosis, primary sclerosing cholangitis (PSC), psoriasis, psoriatic arthritis, pulmonary fibrosis, idiopathic (IPF), pure red cell aplasia, pyoderma gangrenosum, Raynaud’s phenomenon, reactive arthritis / Reiter’s syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, leg syndrome / Willis- Ekbom disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome / autoimmune poly endocrine syndrome type II, systemic sclerosis, scleritis, scleroderma, serpiginous choroidopathy, Sjogren’s syndrome, stiff person syndrome (SPS), systemic lupuserythematosus (SLE), subacute bacterial endocarditis (SBE), Sydenham’s chorea, sympathetic ophthalmia, Takayasu’s arteritis (vasculitis), testicular autoimmunity (vasculitis / orchitis), Tolosa-Hunt syndrome, transverse myelitis (TM), tubulointerstitial nephritis uveitis syndrome (TINU), ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis (anterior), uveitis (intermediate), uveitis (posterior), vasculitis, vitiligo, or Vogt-Koyanagi-Harada syndrome (VKH). In one embodiment, the autoimmune trigger is lupus nephritis. In another embodiment, the autoimmune trigger is systemic sclerosis.

[0326] In certain embodiments, the disease or disorder is age-related macular degeneration, Alzheimer’s disease, amyotrophic lateral sclerosis, anaphylaxis, anthrax poisoning, anti-neutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid syndrome, asthma, atherosclerosis, atopic dermatitis, atypical hemolytic uremic syndrome, autism, autoantibody-mediated disease, Berger disease, brain ischaemia, bronchiectasis, C3 glomerulopathy, cancer, Carnevale syndrome, CHAPLEE syndrome, chron disease, chronic obstructive pulmonary disease, cold agglutin disease, cutaneous lupus erythematosus, dementia, dermatomyositis, diabetic angiopathy, Ehlers-Danlos, epilepsy, frontotemporal dementia, generalized myasthenia gravis, geographic atrophy, glaucoma, glomerulonephritis, Guillain-Barre syndrome, hematopoetic stem cell transplant, complement mediated rejection, hereditary angioedema, hidradenitis supprativa, Huntington's disease, IgA nephropathy, immune thrombocytopenia, lupus nephritis, Malpuech syndrome, membranous glomerulonephritis, Michels syndrome, microscopic polyangiitis, Mingarelli syndrome, mood disorders, multifocal motor neuropathy, multiple sclerosis, myocardial infarction, neonatal HIE, neuromyelitis, optica spectrum disorder, neurotrauma, osteoarthritis, palmoplantar pustulosis, Parkinson's disorder, paroxysmal nocturnal haemoglobinuria, pemphigus, polytrauma, preeclampsia, primary membranous nephropathy, psoriasis, pyoderma gangraenosum, rare neutrophilic dermatoses, rheumatoid arthritis, schizophrenia, sepsis, severe thrombocytopenia, Shiga toxin associated hemolytic uremic syndrome, spinal cord injury, Stargardt disease, stroke, Sweet syndrome, systemic lupus erythematosus, systemic sclerosis, thrombotic microangiopathies, transplant rejection, Traumatic brain injury, ulcerative colitis, or vasculitis.

[0327] In certain embodiments, the application provides a method of treating cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder.

[0328] In certain embodiments, the application provides a method of treating an autoimmune, inflammatory, or neurological disease or disorder. In certain embodiments, the application provides a method of treating a neurological disease or disorder.

[0329] The present disclosure provides a method of antagonizing C5aR1. The present disclosure provides a method of decreasing the activity of C5aR1. In certain embodiments, the application provides a method of antagonizing C5aR1 (e.g., decreasing the activity of C5aR1) in vitro. In certain embodiments, the application provides a method of antagonizing C5aR1 (e.g., decreasing the activity of C5aR1) in vivo. In certain embodiments, the application provides a method of antagonizing C5aR1 in a cell. In certain embodiments, the application provides a method of antagonizing C5aR1 in a human cell.

[0330] In certain embodiments, the methods comprise administering to a subject in need thereof (e.g., a subject with a neurological disease or disorder) a compound that interacts with C5aR1, for example, a compound that is a modulator of C5aR1 (e.g., an antagonist of C5aR1), a binder of C5aR1, or a compound that modifies C5aR1. In certain embodiments, the methods comprise administering a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof.

[0331] Another object of the present disclosure is the use of a compound as described herein (e.g., of any formulae herein) in the manufacture of a medicament for use in the treatment of a disorder or disease described herein. Another object of the present disclosure is the use of a compound as described herein (e.g., of any formulae herein) for use in the treatment of a disorder or disease described herein. EXAMPLES

[0332] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Synthetic Methods

[0333] Compounds of Formula (I) were prepared following the synthetic schemes and procedures described in detail below. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Compounds of the disclosure that are not explicitly described in the following procedures may be prepared by analogous methods. Those having ordinary skill in the art would understand how to make such compounds from the disclosure provided herein and by means known in the art of organic synthesis. For example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof are representative and instructive. Methods for optimizing reaction conditions, if necessary minimizing competing by products, are known in the art. Embodiments of this disclosure include methods of synthesizing compounds delineated herein using any of the compounds, reactants, and / or processes delineated herein. General Procedure A

[0334] 3-Amino-N-methoxy-N,5-dimethylpyrazine-2-carboxamide: To a stirred mixture of 3-amino-5-methylpyrazine-2-carboxylic acid (300 mg, 1.95 mmol, 1 equiv) and N,O-dimethylhydroxylamine (179 mg, 2.93 mmol, 1.5 equiv) in DMF (5.00 mL) were added HATU (1120 mg, 2.93 mmol, 1.5 equiv) and DIEA (1260 mg, 9.79 mmol, 3 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 10 / 1 to afford 3-amino-N-methoxy-N,5-dimethylpyrazine-2-carboxamide (320 mg, 83%) as an off- white solid.General Procedure B

[0335] 3-Amino-5-methylpyrazine-2-carbaldehyde: To a stirred mixture of 3-amino-N- methoxy-N,5-dimethylpyrazine-2-carboxamide (320 mg, 1.63 mmol, 1 equiv) in THF (2 mL) were added LiAlH4(1M in THF, 1.95 mL, 1.95 mmol, 1.2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C. The desired product was detected by LCMS. The reaction was quenched by the addition of Na2SO4·10H2O (147 mg, 2 equiv) at 0°C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-5-methylpyrazine-2-carbaldehyde (200 mg, 89%) as a yellow solid. General Procedure C

[0336] 1-(3-Aminopyrazin-2-yl)ethan-1-one: To a stirred solution of 3-amino-N- methoxy-N-methylpyrazine-2-carboxamide (500 mg, 2.74 mmol, 1 equiv) in THF (10 mL) was added MeMgBr (3M in THF, 1.37 mL, 4.11 mmol, 1.5 equiv) dropwise at 0 °C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-(3-aminopyrazin-2-yl)ethan-1-one (400 mg, crude) as an off-white solid. General Procedure D

[0337] tert-Butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine- 1-carboxylate: To a stirred mixture of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1- carboxylate (450 mg, 1.75 mmol, 1.2 equiv) in THF (10 mL) was added LiHMDS (1M in THF, 8.75 mL, 8.75 mmol, 6 equiv) dropwise at -78°C under argon atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To the above mixture was added 3-amino-5- methylpyrazine-2-carbaldehyde (200 mg, 1.46 mmol, 1 equiv) in THF (5 mL) dropwise over 5 min at -78 °C. The resulting mixture was stirred for additional 5 h at -40 °C. To the above mixture was added KOH (491 mg, 8.75 mmol, 6 equiv) and EtOH (10 mL) at room temperature. The resulting mixture was stirred for additional overnight at 80 °C. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL).The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 10 / 1 to afford tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (320 mg, 63%) as a light brown solid. General Procedure E

[0338] tert-Butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: To a solution of tert-butyl 4- (3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (90 mg, 0.261 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (94.4 mg, 0.392 mmol, 1.5 equiv) in DMF (3 mL) was added K2CO3(108 mg, 0.783 mmol, 3 equiv) under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed by brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography, eluted with EtOAc / PE = 2 / 1, to afford tert-butyl 4-(3- methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin- 7-yl)piperidine-1-carboxylate (70 mg, 53%) as a white solid. General Procedure F

[0339] 3-Methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: A solution of tert-butyl 4-(3-methyl-6-oxo-5- ((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (70 mg, 0.139 mmol, 1 equiv) and HCl (gas) in 1,4-dioxane (4M, 2.00 mL) in DCM (2.00 mL) was stirred for 1 h at room temperature. After removing the solvent, the mixture was basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 3-methyl-7-(piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (45 mg) was used for next step without further purification. General Procedure G

[0340] 7-(1-(5-Fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: To the solution of3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin- 6(5H)-one (45 mg, 0.111 mmol, 1 equiv) and 3-bromo-5-fluoro-2-methylpyridine (25.3 mg, 0.133 mmol, 1.2 equiv) in dioxane (3 mL) were added 1612891-29-8 (4.68 mg, 0.006 mmol, 0.05 equiv) and Cs2CO3(108 mg, 0.333 mmol, 3 equiv) under argon atmosphere. The result mixture was stirred for overnight at 100 °C. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 2 / 1, to afford 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3- methyl-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one(19.3 mg, 33.4%) as a pink solid. General Procedure H

[0341] Ethyl 3-(difluoromethoxy)picolinate: To a solution of 2-bromo-3- (difluoromethoxy)pyridine (200 mg, 0.893 mmol, 1 equiv) and Pd(dppf)Cl2 (65.3 mg, 0.089 mmol, 0.1 equiv) in EtOH (3 mL) was added Et3N (271 mg, 2.67 mmol, 3 equiv) in a pressure tank. The mixture was purged with nitrogen for 5 min and then was pressurized to 50 atm with carbon monoxide at 100 °C for overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The desired product was detected by LCMS. After removing the solvent, the residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford ethyl 3-(difluoromethoxy)picolinate (180 mg, 92.8%) as a light yellow oil. General Procedure I

[0342] (3-(Difluoromethoxy)pyridin-2-yl)methanol: To a stirred mixture of ethyl 3- (difluoromethoxy)picolinate (180 mg, 0.829 mmol, 1 equiv) in MeOH (3 mL) were addedNaBH4(313 mg, 8.29 mmol, 10 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was warmed to 60 °C and stirred for overnight. The desired product was detected by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford (3-(difluoromethoxy)pyridin- 2-yl)methanol (100 mg, 68.8%) as a colorless oil. General Procedure J

[0343] 2-(Chloromethyl)-3-(difluoromethoxy)pyridine: To a stirred mixture of (3- (difluoromethoxy)pyridin-2-yl)methanol (100 mg, 0.571 mmol, 1 equiv) in DCM (3 mL) were added SOCl2(339 mg, 2.85 mmol, 5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 5 h at room temperature. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 2-(chloromethyl)-3-(difluoromethoxy)pyridine (100 mg, crude) which was used to next step without further purification. General Procedure K

[0344] 2-Amino-N-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)benzamide: To a solution of N-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-2-nitrobenzamide (100 mg, 0.280 mmol, 1 equiv) in 5 mL MeOH was added Pd / C (30 mg, 10% Pd on carbon, wetted with water) in a 50 mL round-bottom flask. The mixture was hydrogenated at room temperature for 4 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite®padand concentrated under reduced pressure. This resulted in 2-amino-N-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)benzamide (70 mg, 76.4%) as a colorless oil. General Procedure L

[0345] 3-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)quinazoline-2,4(1H,3H)-dione: To a stirred solution of 2-amino-N-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)benzamide (70 mg, 0.214 mmol, 1 equiv) in ACN (2 mL) was added CDI (52 mg, 0.321 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford 3-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)quinazoline-2,4(1H,3H)-dione (60 mg, 79%) as a white solid. General Procedure M

[0346] tert-Butyl 7-(((3-aminopyrazin-2-yl)methyl)amino)-2-azaspiro[3.5]nonane-2- carboxylate: A solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 0.416 mmol, 1 equiv) and 3-aminopyrazine-2-carbaldehyde (56.3 mg, 0.458 mmol, 1.1 equiv) in TFE (2 mL) was stirred for 1 h at 40 °C. To the above mixture was added NaBH4(23.6 mg, 0.624 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for additional overnight at 40 °C. The desired product was detected by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (2 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE = 5 / 1) to afford tert-butyl 7-(((3-aminopyrazin-2-yl)methyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 69%) as a white solid. General Procedure N

[0347] Benzyl 4-(1-formamido-2-methoxy-2-oxoethylidene)piperidine-1-carboxylate: To a stirred mixture of 2-methoxy-2-oxoacetonitrile (4.74 g, 55.7 mmol, 1.3 equiv) in THF(50 mL) was added NaH (2.57 g, 64.3 mmol, 1.5 equiv, 60%) in portions at 0 °C. The resulting mixture was stirred for 45 min at 0°C. To the above mixture was added benzyl 4- oxopiperidine-1-carboxylate (10 g, 42.9 mmol, 1 equiv) in THF(5 mL) dropwise over 5 min at 0°C. The resulting mixture was stirred for additional 1 h at 0°C. The desired product was detected by LCMS. The reaction was quenched by the addition of Water (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH = 10 / 1 to afford benzyl 4-(1-formamido-2- methoxy-2-oxoethylidene)piperidine-1-carboxylate (3 g, 31%) as an off-white solid. General Procedure O

[0348] Benzyl 4-(2-methoxy-2-oxoacetyl)piperidine-1-carboxylate: To a stirred mixture of benzyl 4-(1-formamido-2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (1 g, 3.01 mmol, 1 equiv) in MeOH(10 mL) were added HCl(g) in MeOH (2 mL, 4M) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in benzyl 4-(2-methoxy-2-oxoacetyl)piperidine-1-carboxylate (1 g, crude) which was used in next step without further purification. General Procedure P

[0349] Benzyl 4-(3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)piperidine-1- carboxylate: A solution of benzyl 4-(2-methoxy-2-oxoacetyl)piperidine-1-carboxylate (1 g, 3.27 mmol, 1 equiv) and pyrazine-2,3-diamine (0.36 g, 3.27 mmol, 1 equiv) in EtOH (10 mL) was stirred for overnight at 100 °C. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford benzyl 4-(3-oxo-3,4- dihydropyrazino[2,3-b]pyrazin-2-yl)piperidine-1-carboxylate (250 mg, 20.8%) as a yellow solid. General Procedure Q

[0350] 3-(Piperidin-4-yl)-1-(2-(trifluoromethyl)benzyl)pyrazino[2,3-b]pyrazin-2(1H)- one: A solution of benzyl 4-(3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3- b]pyrazin-2-yl)piperidine-1-carboxylate (100 mg, 0.191 mmol, 1 equiv)in HBr in AcOH(33%, 3 mL) was stirred for 4 h at room temperature. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 3-(piperidin-4-yl)-1-(2-(trifluoromethyl)benzyl)pyrazino[2,3-b]pyrazin-2(1H)-one (100 mg, crude) which was used in next step without further purification. General Procedure R

[0351] tert-Butyl 4-(2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(2-(methylthio)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (200 mg, 0.531 mmol, 1 equiv) in MeOH (2 mL), THF (2 mL) and H2O (4 mL) was added potassium peroxymonosulfate (357 mg, 2.12 mmol, 4 equiv) at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The desired product was detected by LCMS. The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The resulting solid was dried under vacuum. This resulted in tert-butyl 4-(2- (methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate (200 mg, 92%) as a white solid. General Procedure S

[0352] tert-Butyl 4-(2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate: A solution of EtOH (50.7 mg, 1.1 mmol, 3 equiv) in THF (2 mL) was added t-BuOK (123 mg, 1.1 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 30 min. tert-butyl 4-(2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)piperidine-1-carboxylate (150 mg, 0.367 mmol, 1 equiv) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The desired product was detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford tert-butyl 4-(2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)piperidine-1-carboxylate (90 mg, 65%) as a white solid. General Procedure T

[0353] tert-Butyl 4-(2-methoxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 4-(2-bromo-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.244 mmol, 1 equiv) in MeOH (2 mL) were added sodium methoxide (39.6 mg, 0.732 mmol, 3 equiv) at 25 °C. The resulting mixture was stirred for 4 h at 100 °C. The desired product was detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford tert-butyl 4-(2-methoxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate (60 mg, 68 %) as a yellow solid. General Procedure U

[0354] tert-Butyl 4-(2-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine- 1-carboxylate: To a stirred solution of tert-butyl 4-(2-bromo-6-oxo-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate (40 mg, 0.098 mmol, 1 equiv) and methylboronic acid (8.78 mg, 0.147 mmol, 1.5 equiv) in dioxane (1 mL) were added Cs2CO3(95.5 mg, 0.294 mmol, 3 equiv) and Pd(PPh3)4(11.3 mg, 0.01 mmol, 0.1 equiv) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 100 °C under nitrogen atmosphere. The desired product was detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE = 3 / 1) to afford tert-butyl 4-(2-methyl-6-oxo-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate (30 mg, 89%) as an off-white solid.General Procedure V

[0355] (6-(Trifluoromethyl)pyrazin-2-yl)methanol: To a stirred solution of 2-chloro-6- (trifluoromethyl)pyrazine (400 mg, 2.19 mmol, 1 equiv) and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.219 mmol, 0.1 equiv) in toluene (4 mL) was added (tributylstannyl)methanol (774 mg, 2.41 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE = 5 / 1) to afford (6- (trifluoromethyl)pyrazin-2-yl)methanol (140 mg, 35%) as a colorless oil. General Procedure W

[0356] (6-(Trifluoromethyl)pyrazin-2-yl)methyl methanesulfonate: To a stirred solution of (6-(trifluoromethyl)pyrazin-2-yl)methanol (140 mg, 0.786 mmol, 1 equiv) and TEA (238 mg, 2.35 mmol, 3 equiv) in DCM (2 mL) was added MsCl (135 mg, 1.17 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford (6-(trifluoromethyl)pyrazin-2-yl)methyl methanesulfonate (60 mg, 29%) as a colorless oil. General Procedure X

[0357] tert-Butyl 4-(6-oxo-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b] pyrazine-7-yl)piperidine-1-carboxylate: To a stirred mixture of tert- butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.303 mmol, 1 equiv) and (4-(trifluoromethyl)pyridin-3-yl)methanol (58.9 mg, 0.333 mmol, 1.1 equiv) in THF (3 mL) were added PPh3 (119 mg, 0.455 mmol, 1.5 equiv) and DEAD (79 mg, 0.455 mmol, 1.5 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 3 to afford tert-butyl 4-(6-oxo-5-((4- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazine-7-yl) piperidine-1- carboxylate (87 mg, 58%) as a yellow oil. General Procedure Y

[0358] Benzyl 4-(2-fluoro-6-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate: To a stirred mixture of benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (2 g, 5.82 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (1.32 g, 6.99 mmol, 1.2 equiv) in 1,4-dioxane (25 mL) and H2O (5 mL) were added XPhos Pd G3 (0.49 g, 0.583 mmol, 0.1 equiv) and XPhos (0.28 g, 0.583 mmol, 0.1 equiv) and K2CO3(2.42 g, 17.4 mmol, 3 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 100% gradient in 25 min; detector, UV 254 nm, to afford benzyl 4-(2-fluoro-6-methylphenyl)-3,6-dihydro-2H- pyridine-1-carboxylate (1.6 g, 84%) as a colorless oil.General Procedure Z

[0359] tert-Butyl 4-((5-aminopyrimidin-4-yl)ethynyl)piperidine-1-carboxylate: To a stirred solution of 4-iodopyrimidin-5-amine (200 mg, 0.905 mmol, 1 equiv) and tert-butyl 4- ethynylpiperidine-1-carboxylate (284 mg, 1.35 mmol, 1.5 equiv) in THF (5 mL) were added CuI (17.2 mg, 0.091 mmol, 0.1 equiv), Pd(PPh3)2Cl2(66.2 mg, 0.091 mmol, 0.1 equiv) and Et3N (274 mg, 2.71 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 °C under argon atmosphere. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 5 / 1 to afford tert-butyl 4-[2-(5-aminopyrimidin-4-yl)ethynyl]piperidine-1- carboxylate (200 mg, 73%) as a white solid. General Procedure AA

[0360] tert-butyl 4-(6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1- carboxylate: To a stirred solution of tert-butyl 4-((5-aminopyrimidin-4- yl)ethynyl)piperidine-1-carboxylate (150 mg, 0.496 mmol, 1 equiv) and sodium 2-chloro-2,2- difluoroacetate (151 mg, 0.992 mmol, 2 equiv) in DMF (2 mL) were added CuTc (18.9 mg, 0.099 mmol, 0.2 equiv) and NaHCO3(83.3 mg, 0.992 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for overnight at 100 °C under argon atmosphere. The desired product was detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 toafford tert-butyl 4-(6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (50 mg, 30%) as a white solid. General Procedure AB

[0361] To a stirred solution of 1-(3-fluoropyridin-2-yl)piperidin-4-amine hydrochloride (60 mg, 0.259 mmol, 1 equiv) in DMF (1 mL) were added 1-fluoro-3-methoxy-2- nitrobenzene (48.8 mg, 0.285 mmol, 1.1 equiv) and Cs2CO3(253 mg, 0.777 mmol, 3 equiv) at 25 °C. The resulting mixture was stirred for 2 hours at 25 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford 1-(3- fluoropyridin-2-yl)-N-(3-methoxy-2-nitrophenyl)piperidin-4-amine (60 mg, 66.7%) as a yellow solid. General Procedure AC

[0362] To a stirred solution of methyl 2-hydroxynicotinate (100 mg, 0.653 mmol, 1 equiv) in CH3NO2(2 mL) was added 1-(trifluoromethyl)-1lambda3,2-benziodaoxol-3-one (619 mg, 1.96 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for overnight at 100 °C under oxygen atmosphere. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel columnchromatography, eluted with EtOAc / PE = 1 / 1 to afford methyl 2- (trifluoromethoxy)nicotinate (50 mg, 34.6%) as a colorless oil. General Procedure AD

[0363] To a stirred solution of 4-(trifluoromethyl)pyrimidine-5-carboxylic acid (100 mg, 0.521 mmol, 1 equiv) in THF (1 mL) were added 4-methylmorpholine (94.7 mg, 0.938 mmol, 1.8 equiv) and isobutyl carbonochloridate (106 mg, 0.782 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the mixture was added NaBH4(59 mg, 1.56 mmol, 3 equiv) and MeOH (0.4 mL) at 0 °C. The resulting mixture was stirred for additional 1 h at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched by the addition of water (2 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford (4-(trifluoromethyl)pyrimidin-5-yl)methanol (35 mg, 37.7%) as a light yellow oil. General Procedure AE

[0364] To a stirred solution of 3-methylpyrazine-2-carbaldehyde (200 mg, 1.63 mmol, 1 equiv) in DCM (2 mL) was added DAST (791 mg, 4.91 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for overnight at room temperature. The desired product could be detected by LCMS. The residue was purified by silica gel column chromatography directly, eluted with PE / EA (1:1) to afford 2-(difluoromethyl)-3-methylpyrazine (60 mg, 25.4%) as a colorless oil. General Procedure AF

[0365] To a stirred solution of 2-(difluoromethyl)-3-methylpyrazine (100 mg, 0.694 mmol, 1 equiv) and NBS (185 mg, 1.04 mmol, 1.5 equiv) in CCl4(1 mL) was added AIBN (11.3 mg, 0.069 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for overnight at 80 °C. The desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. General Procedure AG

[0366] To a stirred solution of tert-butyl 4-(2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)piperazine-1-carboxylate (800 mg, 2.11 mmol, 1 equiv) in DCM (5 mL) was added mCPBA (731 mg, 4.23 mmol, 2 equiv) in portions at 0°C under air atmosphere. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl 4-(2-(methylsulfonyl)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)piperazine-1-carboxylate (300 mg, 34.5%) as a white solid. General Procedure AH

[0367] To a stirred mixture of 3-amino-6-ethylpyrazine-2-carboxylate (290 mg, 1.60 mmol, 1 equiv) in THF (3 mL) were added DIBAL-H (1M in THF, 2.4 mL, 2.4 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C. Desired product could be detected by LCMS. The reaction was quenched by the addition of Na2SO4.10H2O at 0°C. The resulting mixture was filtered, the filter cake waswashed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-6-ethylpyrazine-2-carbaldehyde (180 mg, 69.2%) as a yellow solid. General Procedure AI

[0368] To a solution of 3-bromo-5-(trifluoromethyl)pyrazin-2-amine (450 mg, 1.86 mmol, 1 equiv) and Pd(dppf)Cl2(272 mg, 0.372 mmol, 0.2 equiv) in MeOH (5 mL) was added Et3N (569 mg, 5.58 mmol, 3 equiv) in a pressure tank. The mixture was purged with nitrogen for 5 min and then was pressurized to 50 atm with carbon monoxide at 100°C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. Desired product could be detected by LCMS. After removing the solvent, the residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 3 to afford methyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate (250 mg, 57.1%) as a light yellow oil. General Procedure AJ

[0369] To a solution of methyl 3-amino-6-ethenylpyrazine-2-carboxylate (500 mg, 2.79 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (200 mg, 10% Pd on carbon, wetted with water) in a 50 mL round-bottom flask. The mixture was hydrogenated at room temperature for 4 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in methyl 3-amino-6-ethylpyrazine-2- carboxylat (350 mg, 63.8%) as a yellow solid. General Procedure AK

[0370] To a stirred solution of 2-chloro-3-methylpyrazine (500 mg, 3.9 mmol, 1.0 equiv) in EtOH (10 mL) were added Cs2CO3(3.8 g, 11.7 mmol, 3 equiv) at 25 °C. The resulting mixture was stirred for 4 h at 100 °C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE = 1 / 1 to afford 2-ethoxy-3-methylpyrazine (300 mg) as a yellow solid. General Procedure AL

[0371] To a stirred solution of 4-bromo-1,5-dimethylindazole (500 mg, 2.22 mmol, 1 equiv) and ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1- yl]acetate (653 mg, 2.22 mmol, 1.0 equiv)in dioxane (5 mL) and H2O (1 mL) was added Pd(dtbpf)Cl2 (145 mg, 0.222 mmol, 0.1 equiv) and K2CO3(921 mg, 6.66 mmol, 3.0 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred overnight at 80 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 2-[4-(1,5-dimethylindazol-4- yl)cyclohex-3-en-1-yl]acetate (590 mg, 85%) as a light yellow oil. General Procedure AM

[0372] To a stirred solution of 5,6,7,8-tetrahydroquinoxalin-5-ol (850 mg, 5.63 mmol, 1.0 equiv.) in DCM (10 mL) was added DMP (4.7 g, 11.2 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 2h at room temperature. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. Theresidue was purified by silica gel column chromatography, eluted with PE / EA (40% to 100% gradient in 10 min; detector, UV 254 nm.) to afford 7,8-dihydroquinoxalin-5(6H)-one (280 mg, 33.4%) as a white solid. General Procedure AN

[0373] To a stirred mixture of 4-bromo-1,2-thiazole (500 mg, 3.05 mmol, 1 equiv) in THF (15 mL) was added n-BuLi (1.34 mL, 3.35 mmol, 1.1 equiv) dropwise at -78°C under argon atmosphere. The resulting mixture was stirred for 2h at -78°C under argon atmosphere. To the above mixture was added methyl iodide (649 mg, 4.57 mmol, 1.5 equiv) dropwise at - 78°C under argon atmosphere. The resulting mixture was stirred for 2h at -78°C under argon atmosphere. The reaction was quenched by the addition of Na2SO4.10H2O at 0°C. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% to 100% gradient in 20min) to afford 4-bromo-5-methyl-1,2-thiazole (220 mg, 40.5%) as a yellow oil. General Procedure AO

[0374] To a stirred solution of 2-bromo-3,6-difluorobenzaldehyde (250 mg, 1.13 mmol, 1 equiv) and methyl hydrazine hydrochloride (103 mg, 1.24 mmol, 1.1 equiv) in NMP (2 mL) was added Cs2CO3(1106 mg, 3.39 mmol, 3 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for overnight at 100°C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10% to 50% gradient in 20 min; detector, UV 254 / 280 nm.) to afford 4-bromo-5-fluoro-1-methylindazole (138 mg, 53.2%) as a yellow solid. General Procedure AP

[0375] To a stirred mixture of 7-methyl-3-[(1r,4r)-4-(2-methoxy-4-methylpyridin-3- yl)cyclohexyl]-1H-1,8-naphthyridin-2-one (40 mg, 0.11 mmol, 1 equiv) and 2- (chloromethyl)-3-(trifluoromethyl)pyridine (25.8 mg, 0.132 mmol, 1.2 equiv) in DMF (1.5 mL) were added (t-BuO)2Mg (93.8 mg, 0.55 mmol, 5 equiv) and LiBr (47.8 mg, 0.55 mmol, 5 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 4 h at 60°C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (n-hexane / EA 3:1) to afford 3-((1r,4r)-4-(2-methoxy-4- methylpyridin-3-yl)cyclohexyl)-7-methyl-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,8- naphthyridin-2(1H)-one (45.5 mg, 75.3%) as a white solid. General Procedure AQ

[0376] To a stirred solution of 3-cyclopropylpyridine-2-carboxylic acid (300 mg, 1.84 mmol, 1 equiv) in THF (5 mL) was added BH3-Me2S (698 mg, 9.20 mmol, 5.0 equiv) at 0°C. The resulting mixture was stirred for 2 h at 0°C under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (3- cyclopropylpyridin-2-yl)methanol (60 mg, 21.9%) as a colorless oil. General Procedure AR

[0377] ethyl 2-(4-(2-fluoro-6-methylphenyl)cyclohexyl)acetate: A mixture of ethyl 2-[4- (2-fluoro-6-methylphenyl)cyclohex-3-en-1-yl]acetate (18 g, 65 mmol, 1 equiv) and Pd(OH)2 / C (6 g, 20% Pd(OH)2on carbon, wetted with water) in MeOH (200 mL) was stirred for 24 h at 50 °C under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. General Procedure AS

[0378] To a solution of benzyl 4-(6-methyl-3-oxo-4H-quinoxalin-2-yl)piperidine-1- carboxylate (350 mg, 0.927 mmol, 1 equiv) and Boc2O (202 mg, 0.927 mmol, 1 equiv) in 10 mL MeOH was added Pd / C (60%, 246 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 45min, filtered through a Celite pad and concentrated under reduced pressure. This resulted in tert-butyl 4-(6-methyl-3-oxo- 4H-quinoxalin-2-yl)piperidine-1-carboxylate (300 mg, 94.2%) as an off-white solid. General Procedure AT

[0379] To a stirred solution of 3-methylpyrazin-2-ol (1 g, 9.08 mmol, 1.0 equiv) and DHP (2.29 g, 27.2 mmol, 3.0 equiv) in DCM (5 mL) was added PTSA (0.16 g, 0.908 mmol, 0.1 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred overnight at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE / EA (1:10) to afford 2-methyl-3-(oxan-2- yloxy)pyrazine (870 mg, 49.3%) as a yellow oil. General Procedure AU

[0380] To a stirred solution of 1-[(3-hydroxypyrazin-2-yl)methyl]-7-methyl-3-[(1r,4r)-4- (2-fluoro-6-methylphenyl)cyclohexyl]-1,8-naphthyridin-2-one (150 mg, 0.327 mmol, 1.0 equiv) and methyl 2-chloro-2,2-difluoroacetate (56.72 mg, 0.392 mmol, 1.2 equiv) in DMF (3 mL) was added K2CO3(136 mg, 0.981 mmol, 3.0 equiv) at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 4:1) to afford 1-((3- (difluoromethoxy)pyrazin-2-yl)methyl)-3-((1r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 7-methyl-1,8-naphthyridin-2(1H)-one (20.4 mg, 11.6%) as a white solid. General Procedure AV

[0381] ethyl 2-(3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-en-1-yl)acetate: To a stirred mixture of ethyl 2-(3-oxocyclopentyl)acetate (500 mg, 2.94 mmol, 1 equiv) in DCM (20 mL) was added lutidine (944 mg, 8.82 mmol, 3 equiv) dropwise at 0°C under. The resulting mixture was stirred for 30 min at 0°C. To the above mixture was added Tf2O (2.49 g, 8.82 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for overnight at room temperature. The mixture was acidified to pH 6 with 1 mol / L HCl (aq.) at 0°C. The resulting mixture was extracted with DCM (3 x 120 mL). The combined organic layers were washed with brine (2 x 120 mL), dried over anhydrous Na2SO4. After filtration, the filtratewas concentrated under reduced pressure. The crude product was used in the next step directly without further purification. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one (1)

[0382] Step 1: tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate: Followed general procedure D using 3-aminopyrazine-2-carbaldehyde (600 mg, 4.87 mmol, 1 equiv) and tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1880 mg, 7.30 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (500 mg, 31%) as a light yellow solid. MS m / z: 331 [M+H]+.

[0383] Step 2: tert-butyl 4-(6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (200 mg, 0.605 mmol, 1 equiv) and 1-(chloromethyl)-2-(trifluoromethyl)benzene (141 mg, 0.726 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (220 mg, 74%) as a yellow solid. MS m / z: 489 [M+H]+.

[0384] Step 3: 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin- 6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-(2- (trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (220 mg, 0.45 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (180 mg) as a yellow oil. MS m / z: 389 [M+H]+.

[0385] Step 4: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl) pyrido[2,3-b]pyrazin-6(5H)-one (180 mg, 0.463 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methyl benzene (105 mg, 0.556 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (9.8 mg, 4.0%) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, 1H), 8.40 (d, 1H), 7.92 (s, 1H), 7.74 – 7.70 (m, 1H), 7.34 – 7.30 (m, 2H), 7.02 – 6.96 (m, 2H), 6.91 – 6.84 (m, 1H), 6.69 – 6.64 (m, 1H), 5.95 (s, 2H), 3.39 – 3.31 (m, 2H), 3.24 – 3.17 (m, 1H), 3.14 – 3.09 (m, 2H), 2.37 (s, 3H), 2.08 – 2.04 (m, 2H), 1.90 – 1.80 (m, 2H). MS m / z: 497.15 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-(2- (trifluoromethyl)benzyl)pyrido [2,3-b]pyrazin-6(5H)-one (2)

[0386] Step 1: tert-butyl 4-(8-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6- dihydropyrido[2,3-b] pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (250 mg, 0.726 mmol, 1 equiv) and 1-(chloromethyl)-2-(trifluoromethyl)benzene (169 mg, 0.871 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(8-methyl-6- oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (286 mg, 78%) as a yellow oil. MS m / z: 503 [M+H]+.

[0387] Step 2: 8-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(8-methyl-6-oxo-5-(2- (trifluoromethyl)benzyl)-5,6-dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (286 mg, 0.569 mmol, 1 equiv) as the starting material to give the crude product 8-methyl- 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (210 mg) as a yellow oil. MS m / z: 403 [M+H]+.

[0388] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-(2- (trifluoromethyl)benzyl) pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 8-methyl-7-(piperidin-4-yl)-5-(2-(trifluoromethyl) benzyl)pyrido[2,3-b]pyrazin-6(5H)- one (210 mg, 0.522 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (118 mg, 0.626 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-8-methyl-5-(2-(trifluoromethyl)benzyl) pyrido[2,3-b]pyrazin-6(5 H)-one (62.2 mg, 22.8%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, 1H), 8.35 (d, 1H), 7.72 – 7.68 (m, 1H), 7.33 – 7.28 (m, 2H), 7.00 – 6.93 (m, 2H), 6.89 – 6.83 (m, 1H), 6.69 – 6.66 (m, 1H), 5.92 (s, 2H), 3.37 – 3.26 (m, 3H), 3.11 (d, 2H), 2.78 (s, 3H), 2.77 – 2.70 (m, 2H), 2.38 (s, 3H), 1.63 (d, 2H). MS m / z: 511.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methoxypyrazin-2-yl)methyl)-8- methyl pyrido[2,3-b]pyrazin-6(5H)-one (3)

[0389] Step 1: tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-8-methyl-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (140 mg, 0.406 mmol, 1 equiv) and 2-(bromomethyl)-3-methoxypyrazine (98 mg, 0.487 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(5-((3- methoxypyrazin-2-yl)methyl)-8-methyl-6-oxo-5,6-dihydropyrido[2,3-b] pyrazin-7- yl)piperidine-1-carboxylate (168 mg, 88%) as a yellow solid. MS m / z: 467 [M+H]+.

[0390] Step 2: 5-((3-methoxypyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate (168, 0.36 mmol, 1 equiv) as the starting material to give the crude product 5-((3-methoxypyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one (100 mg) as a yellow oil. MS m / z: 367 [M+H]+.

[0391] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methoxypyrazin-2- yl)methyl)-8-methylpyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5- ((3-methoxypyrazin-2-yl)methyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (100 mg, 0.273 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (61.9 mg, 0.328 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4- yl)-5-((3-methoxypyrazin-2-yl)methyl)-8-methylpyrido[2, 3-b]pyrazin-6(5H)-one (22.6 mg, 16.7%) as an off-white solid.1H NMR (300 MHz, Chloroform-d) δ 8.46 (d, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 6.97 – 6.94 (m, 2H), 6.91 – 6.81 (m, 1H), 5.80 (s, 2H), 4.06 (s, 3H), 3.33 – 3.22 (m, 3H), 3.07 (d, 2H), 2.75 – 2.64 (m, 5H), 2.36 (s, 3H), 1.62 (d, 2H). MS m / z: 475.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (4)

[0392] Step 1: tert-butyl 4-(8-methyl-6-oxo-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate (140 mg, 0.406 mmol, 1 equiv) and 2-(bromomethyl)-3-(2,2,2-trifluoroethoxy)pyrazine (131 mg, 0.487 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(8-methyl-6-oxo-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (214 mg, 98%) as a yellow solid. MS m / z: 535 [M+H]+.

[0393] Step 2: 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(8-methyl-6-oxo-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (150 mg, 0.281 mmol, 1 equiv) as the starting material to give the crude product 8-methyl-7-(piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one(100 mg) as an off white solid. MS m / z 435 [M+H]+.

[0394] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 8-methyl-7-(piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (100 mg, 0.231 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (52.4 mg, 0.277 mmol, 1.2 equiv) as the starting materials to give 7- (1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (42 mg, 31.5%) as a yellow solid.1H NMR (300 MHz, Chloroform-d) δ 8.50 (d, 1H), 8.34 (d, 1H), 8.04 – 7.90 (m, 2H), 7.05 – 6.95 (m, 2H), 6.94 – 6.84 (m, 1H), 5.89 (s, 2H), 4.87 (q, 2H), 3.41 – 3.22 (m, 3H), 3.17 – 3.08 (m, 2H), 2.85 – 2.66 (m, 5H), 2.41 (s, 3H), 1.66 (d, 2H).MS m / z: 543.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methoxypyrazin-2- yl)methyl)pyrido[2,3 -b]pyrazin-6(5H)-one (5)

[0395] Step 1: tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (110 mg, 0.333 mmol, 1 equiv) and 1-(bromomethyl)-2-methoxybenzene (73.6 mg, 0.366 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (116 mg, 77%) as a light yellow solid. MS m / z: 453 [M+H]+.

[0396] Step 2: 5-(2-methoxybenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(5-((3-methoxypyrazin-2-yl)methyl)-6-oxo- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (116 mg, 0.256 mmol, 1 equiv) as the starting material to give the crude product 5-(2-methoxybenzyl)-7-(piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one (65 mg) as a yellow oil. MS m / z: 353 [M+H]+.

[0397] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methoxypyrazin-2- yl)methyl)pyrido [2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-(2- methoxybenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (65 mg, 0.185 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (42 mg, 0.222 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methoxypyrazin-2- yl)methyl)pyrido [2,3-b]pyrazin-6(5H)-one (22.1 mg, 25.7%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, 1H), 8.36 (d, 1H), 7.93 – 7.88 (m, 2H), 7.81 (d, 1H), 7.01 – 6.96 (m, 2H), 6.90 – 6.84 (m, 1H), 5.83 (s, 2H), 4.08 (s, 3H), 3.38 – 3.32 (m, 2H), 3.21 – 3.10 (m, 3H), 2.38 (s, 3H), 2.07 – 2.01 (m, 2H), 1.91 – 1.81 (m, 2H). MS m / z: 461.20 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl) methyl)pyrido[2,3-b]pyrazin-6(5H)-one (6)

[0398] Step 1: tert-butyl 4-(6-oxo-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-5,6- dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.303 mmol, 1 equiv) and 1-(bromomethyl)-2-(2,2,2-trifluoroethoxy)benzene (89.5 mg, 0.333 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)-5,6-dihydropyrido [2,3-b] pyrazine-7-yl)piperidine-1- carboxylate (150 mg, 95%) as a light yellow solid. MS m / z: 521 [M+H]+.

[0399] Step 2: 7-(piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4- (6-oxo-5-((3-(2,2,2-trifluoroethoxy) pyrazin-2-yl)methyl)-5,6-dihydropyrido [2,3-b] pyrazine-7-yl)piperidine-1-carboxylate (150 mg, 0.288 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (110 mg) as a yellow oil. MS m / z: 421 [M+H]+.

[0400] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(2,2,2- trifluoroethoxy)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy) pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (108 mg, 0.257 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (58.2 mg, 0.308 mmol, 1.2 equiv) as the starting materials to give 7- (1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl) methyl)pyrido[2,3-b]pyrazin-6(5H)-one (43.5 mg, 31.7%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, 1H), 8.36 (d, 1H), 7.96 – 7.93 (m, 2H), 7.88 (d, 1H), 7.01 –6.96 (m, 2H), 6.91 – 6.84 (m, 1H), 5.90 (s, 2H), 4.85 (q, 2H), 3.38 – 3.30 (m, 2H), 3.21 – 3.10 (m, 3H), 2.37 (s, 3H), 2.06 – 2.02 (m, 2H), 1.89 – 1.80 (m, 2H). MS m / z: 529.25 [M+H]+. 5-(2-Fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one (7)

[0401] Step 1: tert-butyl 4-(5-(2-fluorobenzyl)-8-methyl-6-oxo-5,6-dihydropyrido[2,3- b]pyrazin-7-yl) piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(8- methyl-6-oxo-5,6-dihydropyrido [2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (170 mg, 0.494 mmol, 1 equiv) and 1-(bromomethyl)-2-fluorobenzene (139 mg, 0.741 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(5-(2-fluorobenzyl)-8-methyl-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl) piperidine-1-carboxylate (200 mg, 89%) as a yellow solid. MS m / z: 453 [M+H]+.

[0402] Step 2: 5-(2-fluorobenzyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)- one: Followed general procedure F using tert-butyl 4-(5-(2-fluorobenzyl)-8-methyl-6-oxo- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl) piperidine-1-carboxylate (200 mg, 0.442 mmol, 1 equiv) as the starting material to give the crude product 5-(2-fluorobenzyl)-8-methyl-7- (piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (151 mg) as a yellow oil. MS m / z: 353 [M+H]+.

[0403] Step 3: 5-(2-fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-(2-fluorobenzyl)- 8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (70 mg, 0.199 mmol, 1 equiv) and 1-bromo-2-(trifluoromethyl)benzene (53.6 mg, 0.239 mmol, 1.2 equiv) as the startingmaterials to give 5-(2-fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5 H)-one (50.5 mg, 50.9%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, 1H), 8.41 (d, 1H), 7.67 – 7.53 (m, 3H), 7.24 – 7.17 (m, 2H), 7.08 – 7.03 (m, 1H), 6.99 – 6.90 (m, 2H), 5.78 (s, 2H), 3.57 (s, 1H), 3.29 (d , 2H), 3.04 (t, 2H), 2.79 (s, 5H), 1.72 (d, 2H). MS m / z: 497.25 [M+H]+. 7-(1-(3-Methylpyrazin-2-yl)piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one (8)

[0404] Step 1: tert-butyl 4-(6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (210 mg, 0.636 mmol, 1 equiv) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (229 mg, 0.954 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-(2-(trifluoromethyl)benzyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (180 mg, 57%) as a white solid. MS m / z: 489 [M+H]+.

[0405] Step 2: 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin- 6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-(2- (trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (180 mg, 0.368 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4- yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (180 mg) as a white solid. MS m / z: 389 [M+H]+.

[0406] Step 3: 7-(1-(3-methylpyrazin-2-yl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin- 6(5H)-one (65 mg, 0.135 mmol, 1 equiv) and 2-chloro-3-methylpyrazine (26.1 mg, 0.203 mmol, 1.5 equiv) as the starting materials to give 7-(1-(3-methylpyrazin-2-yl)piperidin-4-yl)- 5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (62.9 mg, 78.2%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.52 (d, 1H), 8.43 (t, 1H), 8.20 (s, 1H), 8.04 (d, 1H), 7.90 (s, 1H), 7.76 – 7.69 (m, 1H), 7.36 – 7.30 (m, 2H), 6.66 (d, 1H), 5.95 (s, 2H), 3.82 (d, 2H), 3.29 (t, 1H), 3.09 (t, 2H), 2.66 (s, 3H), 2.17 (d, 2H), 1.90 – 1.81 (m, 2H). MS m / z: 481.25 [M+H]+. 7-(1-(3-Methoxypyrazin-2-yl)piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3- b]pyrazin-6(5H)-one (9)

[0407] Step 1: 7-(1-(3-methoxypyrazin-2-yl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (65 mg, 0.135 mmol, 1 equiv) and 2-chloro-3-methoxypyrazine (29.3 mg, 0.203 mmol, 1.5 equiv) as the starting materials to give 7-(1-(3-methoxypyrazin-2-yl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (49 mg, 72.6%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, 1H), 8.41 (d, 1H), 7.87 – 7.85 (m, 1H), 7.76 – 7.71 (m, 2H), 7.61 – 7.58 (m, 1H), 7.36 – 7.30 (m, 2H), 6.68 – 6.61 (m, 1H), 5.94 (s, 2H), 4.50 (d, 2H), 4.03 (s, 3H), 3.39 – 3.28 (m, 1H), 3.24 – 3.07 (m, 2H), 2.17 (d, 2H), 1.94 – 1.79 (m, 2H). MS m / z: 497.2 [M+H]+. 5-(2-fluorobenzyl)-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3-b]pyrazin- 6(5H)-one (10)

[0408] Step 1: tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (210 mg, 0.636 mmol, 1 equiv) and 1-(bromomethyl)-2-fluorobenzene (180 mg, 0.954 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate (240 mg, 85.8%) as an off-white solid. MS m / z: 439 [M+H]+.

[0409] Step 2: 5-(2-fluorobenzyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(5-(2-fluorobenzyl)-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (120 mg, 0.274 mmol, 1 equiv) as the starting material to give the crude product 5-(2-fluorobenzyl)-7-(piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one(100 mg) as an off white solid. MS m / z: 339 [M+H]+.

[0410] Step 3: 5-(2-fluorobenzyl)-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-(2-fluorobenzyl)- 7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (100 mg, 0.296 mmol, 1 equiv) and 1- bromo-2-(trifluoromethyl)benzene (99.7 mg, 0.444 mmol, 1.5 equiv) as the starting materials to give 5-(2-fluorobenzyl)-7-(1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one (84.1 mg, 58.3%) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.52 – 8.49 (m, 1H), 8.47 – 8.45 (m, 1H), 7.88 (d, 1H), 7.65 (d, 1H), 7.58 – 7.51 (m, 1H), 7.48 (s, 1H), 7.25 – 7.18 (m, 2H), 7.10 – 7.03 (m, 1H), 7.02 – 6.96 (m, 2H),5.80 (s, 2H), 3.28 – 3.13 (m, 3H), 2.98 (t, 2H), 2.12 – 2.02 (m, 2H), 2.00 – 1.85 (m, 2H). MS m / z: 483.25 [M+H]+. 5-(2-Fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)pyrido [2,3-b]pyrazin-6(5H)-one (11)

[0411] Step 1: 5-(2-fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)pyridin-3- yl)piperidin-4-yl)pyrido [2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-(2- fluorobenzyl)-8-methyl-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (75 mg, 0.213 mmol, 1 equiv) and 3-bromo-2-(trifluoromethyl)pyridine (57.7 mg, 0.256 mmol, 1.2 equiv) as the starting materials to give 5-(2-fluorobenzyl)-8-methyl-7-(1-(2-(trifluoromethyl)pyridin- 3-yl)piperidin-4-yl)pyrido[2,3-b] pyrazine-6(5H)-one (48.6 mg, 44.8%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.58 (d, 1H), 8.45 – 8.43 (m, 1H), 8.03 – 8.01 (m, 1H), 7.71 – 7.67 (m, 1H), 7.31 – 7.20 (m, 2H), 7.05 – 7.01 (m, 1H), 6.83 – 6.80 (m, 1H), 5.63 (s, 2H), 3.24 (d, 1H), 3.14 (d, 2H), 2.98 – 2.93 (m, 2H), 2.69 (s, 3H), 2.65 – 2.58 (m, 2H), 1.62 (d, 2H). MS m / z: 499.20 [M+H]+.7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (12)

[0412] Step 1: tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (45 mg, 0.136 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (49.2 mg, 0.204 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (30 mg, 44%) as a white solid. MS m / z: 491 [M+H]+.

[0413] Step 2: 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (30 mg, 0.061 mmol, 1 equiv) as the starting material to give the crude product 7- (piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (20 mg) as a yellow oil. MS m / z: 391 [M+H]+.

[0414] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (20 mg, 0.041 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (11.5 mg, 0.061 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (7.5 mg, 36.9%) as an off-white solid.1H NMR (400 MHz, Chloroform- d) δ 8.53 – 8.49 (m, 2H), 8.44 (d, 1H), 8.34 (d, 1H), 7.95 (d, 1H), 7.10 – 6.98 (m, 2H), 6.96 – 6.87 (m, 1H), 6.09 (s, 2H), 3.54 – 3.43 (m, 2H), 3.32 – 3.17 (m, 3H), 2.51 (s, 3H), 2.28 – 2.14 (m, 2H), 2.10 – 2.06 (m, 2H). MS m / z: 499.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (13)

[0415] Step 1: 3-(chloromethyl)-2-(trifluoromethyl)pyridine: Followed general procedure J using (2-(trifluoromethyl)pyridin-3-yl)methanol (500 mg, 2.82 mmol, 1.2 equiv) as the starting material to give the crude product 3-(chloromethyl)-2-(trifluoromethyl)pyridine (360 mg) as a yellow solid. MS m / z: 196 [M+H]+.

[0416] Step 2: tert-butyl 4-(6-oxo-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.302 mmol, 1 equiv) and 3-(chloromethyl)-2-(trifluoromethyl)pyridine (88.8 mg, 0.453 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((2- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (95 mg, 65%) as a white solid. MS m / z: 490 [M+H]+.

[0417] Step 3: 7-(piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((2- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (70 mg, 0.143 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (45 mg) as a yellow oil. MS m / z: 390 [M+H]+.

[0418] Step 4: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((2- (trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (30 mg, 0.077 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (21.8 mg, 0.115 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (7.7 mg, 19.9%) as an off-white solid.1H NMR (400 MHz, Chloroform- d) δ 8.58 (d, 1H), 8.53 (d, 1H), 8.40 (d, 1H), 8.03 – 7.92 (m, 1H), 7.33 – 7.28 (m, 1H), 7.10 (d, 1H), 7.07 – 6.97 (m, 2H), 6.96 – 6.86 (m, 1H), 5.96 (s, 2H), 3.53 – 3.37 (m, 2H), 3.30 – 3.16 (m, 3H), 2.54 – 2.38 (m, 3H), 2.19 – 1.97 (m, 4H). MS m / z: 498.20 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (14)

[0419] Step 1: tert-butyl 4-(6-oxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (85 mg, 0.257 mmol, 1 equiv) and 5-(bromomethyl)-2-(trifluoromethyl)pyridine (67.9 mg, 0.283 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (90 mg, 71%) as an off-white solid. MS m / z 490 [M+H]+.

[0420] Step 2: 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((6- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (90 mg, 0.184 mmol, 1 equiv) as the starting material to give the crude product 7- (piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (60 mg) as a yellow oil. MS m / z 390 [M+H]+.

[0421] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((6- (trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one(60 mg, 0.154 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (32 mg, 0.169 mmol, 1.1 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (37.3 mg, 47.7%) as an off-white solid.1H NMR (300 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.59 – 8.54 (m, 1H), 8.53 – 8.48 (m, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.64 (d, 1H), 7.12 – 6.88 (m, 3H), 5.81 (s, 2H), 3.56 – 3.41 (m, 2H), 3.31 – 3.16 (m, 3H), 2.47 (s, 3H), 2.13 – 1.94 (m, 4H).MS m / z: 498.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (15)

[0422] Step 1: tert-butyl 4-(6-oxo-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (85 mg, 0.257 mmol, 1 equiv) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (67.9 mg, 0.283 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((5- (trifluoromethyl)pyridin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (90 mg, 71%) as an off-white solid. MS m / z: 490 [M+H]+.

[0423] Step 2: 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-(2- (trifluoromethyl)benzyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (90 mg, 0.184 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4- yl)-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (60 mg) as a yellow oil. MS m / z 390 [M+H]+.

[0424] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((5- (trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one(60 mg, 0.154 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (32 mg, 0.169 mmol, 1.1 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (28.1 mg, 35.7%) as an off-white solid.1H NMR (300 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.57 – 8.51 (m, 1H), 8.49 – 8.42 (m, 1H), 7.92 (d, 1H), 7.88 (dd, 1H), 7.37 (d, 1H), 7.07 – 6.97 (m, 2H), 6.94 – 6.84 (m, 1H), 5.94 (s, 2H), 3.40 (t, 2H), 3.28 – 3.09 (m, 3H), 2.42 (s, 3H), 2.14 – 2.02 (m, 2H), 2.00 – 1.85 (m, 2H).MS m / z: 498.25 [M+H]+.7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((4-(trifluoromethyl)pyridin-3- yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one (16)

[0425] Step 1: tert-butyl 4-(6-oxo-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)-5,6- dihydropyrido[2,3-b] pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure X using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b] pyrazine-7-yl)piperidine-1-carboxylate (100 mg, 0.303 mmol, 1 equiv) and (4-(trifluoromethyl)pyridin-3-yl)methanol (58.9 mg, 0.303 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((4- (trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (87 mg, 58%) as a yellow oil. MS m / z: 490 [M+H]+.

[0426] Step 2: 7-(piperidin-4-yl)-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((4- (trifluoromethyl) pyridin-3-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (80 mg, 0.163 mmol, 1 equiv) as the starting material to give the crude product 7- (piperidin-4-yl)-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (44.5 mg) as a yellow oil. MS m / z: 390 [M+H]+.

[0427] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((4- (trifluoromethyl)pyridin-3-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((4-(trifluoromethyl) pyridin-3-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (35 mg, 0.09 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (20.3 mg, 0.108 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2, 3- b]pyrazin-6(5H)-one (19.9 mg, 41.9%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, 1H), 8.53 (d, 1H), 8.39 (d, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.01 – 6.96 (m, 2H), 6.90 – 6.84(m, 1H), 5.96 (s, 2H), 3.39 – 3.32 (m, 2H), 3.22 – 3.11 (m, 3H), 2.38 (s, 3H), 2.07 – 2.00 (m, 2H), 1.90 – 1.81 (m, 2H). MS m / z: 475.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-4- yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one (17)

[0428] Step 1: tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-4-yl)methyl)-5,6- dihydropyrido[2,3-b] pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure X using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.303 mmol, 1 equiv) and (3-(trifluoromethyl)pyridin-4-yl)methanol (58.9 mg, 0.303 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyridin-4-yl)methyl)-5,6-dihydropyrido[2,3-b] pyrazin-7-yl)piperidine-1- carboxylate (50 mg, 33%) as a yellow oil. MS m / z: 490 [M+H]+.

[0429] Step 2: 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-4-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl) pyridin-4-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (50 mg, 0.102 mmol, 1 equiv) as the starting material to give the crude product 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-4-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (50 mg) as a yellow oil. MS m / z: 390 [M+H]+.

[0430] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-4-yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((3-(trifluoromethyl) pyridin-4-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (50 mg, 0.128 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (29.1 mg, 0.154 mmol, 1.2 equiv) as the starting materials to give 7-(1-(2-fluoro-6- methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-4-yl)methyl) pyrido[2,3- b]pyrazin-6(5H)-one (25.6 mg, 39.6%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.58 – 8.55 (m, 2H), 8.39 (d, 1H), 7.98 (s, 1H), 7.05 – 6.99 (m, 2H), 6.94 – 6.89 (m, 1H), 6.70 (d, 1H), 5.94 (s, 2H), 3.46 (s, 2H), 3.26 – 3.19 (m, 3H), 2.48 (s, 3H), 2.08 (s, 4H). MS m / z: 498.20 [M+H]+. 5-(2-Fluorobenzyl)-7-(1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)pyrido[2,3- b]pyrazin-6(5H)-one (18)

[0431] Step 1: 5-(2-fluorobenzyl)-7-(1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-4- yl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-(2-fluorobenzyl)- 7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one hydrochloride (100 mg, 0.296 mmol, 1 equiv) and 3-bromo-2-(trifluoromethyl)pyridine (100 mg, 0.444 mmol, 1.5 equiv) as the starting materials to give 5-(2-fluorobenzyl)-7-(1-(2-(trifluoromethyl)pyridin-3-yl)piperidin- 4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (69.3 mg, 48.3%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.52 – 8.49 (m, 1H), 8.49 – 8.44 (m, 2H), 7.88 (s, 1H), 7.75 (d, 1H), 7.51 – 7.45 (m, 1H), 7.25 – 7.18 (m, 1H), 7.10 – 7.03 (m, 1H), 7.02 – 6.96 (m, 2H), 5.81 (s, 2H), 3.28 (d, 2H), 3.19 (ddd, 1H), 2.97 (t, 2H), 2.16 – 2.06 (m, 2H), 1.95 – 1.84 (m, 2H).MS m / z: 484.25 [M+H]+.7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methylpyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (20)

[0432] Step 1: 2-(chloromethyl)-3-methylpyrazine: Followed general procedure J using (3-methylpyrazin-2-yl)methanol (200 mg, 1.61 mmol, 1 equiv) and SOCl2 (574 mg, 4.83 mmol, 3 equiv) as the starting materials to give 2-(chloromethyl)-3-methylpyrazine (170 mg, 74%) as a yellow oil. MS m / z: 143 [M+H]+.

[0433] Step 2: tert-butyl 4-(5-((3-methylpyrazin-2-yl)methyl)-6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using 2-(chloromethyl)-3-methylpyrazine (200 mg, 1.4 mmol, 1 equiv) and tert-butyl 4-(6- oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (556 mg, 1.68 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(5-((3-methylpyrazin-2-yl)methyl)-6-oxo- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (320 mg, 52%) as a white solid. MS m / z: 437 [M+H]+.

[0434] Step 3: 5-((3-methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin- 6(5H)-one: Followed general procedure F using tert-butyl 4-(5-((3-methylpyrazin-2- yl)methyl)-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (100 mg, 0.229 mmol, 1 equiv) as the starting material to give the crude product 5-((3-methylpyrazin- 2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (65 mg) as a yellow oil. MS m / z: 337 [M+H]+.

[0435] Step 4: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-methylpyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 5-((3- methylpyrazin-2-yl)methyl)-7-(piperidin-4-yl)pyrido[2,3-b]pyrazin-6(5H)-one (40 mg, 0.119mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (33.7 mg, 0.178 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- methylpyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (13.9 mg, 25.8%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.53 (d, 1H), 8.34 (d, 1H), 8.15 (d, 1H), 7.94 (s, 1H), 7.07 – 6.93 (m, 3H), 5.78 (s, 2H), 3.22 – 3.15 (m, 2H), 3.10 – 3.03 (m, 2H), 3.02 – 2.95 (m, 1H), 2.72 (s, 3H), 2.33 (s, 3H), 1.96 – 1.89 (m, 2H), 1.87 – 1.74 (m, 2H). MS m / z: 445.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (21)

[0436] Step 1: tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (50 mg, 0.151 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyridine hydrogen bromide (48.5 mg, 0.151 mmol, 1 equiv) as the starting materials to give tert-butyl 4-(6-oxo- 5-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine- 1-carboxylate (50 mg, 69%) as a yellow solid. MS m / z: 490 [M+H]+.

[0437] Step 2: 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyridin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (50 mg, 0.102 mmol, 1 equiv) as the starting material to give the crude product 7- (piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (34.6 mg) as a white solid. MS m / z: 390 [M+H]+.

[0438] Step 3: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-5-((3- (trifluoromethyl)pyridin-2-yl)me-thyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (35 mg, 0.09 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (30.3 mg, 0.135 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2- (trifluoromethyl)phenyl)piperidin-4-yl)-5-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (33.2 mg, 42.3%) as a off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.47 – 8.35 (m, 3H), 7.98 – 7.95 (m, 1H), 7.91 (d, 1H), 7.25 – 7.22 (m, 1H), 7.03 – 6.97 (m, 2H), 6.91 – 6.86 (m, 1H), 6.04 (s, 2H), 3.42 (d, 2H), 3.23 – 3.16 (m, 3H), 2.44 (s, 3H), 2.09 – 1.98 (m, 4H). MS m / z: 498 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (22)

[0439] Step 1: 3-amino-N-methoxy-N,5-dimethylpyrazine-2-carboxamide: Followed general procedure A using 3-amino-5-methylpyrazine-2-carboxylic acid (300 mg, 1.95 mmol, 1 equiv) and N,O-dimethylhydroxylamine (179 mg, 2.93 mmol, 1.5 equiv) as the starting materials to give 3-amino-N-methoxy-N,5-dimethylpyrazine-2-carboxamide (320 mg, 83%) as an off-white solid. MS m / z: 183 [M+H]+.

[0440] Step 2: 1-(3-aminopyrazin-2-yl)ethan-1-one: Followed general procedure C using 3-amino-N-methoxy-N-methylpyrazine-2-carboxamide (500 mg, 2.74 mmol, 1 equiv) as the starting material to give the crude product 1-(3-aminopyrazin-2-yl)ethan-1-one (400 mg) as an off-white solid. MS m / z: 138 [M+H]+.

[0441] Step 3: tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate: Followed general procedure D using 1-(3-aminopyrazin-2- yl)ethan-1-one (200 mg, 1.45 mmol, 1 equiv) and tert-butyl 4-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate (450 mg, 1.75 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (200 mg, 39%) as an off-white solid. MS m / z: 345 [M+H]+.

[0442] Step 4: tert-butyl 4-(8-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(8-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (70 mg, 0.203 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (53.8 mg, 0.223 mmol, 1.1 equiv) as the starting materials to give tert-butyl 4-(8-methyl-6- oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7- yl)piperidine-1-carboxylate (50 mg, 48%) as an off-white solid. MS m / z: 505 [M+H]+.

[0443] Step 5: 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4- (8-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate (50 mg, 0.099 mmol, 1 equiv) as the starting material to give the crude product 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (40 mg) as a light yellow oil. MS m / z: 405 [M+H]+.

[0444] Step 6: 7-(1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 8-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (40 mg, 0.099 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (28 mg, 0.149 mmol, 1.5 equiv) as the starting materials to give 7- (1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-8-methyl-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (21.3 mg, 42%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.52 – 8.46 (m, 2H), 8.46 – 8.41 (m, 1H), 8.28 (d, 1H), 7.03 – 6.93 (m, 2H), 6.92 – 6.81 (m, 1H), 6.07 (s, 2H), 3.35 – 3.24 (m, 3H), 3.15 – 3.08 (m, 2H), 2.78 (s, 3H), 2.75 – 2.64 (m, 2H), 2.39 (s, 3H), 1.68 – 1.61 (m, 2H). MS m / z: 513.25 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)pyrrolidin-3-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl) pyrido[2,3-b]pyrazin-6(5H)-one (23)

[0445] Step 1: tert-butyl 3-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)pyrrolidine-1- carboxylate: Followed general procedure D using 3-aminopyrazine-2-carbaldehyde (120 mg, 0.975 mmol, 1 equiv) and tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (284 mg, 1.17 mmol, 1.2 equiv) as the starting materials to give tert-butyl 3-(6-oxo-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)pyrrolidine-1-carboxylate (191 mg, 62%) as a light yellow solid. MS m / z: 317 [M+H]+.

[0446] Step 2: tert-butyl 3-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b] pyrazine-7-yl)pyrrolidine-1-carboxylate: Followed general procedure E using tert-butyl 3-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)pyrrolidine-1-carboxylate (80 mg, 0.253 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (73.1 mg, 0.304 mmol, 1.2 equiv) as the starting material to give tert-butyl 3-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)pyrrolidine-1- carboxylate (60 mg, 49%) as a light yellow oil. MS m / z: 477 [M+H]+.

[0447] Step 3: 7-(pyrrolidin-3-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 3-(6-oxo-5-((3- (trifluoromethyl) pyrazine-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)pyrrolidine-1- carboxylate (60 mg, 0.126 mmol, 1 equiv) as the starting material to give the crude product 7-(pyrrolidin-3-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (30 mg) as a light yellow oil. MS m / z: 377 [M+H]+.

[0448] Step 4: 7-(1-(2-fluoro-6-methylphenyl)pyrrolidin-3-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl) methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(pyrrolidin-3-yl)-5-((3-(trifluoromethyl) pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (30 mg, 0.08 mmol, 1 equiv) and 2-bromo-1- fluoro-3-methylbenzene (18 mg, 0.096 mmol, 1.2 equiv) as the starting materials to give 7- (1-(2-fluoro-6-methylphenyl)pyrrolidin-3-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3 -b]pyrazin-6(5H)-one (9.3 mg, 23.7%) as a yellow semi-solid.1H NMR (400 MHz, Chloroform-d) δ 8.51 – 8.49 (m, 2H), 8.43 (d, 1H), 8.33 (d, 1H), 8.10 (s, 1H), 6.97 – 6.90 (m, 3H), 6.08 (s, 2H), 3.84 (d, 2H), 3.36 (d, 2H), 2.45 (d, 4H), 2.08 (d, 1H), 1.25 (s, 1H). MS m / z: 485.20 [M+H]+. 7-(4-(2-Fluoro-6-methylphenyl)piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (24)

[0449] Step 1: tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate: Followed general procedure D using tert-butyl 4-(2-ethoxy-2- oxoethyl)piperazine-1-carboxylate (150 mg, 0.551 mmol, 1 equiv) and 3-aminopyrazine-2- carbaldehyde (81.3 mg, 0.661 mmol, 1.2 equiv) as the starting materials to give tert-butyl 4- (6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate (60 mg, 32%) as a yellow solid. MS m / z: 332 [M+H]+.

[0450] Step 2: tert-butyl 4-(6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate: Followed general procedure E using tert-butyl 4-(6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1-carboxylate (60mg, 0.181 mmol, 1 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine (65.4 mg, 0.271 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate (45 mg, 50%) as a yellow solid. MS m / z: 492 [M+H]+.

[0451] Step 3: 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4-(6-oxo-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperazine-1- carboxylate (45 mg, 0.092 mmol, 1 equiv) as the starting material to give the crude product 7- (piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (35 mg) as a yellow oil. MS m / z: 392 [M+H]+.

[0452] Step 4: 7-(4-(2-fluoro-6-methylphenyl)piperazin-1-yl)-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (35 mg, 0.089 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (25.2 mg, 0.134 mmol, 1.5 equiv) as the starting materials to give 7-(4-(2-fluoro-6- methylphenyl)piperazin-1-yl)-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3- b]pyrazin-6(5H)-one (17.5 mg, 39.1%) as an orange solid.1H NMR (400 MHz, Chloroform- d) δ 8.51 (s, 1H), 8.45 (s, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.32 (s, 1H), 7.07 – 6.93 (m, 2H), 6.92 – 6.81 (m, 1H), 6.09 (s, 2H), 4.11 – 3.43 (m, 4H), 3.43 – 3.14 (m, 4H), 2.38 (s, 3H). MS m / z: 500.2 [M+H]+.7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (25)

[0453] Step 1: tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl 4-(3-methyl-6-oxo-5,6-dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1- carboxylate (100 mg, 0.290 mmol, 1 equiv) and 2-(bromomethyl)-3- (trifluoromethyl)pyrazine (104 mg, 0.435 mmol, 1.5 equiv) as the starting materials to give tert-butyl 4-(3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate (90 mg, 61%) as an off- white solid. MS m / z: 505 [M+H]+.

[0454] Step 2: 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure F using tert-butyl 4- (3-methyl-6-oxo-5-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6-dihydropyrido[2,3- b]pyrazin-7-yl)piperidine-1-carboxylate (90 mg, 0.178 mmol, 1 equiv) as the starting material to give the crude product 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (60 mg) as a yellow oil. MS m / z: 405 [M+H]+.

[0455] Step 3: 7-(1-(5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-methyl-5-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 3-methyl-7-(piperidin-4-yl)-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (60 mg, 0.148 mmol, 1 equiv) and 2-bromo-1-fluoro-3-methylbenzene (42 mg, 0.222 mmol, 1.5 equiv) as the starting materials to give 7- (1-(2-fluoro-6-methylphenyl)piperidin-4-yl)-3-methyl-5-((3-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (21.6 mg, 27.3%) as an off-white solid.1H NMR (300 MHz, Chloroform-d) δ 8.55 – 8.44 (m, 2H), 8.37 (s, 1H), 7.97 (s, 1H), 7.21 – 7.10 (m, 1H), 7.08 – 6.89 (m, 2H), 6.08 (s, 2H), 3.64 (t, 2H), 3.51 – 3.40 (m, 2H), 3.34 – 3.17 (m, 1H), 2.67 (s, 3H), 2.52 (s, 5H), 2.15 – 2.08 (m, 2H).MS m / z: 513.2 [M+H]+. 7-(1-(2-fluoro-5-methylpyridin-4-yl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido- [2,3-b]pyrazin-6(5H)-one (26)

[0456] Step 1: 7-(1-(2-fluoro-5-methylpyridin-4-yl)piperidin-4-yl)-5-(2- (trifluoromethyl)benzyl)pyrido-[2,3-b]pyrazin-6(5H)-one: Followed general procedure G using 7-(piperidin-4-yl)-5-(2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (60 mg, 0.154 mmol, 1 equiv) and 2-fluoro-4-iodo-5-methylpyridine (50 mg, 0.231 mmol, 1.5 equiv) as the starting materials to give 7-(1-(2-fluoro-5-methylpyridin-4-yl)piperidin-4-yl)-5- (2-(trifluoromethyl)benzyl)pyrido[2,3-b]pyrazin-6(5H)-one (55 mg, 69.6%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 8.52 (d, 1H), 8.43 (d, 1H), 7.88 (dd, 2H), 7.78 – 7.70 (m, 1H), 7.32 (td, 2H), 6.69 – 6.62 (m, 1H), 6.44 (s, 1H), 5.95 (s, 2H), 3.58 – 3.50 (m, 2H), 3.25 (m, 1H), 2.93 (m, 2H), 2.20 – 2.15 (m, 2H), 1.94 – 1.79 (m, 2H). MS m / z: 498.20 [M+H]+. 7-(1-(2-Fluoro-6-methylphenyl)piperidin-4-yl)-5-((5-(trifluoromethyl)pyrazin-2- yl)methyl)pyrido[2,3-b]pyrazin-6(5H)-one (27)

[0457] Step 1: (5-(trifluoromethyl)pyrazin-2-yl)methanol: Followed general procedure V using 2-chloro-5-(trifluoromethyl)pyrazine (500 mg, 2.73 mmol, 1 equiv) and (tributylstannyl)methanol (1055 mg, 3.28 mmol, 1.2 equiv) as the starting materials to give (5-(trifluoromethyl)pyrazin-2-yl)methanol (120 mg, 24%) as a white oil. MS m / z: 179 [M+H]+.

[0458] Step 2: (5-(trifluoromethyl)pyrazin-2-yl)methyl methanesulfonate: Followed general procedure W using (5-(trifluoromethyl)pyrazin-2-yl)methanol (100 mg, 0.561 mmol, 1 equiv) and MsCl (96.4 mg, 0.842 mmol, 1.5 equiv) as the starting materials to (5- (trifluoromethyl)pyrazin-2-yl)methyl methanesulfonate (80 mg, 55%) as a yellow oil. MS m / z: 257 [M+H]+.

[0459] Step 3: tert-butyl 4-(6-oxo-5-((5-(trifluoromethyl)pyrazin-2-yl)methyl)-5,6- dihydropyrido[2,3-b]pyrazin-7-yl)piperidine-1-carboxylate: Followed general procedure E using tert-butyl ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R2is an optionally substituted carbocyclyl or optionally substituted heterocyclyl; A1, A2, A3, and A4are each independently =C(R3)– or =N–; B1is –C(R4)t– or –N–, wherein t is 0 or 1 as valency permits; B2is =CR4–, –N–, or –C(O)–; Y is –C(R5)2– or a bond; each R3is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaliphatic, –ORA, –N(RA)2, –SRA, –CN, –SCN, – C(=NRA)RA, –C(=NRA)ORA, –C(=NRA)N(RA)2, –C(=O)RA, –C(=O)ORA, –C(=O)N(RA)2, – NO2, –NRAC(=O)RA, –NRAC(=O)ORA, –NRAC(=O)N(RA)2, –NRAC(=NRA)N(RA)2, – OC(=O)RA, –OC(=O)ORA, –OC(=O)N(RA)2, –NRAS(O)2RA, –OS(O)2RA, or –S(O)2RA; each R4is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, –ORA, –N(RA)2, –SRA, or –CN; each R5is independently hydrogen, halogen, or optionally substituted alkyl; and each RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is –C(R5)2–.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R5is independently hydrogen or optionally substituted alkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is –CH2–.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein B1is =C–.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein B1is –N–.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein B2is –C(O)–.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein B2is =C(R4)–.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein B2is =C(H)– or =C(CH3)–.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R4is independently hydrogen or optionally substituted alkyl.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R4is hydrogen.

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R4is optionally substituted alkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein A1is =N–.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein A1is =C(R3)–.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein A2is =N–.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein A2is =C(R3)–.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein A3is =N–.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein A3is =C(R3)–.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein A4is =N–.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein A4is =C(R3)–.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein no more than two of A1, A2, A3, and A4are =N–.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A1and A4are =N–; and A2and A3are =C(R3)–.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A1and A3are =N–; and A2and A4are =C(R3)–.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A2and A4are =N–; and A1and A3are =C(R3)–.

26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A1, A2, and A3are =C(R3)–; and A4is =N–.

27. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A2, A3, and A4are =C(R3)–; and A1is =N–.

28. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, and A4are =C(R3)–.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein each R3is independently hydrogen, optionally substituted alkyl, or –ORA.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted carbocyclyl.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl or optionally substituted heteroaryl.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl.

33. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted heteroaryl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, -SF5, or –ORA; and x is 0, 1, 2, 3, or 4.

35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, -SF5, or –ORA; and x is 0, 1, 2, 3, or 4.

36. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, -SF5, cyclopropyl, -CH3, -CF3, -CHF2, –CF2CH3, –CH2CF3, –CH2CHF2, -O-cyclopropyl, –OCH3, – OCH2CH3, –OCH2CF3, –OCH2CF3, –OCH2CHF2, –OCF3, or –OCHF2; and x is 0, 1, 2, 3, or 4.

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, -SF5, - CH3, -CF3, -CHF2, –OCH2CF3, –OCH3, –OCF3, or –OCHF2; and x is 0, 1, 2, 3, or 4.

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R1is39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein R1is40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted carbocyclyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted cycloalkyl.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted C3-8cycloalkyl.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted cyclohexyl.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R2is, wherein each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R2is,wherein each R7is independently halogen, optionally substituted alkyl, or optionally substituted aryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein R2is47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein R2is.

48. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted heterocyclyl.

49. The compound of any one of claims 1-39 or 48, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted 4-7 membered heterocyclyl comprising 1 or 2 nitrogen atoms in the ring.

50. The compound of any one of claims 1-39, 48, or 49, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted azetidine, pyrrolidine, piperidine, or piperazine.

51. The compound of any one of claims 1-39 or 48-50, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted piperidine.

52. The compound of any one of claims 1-39 or 48-51, or a pharmaceutically acceptable salt thereof, wherein R2is, wherein R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

53. The compound of any one of claims 1-39 or 48-52, or a pharmaceutically acceptable salt thereof, wherein R2is54. The compound of any one of claims 1-39 or 48-53, or a pharmaceutically acceptable salt thereof, wherein R2is55. The compound of claim 1, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1, wherein the compound is of Formula (I-a-1):, or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1, wherein the compound is of Formula (I-a-2):or a pharmaceutically acceptable salt thereof.

58. The compound of claim 1, wherein the compound is of Formula (I-a-3):or a pharmaceutically acceptable salt thereof.

59. The compound of claim 1, wherein the compound is of Formula (I-a-4):or a pharmaceutically acceptable salt thereof.

60. The compound of claim 1, wherein the compound is of Formula (I-a-5):or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, wherein the compound is of Formula (I-a-6):or a pharmaceutically acceptable salt thereof, wherein: R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

62. The compound of claim 1, wherein the compound is of Formula (I-a-7):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

63. The compound of claim 1, wherein the compound is of Formula (I-a-8):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

64. The compound of claim 1, wherein the compound is of Formula (I-a-9):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

65. The compound of claim 1, wherein the compound is of Formula (I-a-10):or a pharmaceutically acceptable salt thereof, wherein: each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

66. The compound of claim 1, wherein the compound is of Formula (I-a-11):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

67. The compound of claim 1, wherein the compound is of Formula (I-a-12):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

68. The compound of claim 1, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt thereof.

70. The compound of claim 1, wherein the compound is of Formula (I-d):or a pharmaceutically acceptable salt thereof.

71. The compound of claim 1, wherein the compound is of Formula (I-e):, or a pharmaceutically acceptable salt thereof.

72. The compound of claim 1, wherein the compound is of Formula (I-e-1):or a pharmaceutically acceptable salt thereof.

73. The compound of claim 1, wherein the compound is of Formula (I-e-2):or a pharmaceutically acceptable salt thereof.

74. The compound of claim 1, wherein the compound is of Formula (I-e-3):or a pharmaceutically acceptable salt thereof, wherein: R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

75. The compound of claim 1, wherein the compound is of Formula (I-e-4):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; and R8is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.

76. The compound of claim 1, wherein the compound is of Formula (I-e-5):, or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

77. The compound of claim 1, wherein the compound is of Formula (I-e-6):or a pharmaceutically acceptable salt thereof, wherein: each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

78. The compound of claim 1, wherein the compound is of Formula (I-e-7):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

79. The compound of claim 1, wherein the compound is of Formula (I-e-8):or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

80. The compound of claim 1, wherein the compound is of Formula (I-f):or a pharmaceutically acceptable salt thereof.

81. The compound of claim 1, wherein the compound is of Formula (I-f-1):or a pharmaceutically acceptable salt thereof.

82. The compound of claim 1, wherein the compound is of Formula (I-f-2):or a pharmaceutically acceptable salt thereof.

83. The compound of claim 1, wherein the compound is of Formula (I-g):or a pharmaceutically acceptable salt thereof.

84. The compound of claim 1, wherein the compound is of Formula (I-g-1):or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1, wherein the compound is of Formula (I-g-2):or a pharmaceutically acceptable salt thereof.

86. The compound of claim 1, wherein the compound is of Formula (I-h):or a pharmaceutically acceptable salt thereof.

87. The compound of claim 1, wherein the compound is of Formula (I-h-1):or a pharmaceutically acceptable salt thereof.

88. The compound of claim 1, wherein the compound is of Formula (I-h-2):or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1, wherein the compound is of Formula (I-h-7):or a pharmaceutically acceptable salt thereof, wherein:each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

90. The compound of claim 1, wherein the compound is of Formula (I-h-8):, or a pharmaceutically acceptable salt thereof, wherein: Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; x is 0, 1, 2, or 3; each R7is independently halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, 1, or 2.

91. The compound of claim 1, wherein the compound is of Formula (I-h-9):or a pharmaceutically acceptable salt thereof, wherein:Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or –ORA; and x is 0, 1, 2, or 3.

92. The compound of claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

93. A pharmaceutical composition comprising a compound of any of claims 1-92, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

94. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound of any of claims 1-92, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 93.

95. The method of claim 94, wherein the disease or disorder is associated with C5aR1.

96. The method of claim 94 or 95, wherein the disease or disorder is cancer, an infectious disease, an autoimmune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a cerebrovascular disease or disorder, a vasculitis disease or disorder, or a neurodegenerative disease or disorder.

97. The method of claim 96, wherein the disease or disorder is a neurological disease or disorder.

98. A method of antagonizing C5aR1, the method comprising contacting C5aR1 with a compound of any of claims 1-92, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 93.

99. The method of claim 98, wherein the contacting is in vitro.

100. The method of claim 98, wherein the contacting is in vivo.

101. A kit comprising a compound of any of claims 1-92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 93, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

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