Pyridazinone 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

PYRIDAZINONE C5AR1 ANTAGONISTS AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application 63 / 565,212 filed March 14, 2024, 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 C5aRl 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 C5aRl (e.g., antagonists). These compounds provide new compositions and methods for the treatment of diseases associated with C5aRl activity.

[0005] In one aspect, provided are compounds of Formula (I):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:R1is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R2is optionally substituted carbocyclyl or optionally substituted heterocyclyl;R3is hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl;R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORA, -N(RA)2, - C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA;Y is -C(R5)2- or a bond; 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

[0006] In another aspect, provided are pharmaceutical compositions comprising a compound of Formula (I), or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In another aspect, provided are methods of treating a disease or disorder in a subject in need thereof, the methods comprising administering 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.

[0008] In another aspect, provided are methods of antagonizing C5aRl, the methods comprising contacting C5aRl 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).

[0009] In another aspect, provided is a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

[0010] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.DEFINITIONSChemical Definitions

[0011] 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.

[0012] 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 high pressure liquid chromatography (HPLC) using chiral columns 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 diastereomers, enantiomers, or other isomers, all such racemic, diastereomer, enantiomer, or other isomer forms of that depicted are included in the present disclosure.

[0013] 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.

[0014] 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.

[0015] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, C1-6, Ci-5, C1-4, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5.6alkyl.

[0016] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0017] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), 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 (Ce) (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 C1-10 alkyl (such as unsubstituted C1-6 alkyl, 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 Ci-io alkyl (such as substituted Ci-6 alkyl, e.g., -CF3, Bn).

[0018] 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 (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFC12, -CF2C1, and the like.

[0019] 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 (“C1-8 alkoxy”). In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms (“C1-6 alkoxy”). In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms (“C1-4 alkoxy”). In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms (“C1-3 alkoxy”). In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms (“C1-2 alkoxy”). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0020] 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 (“C1-8 alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C1-6 alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C1-4 alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms (“C1-3 alkoxy alkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (“C1-2 alkoxy alkyl”).

[0021] 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 (“heteroCi-2o alkyl”). In some embodiments, a heteroalkyl group is a saturatedgroup having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-i8 alkyl”). 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 (“heteroCi-i6 alkyl”). 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 (“heteroCi-14 alkyl”). 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 (“heteroCi-12 alkyl”). 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 (“heteroCi-10 alkyl”). 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 (“heteroCi-s alkyl”). 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 (“heteroCi-6 alkyl”). 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 (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). 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 heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-10 alkyl.

[0022] 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 (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), 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 C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 ormay be an (E)- or (Z)- double bond.

[0023] 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-io alkenyl”). 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 (“heteroC2-9 alkenyl”). 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 (“heteroC2-8 alkenyl”). 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 (“heteroC2-7 alkenyl”). 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 (“heteroC2-6 alkenyl”). 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 (“heteroC2-5 alkenyl”). 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 (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). 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 (“heteroC2-6 alkenyl”). 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-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0024] 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) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2- 7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), 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 C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.

[0025] 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 (z.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-io alkynyl”). 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 (“heteroC2-9 alkynyl”). 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- 8 alkynyl”). 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 (“heteroC2-7 alkynyl”). 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 (“heteroC2-6 alkynyl”). 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 (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). 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 (“heteroC2-6 alkynyl”). 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-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0026] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl 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 C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro [4.5] dec any 1 (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 C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0027] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl 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 C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0028] 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 carboncarbon 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.

[0029] 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.

[0030] 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, tetrahydro thiophenyl, 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, lH-benzo[e][l,4]diazepinyl, l,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-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0031] 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 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cioaryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; 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 C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0032] “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.

[0033] 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 π 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).

[0034] 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.

[0035] 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. Exemplary5-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. Exemplary6-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, pheno thiazinyl, phenoxazinyl, and phenazinyl.

[0036] “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.

[0037] The term “unsaturated bond” refers to a double or triple bond.

[0038] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0039] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0040] 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.

[0041] 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.

[0042] When substituted, exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR33, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X“, -N(ORcc)Rbb, -SH, -SR33, -SSRCC, -SF5, -C(=0)R33, -CO2H, -CHO, -C(ORCC)3, -CO2R33, -OC(=O)Raa, -OCO2R33, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=0)R33, -NRbbC02R33, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R33, -C(=NRbb)0R33, -0C(=NRbb)R33, -0C(=NRbb)0R33, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02R33, -NRbbS02R33, -SO2N(Rbb)2, -SO2R33, -SO2OR33, -OSO2R33, -S(=0)R33, -0S(=0)R33, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=0)SR33, -C(=S)SR33, -SC(=S)SR33, -SC(=0)SR33, -0C(=0)SR33, -SC(=0)0R33, -SC(=0)R33, -P(=0)(R33)2, -P(=O)(ORCC)2, -OP(=O)(R33)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=0)(R33)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(R33)2, -B(ORCC)2, -BR33(0RCC), -R33, Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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 =0, =S, =NN(Rbb)2, =NNRbbC(=0)R33, =NNRbbC(=0)0R33, =NNRbbS(=0)2R33, =NRbb, or =NORCC; each instance of R33is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R33groups 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, -OR33, -N(RCC)2, -CN, -C(=0)R33, -C(=O)N(RCC)2, -CO2R33, -SO2R33, -C(=NRcc)0R33,-C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR” -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, CI-IO alkyl, Ci-io perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-i oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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, Ci-6alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 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 =0 or =S; wherein X- is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 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, Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl 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, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X-, -NH(CI-6alkyl)2+X-, -NH2(CI-6alkyl)+X“, -NH3+X“, -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)( C1-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(=NH)NH(CI-6alkyl), -OC(=NH)NH2, -NHC(=NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2(Ci-6alkyl), -SO2O(Ci-6alkyl), -OSO2(Ci-6alkyl), -SO(Ci-6alkyl), -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X- is a counterion.

[0043] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0044] 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-, R^, Rbb, and Rccare as defined herein.

[0045] 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.

[0046] 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, -NHSChR^, -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.

[0047] 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, -NR^SO^, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein R^, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0048] 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.

[0049] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and -SO2ORaa, wherein Raaand Rbbare as defined herein.

[0050] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0051] 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- hetero alkylamino, 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, hetero aliphatic, 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).

[0052] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0053] 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, -OR33, -N(Rcch, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -S02R33, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOR33, -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, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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.

[0054] 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, -S02R33, -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, CI-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-io alkenyl, C2-10 alkynyl, heteroCi-io alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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.

[0055] 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-nitrophenoxy acetamide, 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.

[0056] 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), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- 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-(l,3- dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl 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, l-methyl-l-(3,5- dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1 -phenylethyl carbamate, 1 -methyl- l-(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.

[0057] 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), P- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0058] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl- (lO)-acyl derivative, N'-p-toluenesulfonylami noacyl derivative, N'-phcny lam i noth ioacyl 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-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,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-(l-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 (Fem), 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-l-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), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3 -nitropyridinesulf enamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tertbutyloxycarbonyl (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).

[0059] 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, -R^, -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(=0)(0RCC)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.

[0060] 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- methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,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 -ethoxy ethyl, 1- (2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 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, a- 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-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,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-l-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, a-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- trichloroethoxy ethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxy trityl (MMT), dimethoxy trityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0061] 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, -R^, -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.

[0062] 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 (z.e., including one formal negative charge). An anionic counterion may also be multivalent (z.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 ", CIO4 ", OH ", H2PO4", HCOa", 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", PFe , AsFe", SbFe , B[3,5- (CF3)2C6H3]4]", B(C6FS)4_, BPI14", A1(OC(CF3)3)4", and carborane anions (e.g., CBnHi2" or (HCB 11 McsBiv,) ). 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.

[0063] A “leaving group” (EG) 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, -OCO^, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, - OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO^, -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 R^, 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, A,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.

[0064] 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

[0065] 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 C5aRl.

[0066] 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.

[0067] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0068] 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+(CI-4 alkyl)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.

[0069] 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.

[0070] 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)).

[0071] 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.

[0072] 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”.

[0073] 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 (z.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”.

[0074] 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 (z.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.

[0075] 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 cocrystal 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.

[0076] 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. Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.

[0077] The terms “composition” and “formulation” are used interchangeably.

[0078] The term “modulate” means decreasing or inhibiting activity and / or increasing or augmenting activity. For example, modulating C5aRl activity means decreasing or inhibiting C5aRl activity and / or increasing or augmenting C5aRl activity. The compounds disclosed herein may be administered to modulate C5aRl for example, as an antagonist.

[0079] A “subject” to which administration is contemplated refers to a human (z.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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0084] 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.

[0085] 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 C5aRl 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 C5aRl). 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 C5aRl deactivation and treating a disease or disorder (e.g., neurological disorder).

[0086] A “prophylactic ally 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 C5aRl 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 C5aRl deactivation and treating a disease or disorder (e.g., neurological disorder).

[0087] As used herein, the term “activate” or “activation” in the context of proteins, for example, in the context of C5aRl, 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 C5aRl). 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.

[0088] 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.

[0089] 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. Biologies may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologies may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.

[0090] 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 (z.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.

[0091] 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 biologies or small molecule therapeutics, or combinations thereof.

[0092] 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.

[0093] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measuDETAILED DESCRIPTION OF CERTAIN EMBODIMENTSCompounds

[0094] Provided herein are compounds (e.g., a compound of any of the formulae herein) that are modulators of C5aRl (e.g., C5aRl antagonists). In one aspect, the provided C5aRl 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 C5aRl (e.g., neurological diseases and disorders) in a subject in need thereof.

[0095] The compounds described herein interact with C5aRl. As described herein, the therapeutic effect may be a result of modulation (e.g., antagonism), binding, and / or modification of C5aRl 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)

[0096] In one aspect, disclosed is a compound of Formula (I):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:R1is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R2is optionally substituted carbocyclyl or optionally substituted heterocyclyl;R3is hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl;R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORA, -N(RA)2, - C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA;Y is -C(R5)2- or a bond; 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

[0097] In certain embodiments:R1is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R2is optionally substituted carbocyclyl or optionally substituted heterocyclyl;R3is hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl;R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORA, -N(RA)2, - C(=O)N(RA)2, or -NRAC(=O)RA;Y is -C(R5)2- or a bond; each R5is independently hydrogen, halogen, or optionally substituted alkyl; andeach 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.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- or a bond. In certain embodiments, Y is -C(R5)2-; and each R5is independently hydrogen or optionally substituted alkyl. In certain embodiments, Y is -C(R5)2- In some embodiments, 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 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In some embodiments, R1is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

[0100] 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.

[0101] In certain embodiments, R1is optionally substituted aryl. In certain embodiments, R1is optionally substituted phenyl.

[0102] 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.

[0103] In certain embodiments, R1iswherein 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, 3, or 4. In some embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4.

[0104] In certain embodiments, R1iswherein 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.

[0105] In certain embodiments, R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and x is 0 or 1.

[0106] In certain embodiments, R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, or -ORA; and x is 0 or 1.

[0107] In certain embodiments, R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or -ORA; RAis alkyl or haloalkyl; and x is 0 or 1.

[0108] In certain embodiments, R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, alkyl, haloalkyl, or -ORA; RAis alkyl or haloalkyl; and x is 0 or 1.

[0109] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently haloalkyl, or -ORA; and x is 0, 1, 2,3, or 4.

[0110] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, cyclopropyl, -CH3, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -O-cyclopropyl, -OCH3, -OCH2CH3, -OCH2CF3, - OCH2CHF2, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

[0111] In certain embodiments, R1is, wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently -F, -CH3, -CF3, -CHF2, -OCH2CF3, -OCH3, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

[0112] 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.

[0113] In certain embodiments, R1is, wherein each R6is independently -F,-CH3, -CF3, -CHF2, -OCH2CF3, -OCH3, -OCF3, or -OCHF2; and x is 0 or 1. z26^1

[0114] In some embodiments, R1is (R)x , wherein Z1and Z2are each independently CH, CR6, or N; each R6is independently cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

[0115] In certain embodiments, R1is, wherein each R6is independently haloalkyl or optionally substituted cycloalkyl; and x is 0 or 1.

[0116] In certain embodiments, R1is, wherein each R6is independently -F, cyclopropyl, -CH3, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -O-cyclopropyl, -OCH3, - OCH2CH3, -OCH2CF3, -OCF3, -OCH2CHF2, or -OCHF2; and x is 0 or 1.

[0117] In certain embodiments, R1is, wherein each R6is independently -F,-CH3, -CF3, -CHF2, -OCH2CF3, -OCH3, -OCF3, or -OCHF2; and x is 0 or 1.

[0118] 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.

[0119] In certain embodiments, R1is, wherein each R6is independently -F,-CH3, -CF3, -CHF2, -OCH2CF3, -OCH3, -OCF3, or -OCHF2; and x is 0 or 1.

[0120] 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.

[0121] 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.

[0122] In certain embodiments, R1is, wherein each R6is independently -F,-CH3, -CF3, -CHF2, -OCH2CF3, -OCH3, -OCF3, or -OCHF2; and x is 0 or 1.

[0123] In certain embodiments, R1is, wherein each R6is independently cyclopropyl, -CF3, -CF2CH3, or -CH2CF3; and x is 0 or 1.

[0124] In some embodiments, R1iswherein each R6is independently cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

[0125] In some embodiments, R1iswherein R6is cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2.

[0126] In some emodiments, R1iswherein R6is cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2.

[0127] In certain embodiments,, wherein R6is halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or -ORA; and RAis alkyl or haloalkyl.

[0128] In certain embodiments,wherein R6is haloalkyl or optionally substituted cycloalkyl.

[0129] In certain embodiments,, wherein R6is -F, cyclopropyl, -CH3, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -O-cyclopropyl, -OCH3, -OCH2CH3, -OCH2CF3, -OCH2CHF2, -OCF3, or -OCHF2.

[0130] In certain embodiments,, wherein R6is cyclopropyl, -CF3, -CF2CH3, or -CH2CF3.

[0131] In certain embodiments, R1is, wherein R6is halogen, alkyl, haloalkyl, optionally substituted cycloalkyl, or -ORA; and RAis alkyl or haloalkyl.

[0132] In certain embodiments, R1iswherein R6is haloalkyl or optionally substituted cycloalkyl.

[0133] In certain embodiments, R1is, wherein R6is -F, cyclopropyl, -CH3, -CF3,-CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -O-cyclopropyl, -OCH3, -OCH2CH3, -OCH2CF3, -OCH2CHF2, -OCF3, or -OCHF2.

[0134] In certain embodiments, R1is, wherein R6is cyclopropyl, -CF3, -CF2CH3, or -CH2CF3.

[0135] In certain embodiments, R1is

[0137] In certain embodiments, R1isR1isIn certain embodiments, R1is. in certain embodiments, R1isIn certain embodiments, R1isIn certain embodiments, R1is

[0138] 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-i4 carbocyclyl, wherein the carbocyclyl is fused with a heteroaryl ring.R2

[0139] 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 C3-12 cycloalkyl. In certain embodiments, R2is optionally substituted C3-8 cycloalkyl. In certain embodiments, R2is optionally substituted C3-6 cycloalkyl. In certain embodiments, R2is optionally substituted C4-6 cycloalkyl. In certain embodiments, R2is optionally substituted C5-6 cycloalkyl. In certain embodiments, R2is optionally substituted cyclopentyl. In certain embodiments, R2is optionally substituted cyclobutyl. In certain embodiments, R2is optionally substituted cyclohexyl.

[0140] In some 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 an optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted aryl; and y is 0, 1, or 2.

[0141] 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.

[0142] 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.

[0143] In certain embodiments, R2is, wherein each R7is independently optionally substituted aryl or optionally substituted heteroaryl; and y is 1.

[0144] 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.

[0145] 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.

[0146] 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.

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

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

[0149] In certain embodiments, R2is, wherein R7is optionally substituted heteroaryl; and y is 1.

[0150] In certain embodiments, R2is, wherein R7is substituted heteroaryl; and y is 1.

[0151] In certain embodiments, R2is, wherein R7is substituted pyridine, substituted thiazole, substituted isothiazole, substituted pyrazole, or substituted indazole; and y is 1.

[0152] 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, l, or 2.

[0153] 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. y

[0154] 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.

[0155] In certain embodiments, R2is, wherein each R7is independently optionally substituted aryl or optionally substituted heteroaryl; and y is 1.

[0156] 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.

[0157] 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.

[0158] 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.

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

[0160] In certain embodiments, R2is, wherein R7is substituted aryl; and y is 1.

[0161] In certain embodiments, R2is, wherein R7is substituted phenyl; and y is 1.

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

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

[0164] In certain embodiments, R2is, wherein R7is substituted pyridine, substituted thiazole, substituted isothiazole, substituted pyrazole, or substituted indazole; and y is 1.^\ / (R7)y

[0165] In certain embodiments, R2is X , wherein two instances of R7together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl; and y is 2.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] In certain embodiments,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, l, or 2.

[0170] In certain embodiments,, wherein R7is optionally substituted aryl; and y is 1.

[0171] In certain embodiments,wherein R7is substituted aryl; and y is1.

[0172] In certain embodiments,, wherein R7is substituted phenyl; and y is 1.

[0173] In certain embodiments,certain embodiments, R2is. In certain embodiments, R2is. In certain embodiments, R2is

[0174] In certain embodiments,, 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 asubstituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and y is 0, l, or 2.

[0175] In certain embodiments, R2is, wherein R7is optionally substituted aryl; and y is 1.

[0176] In certain embodiments, R2is, wherein R7is substituted aryl; and y is 1.

[0177] In certain embodiments, R2is, wherein R7is substituted phenyl; and y is 1.

[0178] In certain embodiments, R2is. In certain embodiments, R2is

[0179] In some embodiments, wherein R2is, wherein R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

[0180] In certain embodiments, R2is, wherein R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl . In some embodiments,R2is. In certain embodiments, R2is. In certain embodiments, R2is

[0181] In certain embodiments,wherein Z3and Z4are each independently -N- or -CR9-; and R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.optionally substituted alkyl, or -ORA. In some embodiments,wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA. In some embodiments,wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA. In some embodiments,wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

[0183] In certain embodiments, R2isx , x , xO, o, orr '

[0184] In certain embodiments, R2is

[0185] In some embodiments, R2is' , ' , \, or.

[0186] In some embodiments, R2is,

[0187] In some embodiments, R2is. In some embodiments, R2issome embodiments, R2is

[0188] In certain embodiments, R2is

[0189] In some embodiments,wherein Z3and Z4are each independently -N- or -CR9; and R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

[0190] In some embodiments,, wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

[0191] In certain embodiments,, wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA. In some, wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA. In some embodiments, R2is, wherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.; X

[0192] In some embodiments, R isX , X , X ,

[0195] In certain embodiments, R2is. In certain embodiments, R2iscertain embodiments, R2isIn certain embodiments, R2isIn certain embodiments, R2is . In certain embodiments,. In certain embodiments, R2iscertain embodiments, R2isIn certain embodiments, R2isIn certain embodiments, R2isIn certain embodiments, R2is

[0196] In certain embodiments, R2isIn certain embodiments, R2is

[0197] 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.R3

[0198] As described herein, R3is hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl. In certain embodiments, R3is hydrogen or optionally substituted aryl. In certain embodiments, R3is optionally substituted aryl. In certain embodiments, R3is hydrogen or optionally substituted phenyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is optionally substituted phenyl. In certain embodiments, R3is unsubstituted phenyl.R4

[0199] As described herein, R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, - ORA, -N(RA)2, -C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA. In certain embodiments, R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORA, -N(RA)2, - C(=O)N(RA)2, or -NRAC(=O)RA. In certain embodiments, R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6- membered heterocyclyl, optionally substituted 5-6-membered heteroaryl, -ORA, -N(RA)2, - C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA. In certain embodiments, R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6-membered heterocyclyl, optionally substituted 5-6-membered heteroaryl, -ORA, -N(RA)2, -C(=O)N(RA)2, or -NRAC(=O)RA. In certain embodiments, R4is hydrogen. In certain embodiments, R4is haloalkyl. In certain embodiments, R4is optionally substituted alkyl. In certain embodiments, R4is optionally substituted C4-6 cycloalkyl. In certain embodiments, R4is optionally substituted 4-6-membered heterocyclyl. In certain embodiments, R4is optionally substituted 5-6-membered heteroaryl. In certain embodiments, R4is -ORA, -N(RA)2, -C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA. In certain embodiments, R4is -ORA, -N(RA)2, -C(=O)N(RA)2, or -NRAC(=O)RA.

[0200] In certain embodiments, R4is optionally substituted 5-membered heteroaryl.

[0201] In certain embodiments, R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6-membered heterocyclyl, optionally substituted 5-6-membered heteroaryl, -ORA, -N(RA)2, -C(=O)N(RA)2, or - NRAC(=O)RA; and each RAis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, or two instances ofRAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

[0202] In certain embodiments, R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6-membered heterocyclyl, optionally substituted 5-6-membered heteroaryl, -ORA, -N(RA)2, -C(=O)N(RA)2, - C(=NRA)NRAORA, or -NRAC(=O)RA; and each RAis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

[0203] In certain embodiments, R4is optionally substituted thiazole, optionally substituted pyrazole, optionally substituted triazole, optionally substituted dithiazole, optionally substituted imidazole, optionally substituted oxadiazole, or optionally substituted oxazole.

[0204] In certain embodiments, R4is optionally substituted thiazole. In certain embodiments, R4is optionally substituted pyrazole. In certain embodiments, R4is optionally substituted triazole. In certain embodiments, R4is optionally substituted dithiazole. In certain embodiments, R4is optionally substituted imidazole. In certain embodiments, R4is optionally substituted oxadiazole. In certain embodiments, R4is optionally substituted oxazole.

[0205] In some embodiments, R4is:embodiments,certain embodiments,certain embodiments,certain embodiments,certain embodiments, R4is. In certain embodiments,certain embodiments, R4isIn certain embodiments, R4is. In certain embodiments, R4is N N In certain embodiments, R4is. in certain embodiments,Certain Embodiments

[0212] 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, and R4are as defined herein.

[0213] In certain embodiments, the compound of Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1, R2, and R4are as defined herein.

[0214] In certain embodiments, the compound of Formula (I) is of Formula (I-c):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R1and R4are as defined herein; 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.

[0215] In certain embodiments of the compound of Formula (I-c), each R7is independently 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.

[0216] In certain embodiments of the compound of Formula (I-c), each R7is independently optionally substituted aryl or optionally substituted heteroaryl; and y is 1.

[0217] In certain embodiments, the compound of Formula (I) is of Formula (I-d):

[0218] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R1and R4are as defined herein; andR7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

[0219] In certain embodiments of the compound of Formula (I-d), R7is optionally substituted heteroaryl or optionally substituted aryl. In certain embodiments of the compound of Formula (I-d), R7is optionally substituted heteroaryl. In certain embodiments of the compound of Formula (I-d), R7is optionally substituted aryl.

[0220] 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 R4is as defined herein;Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA;R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl,; and x is 0, 1 , or 2.

[0221] In certain embodiments of the compound of Formula (I-e), Z1and Z2are each independently CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and R7is optionally substituted heteroaryl, or optionally substituted aryl.

[0222] In certain embodiments, the compound of Formula (I) is of Formula (I-f):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein. r a pharmaceutically acceptable salt thereof, wherein:Z2is CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA;R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl; and x is 0, 1, or 2.

[0223] In certain embodiments, the compound of Formula (I) is of Formula (I-f- 1) :or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH, CR6, or N;Z3and Z4are each independently -N- or -CR9-; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA; and x is 0, 1, or 2.

[0224] In certain embodiments, the compound of Formula (I) is of Formula (I-f-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH, CR6, or N;Z3and Z4are each independently -N- or -CR9-; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA; and x is 0, 1, or 2.

[0225] In certain embodiments, the compound of Formula (I) is of Formula (I-g):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH or N;R6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; andR7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

[0226] In certain embodiments, the compound of Formula (I) is of Formula (I-g-1):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH or N;Z3and Z4are each independently -N- or -CR9-; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA

[0227] In certain embodiments, the compound of Formula (I) is of Formula (I-g-2):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH or N;Z3and Z4are each independently -N- or -CR9-; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA

[0228] In certain embodiments, the compound of Formula (I) is of Formula (I-g-3):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH or N;R6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA

[0229] In certain embodiments, the compound of Formula (I) is of Formula (I-g-4):or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R4is as defined herein;Z2is CH or N;R6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA

[0230] In certain embodiments, the compound of Formula (I) is of formula:or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0231] In certain embodiments, the provided compounds (e.g., compounds of Formula (I)), antagonize C5aRl with an IC50 of 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.

[0232] In certain embodiments, the provided compounds (e.g., compounds of Formula (I)), inhibit C5aRl with an IC50 of 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

[0233] 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.

[0234] In certain embodiments, the compound of Formula (I) 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 effective amount 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 certainembodiments, 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.

[0235] 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.

[0236] In certain embodiments, the effective amount is an amount effective for antagonizing C5aRl in a subject, tissue, biological sample, or cell.

[0237] 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.

[0238] In certain embodiments, the effective amount is an amount effective for decreasing the activity of C5aRl 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 for decreasing the activity of C5aRl by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0239] The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) C5aRl for use in treating a C5aRl-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) C5aRl for use in treating a disease or disorder associated with aberrant activity of C5aRl in a subject in need thereof. The present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., antagonizes) C5aRl for use in treating a disease or disorder associated with mutated C5aRl in a subject in need thereof.

[0240] 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.

[0241] 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 compounds and the additional pharmaceutical agent, but not both.

[0242] 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 Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides 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.

[0243] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing 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.

[0244] 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.

[0245] The compound and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol.

[0246] 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 suitablecontainer). 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.

[0247] 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 C5aRl in a subject or cell. In certain embodiments, the kits are useful for antagonizing C5aRl in a subject or cell.

[0248] 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 certain embodiments, the kits and instructions provide for decreasing the activity of C5aRl in a subject or cell. In certain embodiments, the kits and instructions provide for antagonizing C5aRl 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

[0249] 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 C5aRl (e.g., C5aRl activity).

[0250] In certain embodiments, the disease or disorder is any of the following:

[0251] 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).

[0252] 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 from transplants, 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).

[0253] 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).

[0254] 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).

[0255] 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).

[0256] Neurodegenerative disorders and related diseases (e.g., Alzheimer's disease, multiple sclerosis, and cognitive function decline associated with cardiopulmonary bypass surgery and related procedures).

[0257] 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 cell carcinomas, 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 prostatecancer, 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, nonHodgkin'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).

[0258] 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 (z.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.

[0259] 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).

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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 bums, 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, bronchial asthma, 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.

[0265] 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.

[0266] 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, ovariancancer, 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.

[0267] 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, Dressier’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 lupus erythematosus (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.

[0268] In certain embodiments, the disease or disorder is age-related macular degeneration, Alzheimer’s disease, amyotrophic lateral sclerosis, anaphylaxis, anthraxpoisoning, 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.

[0269] 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.

[0270] 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.

[0271] The present disclosure provides a method of antagonizing C5aRl. The present disclosure provides a method of decreasing the activity of C5aRl. In certain embodiments, the application provides a method of antagonizing C5aRl (e.g., decreasing the activity of C5aRl) in vitro. In certain embodiments, the application provides a method of antagonizing C5aRl (e.g., decreasing the activity of C5aRl) in vivo. In certain embodiments, the application provides a method of antagonizing C5aRl in a cell. In certain embodiments, the application provides a method of antagonizing C5aRl in a human cell.

[0272] 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 C5aRl, for example, a compound that is a modulator of C5aRl (e.g., an antagonist of C5aRl), a binder of C5aRl, or a compound that modifies C5aRl. 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.

[0273] 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

[0274] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological 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 in their scope.Example 1: Synthetic Methods

[0275] 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 Groupsin 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 E. 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

[0276] Ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohex-3-ene-l-carboxylate: To a stirred solution of ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate (2.00 g, 7.14 mmol, 1.0 equiv) and 3-bromo-4-(trifluoromethyl)pyridine (1.94 g, 8.56 mmol, 1.2 equiv) in dioxane (20 mF) and H2O (4 mF) were added Pd(dtbpf)Ch (0.470 g, 0.714 mmol, 0.1 equiv) and K2CO3 (2.96 g, 21.4 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at 80 °C under argon atmosphere and monitored by ECMS. The resulting mixture was diluted with water (200 mF), extracted with EtOAc (3 x 200 mF). The combined organic layers were washed with brine (200 mF), 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 / 5 to afford ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohex-3-ene-l- carboxylate (1.91 g, 89%) as a light orange oil.General Procedure B

[0277] Ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexane-l-carboxylate. A solution of ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohex-3-ene-l -carboxylate (1.9 g, 6.3 mmol, 1.0 equiv) and Pd / C (600 mg, 10% Pd on carbon, wetted with water) in MeOH (200 mL) was stirred for 2 days at room temperature under H2 atmosphere using a hydrogen balloon. The reaction was monitored by LCMS. After the complete disappearance of the starting material, the resulting mixture was filtered through a Celite pad and concentrated under reduced pressure. This resulted in ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexane-l -carboxylate (1 g, crude) as a light yellow oil.General Procedure C

[0278] 4-(4-(Trifluoromethyl)pyridin-3-yl)cyclohexane-l-carboxylic acid. A solution of ethyl 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexane-l -carboxylate (1.05 g, 3.48 mmol, 1.0 equiv) and LiOH (0.500 g, 20.9 mmol, 6.0 equiv) in EtOH (10 mL) and H2O (10 mL) was stirred for 4 h at 50 °C and monitored by LCMS. After the complete disappearance of the starting material, the mixture was acidified to pH ~ 6 with HC1 (aq., 2M), 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 to afford 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexane-l -carboxylic acid (900 mg, crude) as a white solid.General Procedure D

[0279] 3,6-Dichloro-4-(4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazine. To a stirred solution of 4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexane-l -carboxylic acid (1.09 g, 3.99 mmol, 1.0 equiv) and 3,6-dichloropyridazine (0.590 g, 3.99 mmol, 1.0 equiv) in ACN (5 mL), H2O (5 mL) and sulfolane (5 mL) were added AgNOa (0.680 g, 3.99 mmol, 1.0 equiv) and H2SO4 (1.17 g, 12.0 mmol, 3.0 equiv) in portions at 60 °C. To the above mixture was added (NH4)2S20s (2.28 g, 9.97 mmol, 2.5 equiv) in H2O (5 mL) dropwise over 3 min at 60 °C. The resulting mixture was stirred for an additional 1 h at 60 °C and monitored by LCMS. The resulting mixture was diluted with water (100 mL), 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 EtOAc / PE = 1 / 5 to afford 3,6- dichloro-4-(4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazine (320 mg, 21%) as a white solid.General Procedure E

[0280] 6-Chloro-4-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin- 3(2H)-one. A solution of 3,6-dichloro-4-(4-(4-(trifluoromethyl)pyridin-3- yl)cyclohexyl)pyridazine (310 mg, 0.824 mmol, 1.0 equiv) in AcOH (3 mL) was stirred for overnight at 100 °C and monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 6-chloro-4-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin- 3(2H )-one (80 mg, 27%) as a white solid.General Procedure F

[0281] 6-Chloro-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin-3(2H)-one. To a stirred solution of 6- chloro-4-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin-3(2H )-one (80 mg, 0.22 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(trifluoromethyl)pyridine (52 mg, 0.27 mmol, 1.2 equiv) in DMF (2 mL) was added K2CO3 (92 mg, 0.67 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred overnight at 60 °C. The reaction was monitored by LCMS. 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 = 1 / 1 to afford 6-chloro-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin-3(2H )-one (65 mg, 56%) as a white solid.General Procedure G

[0282] (6-Oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)-l,6-dihydropyridazin-3-yl)boronic acid. To a stirred solution of 6-chloro-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)pyridazin-3(2H)-one (60 mg, 0.12 mmol, 1.0 equiv) and bis(pinacolato)diboron (58.9 mg, 0.232 mmol, 2.0 equiv) in dioxane (2 mL) were added Pd(dppf)Ch (8.5 mg, 0.012 mmol, 0.1 equiv) and KOAc (34 mg, 0.35 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under argon atmosphere and monitored by LCMS. After the complete disappearance of the starting material, the resulting mixture was used in the next step directly without further purification.General Procedure H

[0283] l-Methyl-4-(6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)- l,6-dihydropyridazin-3-yl)- lH-pyrazole-5- carbaldehyde. To a stirred solution of (6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5- ((lr,4r)-4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.12 mmol, 1.0 equiv) and 4-bromo-2-methylpyrazole-3-carbaldehyde (43 mg, 0.24 mmol, 2.0 equiv) in dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Ch (8.5 mg, 0.012 mmol, 0.1 equiv) and K2CO3 (48 mg, 0.36 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under argon atmosphere. The reaction was monitored by LCMS. 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 = 1 / 1 to afford l-methyl-4-(6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(4- (trifluoromethyl)pyridin-3-yl)cyclohexyl)- 1 ,6-dihydropyridazin-3-yl)- 1 / / -pyrazolc-5- carbaldehyde (25 mg, 37 %) as a white solid.General Procedure I

[0284] 6-(5-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3- yl)cyclohexyl)pyridazin-3(2H)-one. To a stirred solution of l-methyl-4-(6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3-yl)cyclohexyl)-l,6-dihydropyridazin-3-yl)-177-pyrazole-5-carbaldehyde (40 mg, 0.068 mmol, 1.0 equiv) in DCM (2 mL) was added DAST (54 mg, 0.34 mmol, 5.0 equiv) dropwise at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was 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 Prep-TLC (EtOAc / Hexane = 1 / 2) to afford 6-(5-(difluoromethyl)-l-methyl-177-pyrazol-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(4-(trifluoromethyl)pyridin-3- yl)cyclohexyl)pyridazin-3(2H )-one (20.4 mg, 48%) as a white solid.General Procedure J

[0285] 4- Bromo- 1 -met hyl-5-( trifluoromethyl )- 1H- 1,2, 3-triazole. To a stirred mixture of 4-bromo-l -methyl- 1, 2, 3-triazole (1.00 g, 6.17 mmol, 1.0 equiv) and sodium trifluoromethanesulfinate (2.89 g, 18.5 mmol, 3.0 equiv) in DCM (10 mL) and H2O (4 mL) was added tert-butyl hydroperoxide (3.97 g, 30.8 mmol, 5.0 equiv, 70%) dropwise at 0 °C. The resulting mixture was stirred for 2 days at room temperature. The reaction was monitored by GCMS. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0% to 80% gradient in 30 min) to afford 4-bromo-l-methyl-5-(trifluoromethyl)- 1H- 1,2, 3-triazole (150 mg, 10%) as a light yellow oil.General Procedure K

[0286] 4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2-(2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one. A solution of 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50 mg, 0.087 mmol, 1.0 equiv) and CS2CO3 (85.4 mg, 0.261 mmol, 3.0 equiv) in CF3CH2OH (2 mL) was stirred for 2 h at 60 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / Hexane = 1 / 2) to afford 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5- methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (26.5 mg, 44%) as a white solid.General Procedure L

[0287] 4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(4-(hydroxymethyl)thiazol-5-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H)-one. To a stirred mixture of methyl 5-(5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazin-3-yl)thiazole-4-carboxylate (90 mg, 0.15 mmol, 1.0 equiv) in MeOH (3 mL) was added NaBtk (58 mg, 1.5 mmol, 10 equiv) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS.After the complete disappearance of the starting material, the reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at 0 °C. 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 to dry. The resulting crude product was used in the next step directly without further purification.General Procedure M

[0288] 4-(5-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)-l-(tetrahydro-2H- pyran-2-yl)-LH-l,2,3-triazole-5-carbaldehyde. To a stirred mixture of 4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-6-(5-(hydroxymethyl)-l-(tetrahydro-2H -pyran-2-yl)-177- l,2,3-triazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (75 mg, 0.12 mmol, 1.0 equiv) in DCM (2 mL) was added MnCL (104 mg, 1.2 mmol, 10 equiv) at room temperature. The resulting mixture was stirred for 6 h at room temperature and monitored by LCMS. After the complete disappearance of the starting material, the resulting mixture was filtered, the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under reduced pressure to dry. The resulting crude product was used in the next step directly without further purification.General Procedure N

[0289] 5-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3(trifluoromethoxy)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carbohydrazide. To a stirred mixture of methyl 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethoxy)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboxylate (100 mg, 0.192 mmol, 1.0 equiv) in MeOH (2 mL) was added hydrazine hydrate (29.5 mg, 0.576 mmol, 3.0 equiv, 98%) dropwise at room temperature. The resulting mixture was stirred for 1 h at 80 °C and monitored by LCMS. After the complete disappearance of the starting material, the resulting mixture was concentrated under reduced pressure to dry. The resulting crude product was used in the next step directly without further purification.General Procedure O

[0290] 2V'-(2,2-Difluoroacetyl)-5-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-6- oxo- 1 - ((3- (trifluoromethoxy)pyridin-2-yl)methyl) - 1 ,6-dihydropyridazine-3- carbohydrazide. To a stirred mixture of 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- 1 -((3-(trifluoromethoxy)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazine-3-carbohydrazide (100 mg, 0.192 mmol, 1.0 equiv) in THF (2 mL) was added 2,2-difluoroacetyl 2,2- difluoroacetate (100 mg, 0.576 mmol, 3.0 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 60 °C and monitored by LCMS. After complete disappearance of the starting material, the resulting mixture was diluted with water (80 mL), extracted with EtOAc (3 x 80 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 PE / EA (30% to 90% gradient in 20 min) to afford A^-(2,2-difluoroacetyl)-5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethoxy)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carbohydrazide (100 mg, 86%) as a light yellow solid.General Procedure P

[0291] 6-(5-(Difluoromethyl)-l,3,4-oxadiazol-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H)- one. To a stirred mixture of A^-(2,2-difluoroacetyl)-5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethoxy)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carbohydrazide (55 mg, 0.092 mmol, 1.0 equiv) in THF (1.5 mL) was added Burgess reagent (109 mg, 0.46 mmol, 5.0 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 60 °C under and monitored by LCMS. The resulting mixture was diluted with water (80 mL), extracted with EtOAc (3 x 80 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 Prep-TLC (hexane / EA 3:1) to afford 6-(5-(difluoromethyl)-l,3,4-oxadiazol- 2-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2- yl)methyl)pyridazin-3(2H )-one (14.9 mg, 27%) as a white solid.General Procedure Q

[0292] 2-(Chloromethyl)-3-cyclopropylpyrazine hydrochloride. A solution of (3- cyclopropylpyrazin-2-yl)methanol (220 mg, 1.46 mmol, 1.0 equiv) and SOCh (871 mg, 7.32 mmol, 5.0 equiv) in DCM (3 mL) was stirred for 1 h at room temperature under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.General Procedure R

[0293] l,3-Dioxoisoindolin-2-yl 4-(2-methoxy-4-methylpyridin-3-yl)cyclohexane-l- carboxylate. To a stirred mixture of 4-(2-methoxy-4-methylpyridin-3-yl)cyclohexane-l- carboxylic acid (600 mg, 2.41 mmol, 1.0 equiv) and N-hydroxyphthalimide (431 mg, 2.64 mmol, 1.1 equiv) in DCM (6 mL) were added DMAP (29 mg, 0.24 mmol, 0.1 equiv) and DCC (595 mg, 2.88 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature and monitored by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EA (0% to 100%) to afford 1,3- dioxoisoindolin-2-yl 4-(2-methoxy-4-methylpyridin-3-yl)cyclohexane-l -carboxylate (800 mg, 84%) as a white solid.General Procedure S

[0294] Methyl 5-((lr,4r)-4-(2-methoxy-4-methylpyridin-3-yl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboxylate. To a stirred mixture of methyl 5-bromo-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carboxylate (300 mg, 0.765 mmol, 1.0 equiv) and l,3-dioxoisoindol-2- yl 4-(2-methoxy-4-methylpyridin-3-yl)cyclohexane-l -carboxylate (452 mg, 1.14 mmol, 1.5 equiv) in DMA (5 mL) was added Zn (150 mg, 2.29 mmol, 3.0 equiv) at room temperatureunder argon atmosphere. NiBnDME (47 mg, 0.15 mmol, 0.2 equiv) and pyridine-2,6- dicarboximidamide dihydrochloride (36 mg, 0.15 mmol, 0.2 equiv) were premixed for 30 min in DMA (0.5 mL) at 60 °C under argon atmosphere and subsequently added to the above mixture. The resulting mixture was stirred for overnight at 30 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL), 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 PE / EA (0% to 100% in 30 min) to afford methyl 5-((lr,4r)-4-(2-methoxy-4- methylpyridin-3-yl)cyclohexyl)-6-oxo- 1 -((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6- dihydropyridazine-3-carboxylate (200 mg, 50%) as a white solid.General Procedure T

[0295] 2-(Bromomethyl)-3-(difluoromethyl)pyridine. To a stirred mixture of 3- (difluoromethyl)-2-methylpyridine (500 mg, 3.49 mmol, 1.0 equiv) and NBS (1.24 g, 6.98 mmol, 2.0 equiv) in CCU (5 mL) was added AIBN (57 mg, 0.35 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C. The reaction was monitored by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EA (0% to 100% in 30 min) to afford 2-(bromomethyl)-3- (difluoromethyl)pyridine (160 mg, 20%) as a light yellow oil.General Procedure U

[0296] Ethyl 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboxylate. To a stirred mixture of 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (120 mg, 0.250 mmol, 1.0 equiv) and Pd(dppf)Ch (18 mg, 0.025 mmol, 0.1 equiv) in EtOH (10 mL) was added TEA (76 mg, 0.75 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under carbon monoxide atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 10 mL). 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 5-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carboxylate (80 mg, 61%) as a white solid.General Procedure V

[0297] 6-Chloro-2-((3-cyclopropylpyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl) pyridazin-3(2H)-one. To a stirred solution of 6-chloro-4- ((lr,4r)-4-(2-fluoro-6-methylphenyl) cyclohexyl)pyridazin-3(2H )-one (150 mg, 0.468 mmol, 1.0 equiv) and 2-(chloromethyl)-3-cyclopropylpyridine (94.0 mg, 0.562 mmol, 1.2 equiv) in DMF (3 mL) were added (tBuOhMg (399 mg, 2.34 mmol, 5.0 equiv) and LiBr (201 mg, 2.34 mmol, 5.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 60 °C and monitored by LCMS. The resulting mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 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 Prep-TLC (hexane / EA 5:1) to afford 6-chloro-2-((3- cyclopropylpyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl) pyridazin-3(2H )-one (150 mg, 70%) as a pink solid.General Procedure W

[0298] 5-((lr,4r)-4-(2,6-Difluorophenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carbonitrile. To a stirred solution of 6-chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (200 mg, 0.413 mmol, 1.0 equiv) and Zn(CN)2 (72.8 mg, 0.619 mmol, 1.5 equiv) in DMSO (3 mL) were added Pd(dppf)Ch (60.5 mg, 0.083 mmol, 0.2 equiv) and Zn (16.2 mg, 0.248 mmol, 0.6 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C under air atmosphere and monitored by LCMS. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 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 = 1 / 1 to afford 5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin- 2-yl)methyl)-l,6-dihydropyridazine-3-carbonitrile (160 mg, 81.5%) as a white solid.General Procedure X

[0299] 5-((lr,4r)-4-(2,6-Difluorophenyl)cyclohexyl)-A^-hydroxy-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboximidamide. To a stirred solution of 5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carbonitrile (160 mg, 0.337 mmol, 1.0 equiv) and hydroxylamine hydrochloride (28.1 mg, 0.404 mmol, 1.2 equiv) in EtOH (3 mL) were added K2CO3 (139 mg, 1.01 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C and monitored by LCMS. The resulting mixture was concentrated under vacuum. The resulting mixture was filtered, the filter cake waswashed with water (3 x 5 mL). This resulted in 5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-A-hydroxy-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3- carboximidamide (140 mg) as a white solid.General Procedure Y

[0300] 6-(5-(Difluoromethyl)-l,2,4-oxadiazol-3-yl)-4-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one. To a stirred solution of 2,2-difluoroacetic acid (34.0 mg, 0.354 mmol, 3.0 equiv) and TEA (36.0 mg, 0.354 mmol, 3.0 equiv) in DMF (3 mL) were added T3P (56.4 mg, 0.177 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for 5 min at room temperature under nitrogen atmosphere followed by adding. 5-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-N-hydroxy-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)- l,6-dihydropyridazine-3-carboximidamide (60.0 mg, 0.118 mmol, 1.0 equiv) in portions at room temperature over 1 min. The resulting mixture was stirred for an additional 1 h at 80 °C and monitored by LCMS. The resulting mixture was diluted with water (10 mL), extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 3:2) to afford 6-(5- (difluoromethyl)-l,2,4-oxadiazol-3-yl)-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (52.7 mg, 74.3%) as a white solid.General Procedure Z

[0301] 6-(3,3-Dimethylmorpholino)-4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,r- biphenyl] -4-y 1 )-2-( ( 3-( t rifluoromethy 1 ) py ridin-2-y 1 )methy 1 ) py ridazin-3( 2H )-one. To a stirred solution of 6-chloro-4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (200 mg, 0.42 mmol, 1.0 equiv) and 3, 3 -dimethylmorpholine (72.3 mg, 0.63 mmol, 1.5 equiv) in dioxane (5 mL) were added Pd2(dba)3 (76.6 mg, 0.08 mmol, 0.2 equiv), RuPhos (39.1 mg, 0.08 mmol, 0.2 equiv) and CS2CO3 (409 mg, 1.26 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under argon atmosphere and monitored by LCMS. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3 x 20 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 = 1 / 2 to afford 6-(3,3- dimethylmorpholino)-4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro-[l, l'-biphenyl]-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (130 mg, 56%) as a white solid. MS m / z: 557 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(tetrahydro-2H-pyran-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (1)

[0302] Step 1: 6-(3,6-dihydro-2H -pyran-4-yl)-4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro- [1,1 '-biphenyl] -4-yl)-2-((3-(trifhioromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure A using 6-chloro-4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro- [1,1 '-biphenyl] -4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (100 mg, 0.209 mmol, 1.0 equiv) and 2-(3,6-dihydro-2H -pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (65.9 mg, 0.314 mmol, 1.5 equiv) as the starting materials to give 6-(3,6- dihydro-2 / / -pyran-4-yl)-4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro-[l,l'-biphenyl]-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (120 mg, 72%) as a colorless oil. MS m / z: 526 [M+H]+.

[0303] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(tetrahydro-2H- pyran-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure B using6-(3,6-dihydro-2H -pyran-4-yl)-4-(2'-fluoro-6'-methyl-l,2,3,6- tctrahydro-| I J '-biphenyl |-4-yl)-2-((3-( tri fluoromcthyl)pyridin-2-yl)mcthyl)pyridazin-3(2 / 7)- one (120 mg, 0.228 mmol, 1.0 equiv) as the starting material to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(tetrahydro-2H -pyran-4-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (16.1 mg, 12.6%) as a white solid.1H NMR (400 MHz, Chloroform-6?) δ 8.64 (s, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J= 11.7 Hz, 2H), 6.94 - 6.80 (m, 2H), 5.65 (s, 2H), 4.10 - 4.00 (m, 2H), 3.53 - 3.44 (m, 2H), 3.04 (t, J = 11.7 Hz, 1H), 2.92 - 2.74 (m, 2H), 2.36 (s, 3H), 2.11 (t, J= 13.4 Hz, 4H), 1.86 - 1.78 (m, 6H), 1.46 (d, J = 12.7 Hz, 2H). MS m / z: 530.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (2)

[0304] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure F using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (80.0 mg, 0.249 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(trifluoromethyl)pyridine (58.5 mg, 0.299 mmol, 1.2 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (100 mg, 80%) as a white solid. MS m / z: 480 [M+H]+.

[0305] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin- 5-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (30 mg, 0.063 mmol, 1.0 equiv) and (2-methylpyrimidin-5-yl)boronic acid (11.2 mg, 0.082 mmol, 1.3 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2- methylpyrimidin-5-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (23 mg, 67%) as a white solid.1H NMR (300 MHz, Chlorol'orm-d) δ 9.05 (s, 2H), 8.69 - 8.57 (m, 1H), 8.08 - 7.96 (m, 1H), 7.53 (s, 1H), 7.35 (dd, J= 8.0, 4.8 Hz, 1H), 7.12 - 7.00 (m, 1H), 7.00 - 6.80 (m, 2H), 5.79 (s, 2H), 3.15 (t, J= 11.8 Hz, 1H), 2.91 (d, J= 12.6 Hz, 1H), 2.83 (s, 3H), 2.39 (s, 3H), 2.18 (d, J = 12.1 Hz, 4H), 1.89 (d, J = 12.3 Hz, 2H), 1.59 (t, J = 12.3 Hz, 2H). MS m / z: 538.15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (3)

[0306] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2Z7)-one (40 mg, 0.083 mmol, 1.0 equiv) and pyrazin-2-ylboronic acid (51.6 mg, 0.415 mmol, 5.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (6.6 mg, 15%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.70 - 8.49 (m, 3H), 8.18 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.07 - 7.00 (m, 1H), 6.94 - 6.81 (m, 2H), 5.79 (s, 2H), 3.13 (t, J = 12.1 Hz, 1H), 2.90 (t, J = 11.7 Hz, 1H), 2.36 (s, 3H), 2.14 (t, J = 11.1 Hz, 4H), 1.90 - 1.81 (m, 2H), 1.59 (s, 2H). MS m / z: 524.15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(6-(trifluoromethoxy)pyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (4)

[0307] Step 1: 4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-6-(6- (trifluoromethoxy)pyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one. Followed the general procedure A using 6-chloro-4-(2'-fluoro-6'-methyl-l,2,3,6- tetrahydro-[l ,r-biphenyl]-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )- one (125 mg, 0.262 mmol, 1.0 equiv) and (6-(trifluoromethoxy)pyridin-3-yl)boronic acid (81.2 mg, 0.392 mmol, 1.5 equiv) as the starting materials, using XPhos (25 mg, 0.052 mmol, 0.2 equiv) and XPhos Pd G4 (45 mg, 0.052 mmol, 0.2 equiv) as the catalyst to give 4-(2'- fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,r-biphenyl]-4-yl)-6-(6-(trifluoromethoxy)pyridin-3- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (70 mg, 44%) as a withe solid. MS m / z: 605 [M+H]+.

[0308] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(6- (trifluoromethoxy)pyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one: Followed the general procedure B using 4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro-[ 1,1'- biphenyl]-4-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2 / / )-one (70.0 mg, 0.116 mmol, 1.0 equiv) as the starting material to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(6-(trifluoromethoxy)pyridin-3- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (10.1 mg, 14.4%) as a white solid.1H NMR (300 MHz, Chlorolorm-d) δ 8.76 - 8.64 (m, 2H), 8.23 (dd, J= 8.6, 2.5 Hz, 1H), 8.05 (d, J= 7.9 Hz, 1H), 7.52 (s, 1H), 7.38 (t, J= 6.5 Hz, 1H), 7.13 - 6.99 (m, 2H), 6.96 - 6.79 (m, 2H), 5.78 (s, 2H), 3.11 (t, J= 11.9 Hz, 1H), 2.89 (t, J= 12.5 Hz, 1H), 2.36 (s, 3H), 2.15 (d, J= 12.1 Hz, 4H), 1.88 (s, 2H), 1.52 (q, J= 12.7 Hz, 2H). MS m / z: 607.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)-2-((3- (trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H)-one (5)

[0309] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-( trifluoromethoxy )pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure F using 6-chloro-4-(( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (35.0 mg, 0.109 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(trifluoromethoxy)pyridine (27.7 mg, 0.131 mmol, 1.2 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2-fluoro- 6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )- one (30 mg, 52%) as a white solid. MS m / z'- 496 [M+H]+.

[0310] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin- 5-yl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )-one (25 mg, 0.050 mmol, 1.0 equiv) and (2-methylpyrimidin-5-yl)boronic acid (8.3 mg, 0.06 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2- methy Ipyrimidin- 5 -y 1) -2- ((3 - ( t r i 0 uo ro met ho x y ) py r i d i n -2- y I ) met h y I ) py ri daz i n -3 ( 2 / 7) -one (13.0 mg, 45.1%) as a light yellow solid.1H NMR (300 MHz, Chloroform-t / ) δ 9.03 (s, 2H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.51 (s, 1H), 7.32 (dd, J = 8.3, 4.7 Hz, 1H), 7.13 - 7.01 (m, 1H), 6.98 - 6.81 (m, 2H), 5.70 (s, 2H), 3.14 (t, J = 12.0 Hz, 1H), 2.92 (t, J = 12.4 Hz, 1H), 2.83 (s, 3H), 2.39 (s, 3H), 2.17 (t, J = 11.1 Hz, 4H), 1.88 (d, J = 13.0 Hz, 2H), 1.57 (t, J = 12.4 Hz, 2H). MS m / z: 554.10 [M+H]+.

[0311] 2-((3-(Difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)pyridazin-3(2H)-one (6)

[0312] Step 1: 6-chloro-2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H)-one: Followed the general procedure F using 6-chloro-4-(( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H)-one (40.0 mg, 0.125 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(difluoromethoxy (pyridine (31.4 mg, 0.162 mmol, 1.3 equiv) as the starting materials to give 6-chloro-2-((3- (difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)pyridazin-3(2J7)~one (40 mg, 67%) as a white solid. MS m / z: 478 [M+H]+.

[0313] Step 2: 2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)- 4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H)-one (40 mg, 0.084 mmol, 1.0 equiv) and (2-methylpyrimidin-5-yl)boronic acid (15.0 mg, 0.108 mmol, 1.3 equiv) as the starting materials to give 2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)pyridazin-3(2H )-one (8.8 mg, 19.6%) as a white solid.1H NMR (300 MHz, Chlorol'orm-d) δ 9.08 (s, 2H), 8.39 (s, 1H), 7.53 (d, J = 20.6 Hz, 2H), 7.38 - 7.28 (m, 1H), 7.04 (q, J= 7.1, 6.6 Hz, 1H), 6.98 - 6.39 (m, 3H), 5.66 (s, 2H), 3.11 (t, J= 12.1 Hz, 1H), 3.01 - 2.82 (m, 4H), 2.37 (s, 3H), 2.12 (d, J= 11.5 Hz, 4H), 1.86 (d, J = 12.8 Hz, 2H), 1.52 (d, J = 10.5 Hz, 2H). MS m / z: 536.15 [M+H]+.6-(2-Ethyl-4-methylthiazol-5-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (7)

[0314] Step 1: 6-(2-ethyl-4-methylthiazol-5-yl)-4-(2'-fluoro-6'-methyl- 1,2,3, 6-tetrahydro- [1,1 '-biphenyl] -4-yl)-2-((3-(trifhioromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one. To a stirred mixture of 6-chloro-4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (100 mg, 0.209 mmol, 1.0 equiv) and 2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-thiazole (158 mg, 0.627 mmol, 3.0 equiv) in 1,4-dioxane (2 mL) were added XPhos (19.9 mg, 0.042 mmol, 0.2 equiv), XPhos Pd G4 (36 mg, 0.042 mmol, 0.2 equiv) and NaHCOa (52.7 mg, 0.627 mmol, 3.0 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 8 h at 80 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 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 6-(2-ethyl-4-methylthiazol-5-yl)-4-(2'-fluoro-6'- methyl- 1 ,2,3,6-tetrahydro-[ 1 , 1 '-biphenyl] -4-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (60 mg, 50%) as a light yellow oil. MS m / z’ 569 [M+H]+.

[0315] Step 2: 6-(2-ethyl-4-methylthiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure B using 6-(2-ethyl-4-methylthiazol-5-yl)-4-(2'-fluoro-6'- methyl- 1 ,2,3,6-tetrahydro-[ 1 , 1 '-biphenyl] -4-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)mcthyl)pyridazin-3(2 / 7)-onc (80.0 mg, 0.141 mmol, 1.0 equiv) as the starting material to give 6-(2-ethyl-4-methylthiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (10.3 mg, 11.8%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J= 4.8 Hz, 1H), 7.98 (d, J= 8.0 Hz, 1H), 7.31 (d, J = 4.4 Hz, 2H), 7.04 - 6.99 (m, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.87 - 6.82 (m, 1H), 5.70 (s, 2H), 3.17 - 2.97 (m, 3H), 2.88 (t, J= 12.4 Hz, 1H), 2.52 (s, 3H), 2.36 (s, 3H),2.14 (t, 7= 11.4 Hz, 4H), 1.87 - 1.82 (m, 2H), 1.48 (d, 7= 12.4 Hz, 2H), 1.40 (t, 7= 7.6 Hz, 3H). MS m / z: 571.25 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one(8)

[0316] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (30 nig, 0.063 mmol, 1.0 equiv) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(177)-one (22.0 mg, 0.095 mmol, 1.5 equiv) as the starting materials to give 4- ((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / 7)-one (8.5 mg, 24%) as a light brown solid. NMR (400 MHz, Methanol-^) 6 8.63 - 8.57 (m, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.17 (dd, 7= 8.1, 1.6 Hz, 1H), 8.03 (dd, J = 9.5, 2.7 Hz, 1H), 7.78 (s, 1H), 7.48 (dd, J = 8.1, 4.9 Hz, 1H), 7.05 (td, J= 7.9, 5.5 Hz, 1H), 6.96 (d, 7= 7.5 Hz, 1H), 6.84 (dd, 7= 12.1, 8.1 Hz, 1H), 6.59 (d, 7= 9.5 Hz, 1H), 5.72 (s, 2H), 3.65 (s, 3H), 3.02 (dt, 7= 15.3, 5.0 Hz, 2H), 2.38 (s, 3H), 2.19 - 2.02 (m, 4H), 1.90 - 1.82 (m, 2H), 1.66 (q, J= 12.8 Hz, 2H). MS m / z: 553.15 [M+H]+.

[0317] 4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one(9)

[0318] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one.Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (30 mg, 0.063 mmol, 1.0 equiv) and l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one (14.7 mg, 0.063 mmol, 1.0 equiv) as the starting materials to give 4- (( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-( 1 -methyl-2-oxo- 1 ,2-dihydropy ridin-4- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / 7)-one (6.4 mg, 18%) as a white solid. NMR (400 MHz, Chloroform-d) 8 8.61 (d, J = 4.6 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.33 (s, 2H), 7.09 - 6.99 (m, 2H), 6.95 - 6.83 (m, 2H), 6.77 (s, 1H), 5.75 (s, 2H), 3.60 (s, 2H), 3.15 - 2.82 (m, 2H), 2.38 (s, 3H), 2.12 (d, J = 11.5 Hz, 4H), 1.86 (d, J = 13.1 Hz, 2H), 1.50 (d, J = 12.2 Hz, 2H), 1.26 (s, 1H). MS m / z: 553.15 [M+H]+.

[0319] 6-(l-(Cyclopropylmethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (10)

[0320] Step 1: 6-(l-(cyclopropylmethyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one:Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (40 mg, 0.042 mmol, 1.0 equiv) and l-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l / / -pyrazole (20.6 mg, 0.084 mmol, 2.0 equiv) as the starting materials to give 6-(l -(cyclopropylmethyl)- lH-pyrazol-4-yl)-4-(( Ir, 4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (22.5 mg, 47.6%) as a white solid.1H NMR (400 MHz, Chloroform-tf) δ 8.73 (s, 1H), 8.15 (d, J= 7.6 Hz, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 7.06 - 6.99 (m, 1H), 6.94 - 6.81 (m, 2H), 5.77 (s, 2H), 4.22 (d, J = 7.2 Hz, 2H), 3.08 (t, J= 12.0 Hz, 1H), 2.89 (s, 1H), 2.36 (s, 3H), 2.13 (t, J= 11.7 Hz, 4H), 1.85 (d, J= 13.2 Hz, 2H), 1.26 (s, 1H), 0.74 (d, J = 7.6 Hz, 2H), 0.74 (d, J = 7.6 Hz, 2H), 0.50 (d, J = 5.0 Hz, 2H). MS m / z: 566.20 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H)-one (11)

[0321] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure F using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (50.0 mg, 0.156 mmol, 1.0 equiv) and 2-(bromomethyl)-3-(trifluoromethyl)pyrazine hydrochloride (56.2 mg, 0.203 mmol, 1.5 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyridazin- 3(2H )-one (40 mg, 53%) as a white solid. MS m / z: 481 [M+H]+.

[0322] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin- 5-yl)-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H )-one (40 mg, 0.083 mmol, 1.0 equiv) and (2-methylpyrimidin-5-yl)boronic acid (13.8 mg, 0.1 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-5-yl)-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H)-one (34 mg, 88%) as a white solid.1H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 2H), 8.59 (d, J= 10.2 Hz, 2H), 7.52 (s, 1H), 7.05 - 7.01 (m, 1H), 6.94 - 6.82 (m, 2H), 5.82 (s, 2H), 3.12 - 3.09 (m, 1H), 2.91 - 2.81 (m, 4H), 2.36 (s, 3H), 2.16 - 2.13 (m, 4H), 1.89 - 1.85 (m, 2H), 1.56 -1.53 (m, 2H). MS m / z: 539.15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (12)

[0323] Step 1: (5-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,r- biphenyl]-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (160 mg, 0.335 mmol, 1.0 equiv) as the starting material to give (5-(2'-fluoro-6'-methyl-l,2,3,6- tetrahydro- [1,1 '-biphenyl]-4-yl)-6-oxo- 1 -((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6- dihydropyridazin-3-yl)boronic acid which was used directly in the next step. MS m / z: 488 [M+H]+.

[0324] Step 2: 4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-6-(5- methylpyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,r- biphenyl]-4-yl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin~3- yl)boronic acid (crude, 0.334 mmol, 1.0 equiv) and 2-bromo-5-methylpyrazine (116 mg, 0.669 mmol, 2.0 equiv) as the starting materials to give 4-(2'-fluoro-6'-methyl-l,2,3,6- tetrahydro-[l,l'-biphenyl]-4-yl)-6-(5-methylpyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (150 mg, 83%) as a light yellow solid. MS m / z: 536 [M+H]+.

[0325] Step 3: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrazin-2- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the generalprocedure B using 4-(2'-fluoro-6'-methyl-l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)-6-(5- methylpyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (150 mg, 0.280 mmol, 1.0 equiv) as the starting material to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(5-methylpyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (11.5 mg, 11.5%) as a white solid. ’H NMR (400 MHz, Chloroform-7) δ 9.14 (d, 7= 1.5 Hz, 1H), 8.62 (d, 7= 4.4 Hz, 1H), 8.47 (d, 7- 1.5 Hz, 1H), 8.15 (s, 1H), 8.01 (d, J= 7.7 Hz, 1H), 7.33 (dd, J = 8.0, 4.8 Hz, 1H), 7.03 (td, 7= 7.8, 5.4 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.85 (dd, 7= 11.8, 8.1 Hz, 1H), 5.78 (s, 2H), 3.18 - 3.06 (m, 1H), 2.90 (t, 7 = 12.3 Hz, 1H), 2.63 (s, 3H), 2.36 (s, 3H), 2.22 - 2.08 (m, 4H), 1.90 - 1.80 (m, 2H), 1.66 - 1.50 (m, 2H). MS m / z: 538.10[M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (13)

[0326] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (42 mg, 0.088 mmol, 1.0 equiv) the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in the next step. MS m / z: 490 [M+H]+.

[0327] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrimidin- 4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.088 mmol, 1.0 equiv) and 4-chloro-5-methylpyrimidine (28.1 mg, 0.22 mmol, 2.5 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (23.4 mg, 49.4%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 9.13 (s, 1H), 8.64 - 8.59 (m, 2H), 8.12 (s, 1H), 8.00 - 7.99 (m, 1H), 7.36 - 7.32 (m, 1H), 7.06 - 7.01 (m, 1H), 6.92 (d, J= 7.6 Hz, 1H), 6.87 - 6.82 (m, 1H), 5.76 (s, 2H), 3.12 (t, J= 12.4 Hz, 1H), 2.90 (t, J= 12.4 Hz, 1H), 2.37 (d, J= 4.8 Hz, 6H), 2.21 - 2.10 (m, 4H), 1.88 - 1.83 (m, 2H), 1.63 - 1.53 (m, 2H). MS m / z: 538.15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(6-methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (14)

[0328] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid. Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in the next step. MS m / z: 490 [M+H]+.

[0329] Step 2: 4-((l r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(6-methylpyrimidin- 4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one. Followed the general procedure H using (5-(( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo- 1 -((3- (trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-6-methylpyrimidine (13.2 mg, 0.104 mmol, 1.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(6- methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (23.3 mg, 48.4%) as a white solid. 1H NMR (300 MHz, Chloroform-d) 69.07 (s, 1H), 8.57 - 8.49 (m, 1H), 8.19 (s, 1H), 7.98 - 7.88 (m, 1H), 7.84 (s, 1H), 7.30 - 7.20 (m, 1H), 7.03 - 6.90 (m, 1H), 6.89 - 6.72 (m, 2H), 5.72 (s, 2H), 3.04 (t, J = 12.0 Hz, 1H), 2.83 (t, J = 12.0 Hz, 1H),2.52 (s, 3H), 2.29 (s, 3H), 2.05 (t, J = 11.5 Hz, 4H), 1.84 - 1.73 (m, 2H), 1.61 - 1.42 (m, 2H), 1.24 - 1.13 (m, 1H). MS m / z: 538. 15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(2-methoxy-5-methylpyrimidin-4- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (15)

[0330] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid. Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) and as the starting material to give (5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazin-3-yl)boronic acid which was used directly in the next step. MS m / z: 490[M+H]+.

[0331] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methoxy-5- methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one.Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-2-methoxy-5-methylpyrimidine (24.6 mg, 0.156 mmol, 1.5 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(2-methoxy-5-methylpyrimidin-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (24.0 mg, 57.9%) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.66 - 8.60 (m, 1H), 8.35 (d, J= 2.8 Hz,1H), 8.08 (d, J= 1.0 Hz, 1H), 8.04 - 7.95 (m, 1H), 7.33 (dd, J= 8.0, 4.9 Hz, 1H), 7.07 - 6.99 (m, 1H), 6.94 - 6.80 (m, 2H), 5.75 (s, 2H), 4.08 (s, 3H), 3.17 - 3.05 (m, 1H), 2.95 - 2.84 (m, 1H), 2.37 (s, 3H), 2.25 (s, 3H), 2.22 - 2.07 (m, 4H), 1.85 (dd, J= 13.7, 3.7 Hz, 2H), 1.63 - 1.51 (m, 2H). MS m / z: 568.20 [M+H]+.6-(l-(2,2-Difluoroethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (16)

[0332] Step 1: 6-(l-(2,2-difluoroethyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (30 mg, 0.06 mmol, 1.0 equiv) and l-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-177-pyrazole (16.1 mg, 0.06 mmol, 1.0 equiv) as the starting materials to give 6-(l-(2,2-difluoroethyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (10.3 mg, 28.5%) as a white solid.1H NMR (300 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.87 (d, 7= 8.8 Hz, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 7.10 - 6.97 (m, 1H), 6.94 - 6.80 (m, 2H), 6.11 (t, J = 55.3 Hz, 1H), 5.74 (s, 2H), 4.57 - 4.41 (m, 2H), 3.08 (t, J = 12.0 Hz, 1H), 2.89 (t, J= 12.2 Hz, 1H), 2.36 (s, 3H), 2.13 (s, 4H), 1.91 - 1.79 (m, 2H), 1.51 (q, J = 12.1 Hz, 2H). MS m / z: 576.15 [M+H]+.6-( l-Ethyl-3-methyl- lH-pyrazol-4-yl)-4-(( lr,4r )-4-(2-fhioro-6-methyl phenyl )cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (17)

[0333] Step 1: 6-(l-ethyl-3-methyl-l / / -pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / 7)-one (45 mg, 0.094 mmol, 1.0 equiv) and l-ethyl-3-methyl-4-(4, 4,5, 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole (26.7 mg, 0.113 mmol, 1.2 equiv) as the starting materials to give 6-(l-ethyl-3-methyl-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (10.9 mg, 21.0%) as a grey white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 8.65 (d, J = 4.8 Hz, 1H), 7.98 (dd, J= 8.0, 1.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, J= 8.0, 4.9 Hz, 1H), 7.24 (s, 1H), 7.04 (td, J= 7.9, 5.5 Hz, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.89 - 6.79 (m, 1H), 5.70 (s, 2H), 4.13 (q, J = 7.3 Hz, 2H), 3.17 - 3.02 (m, 1H), 2.88 (t, J = 12.6 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.14 (t, J - 11.5 Hz, 4H), 1.90 - 1.77 (m, 2H), 1.49 (t, 7.3 Hz, 5H). MS m / z:554.15 [M+H]+.6-( 1 -Cyclopropyl- lH-pyrazol-4-yl)-4-(( lr,4r )-4-(2-fluoro-6-methyl phenyl )cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (18)

[0334] Step 1: 6-(l-cyclopropyl-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one:Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2Z7)-one (30 mg, 0.063 mmol, 1.0 equiv) and l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lZZ-pyrazole (17.6 mg, 0.076 mmol, 1.2 equiv) as the starting materials to give 6-(l -cyclopropyl- lZZ-pyrazol-4-yl)-4-((l r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2ZZ)-one (20.8 mg, 59.9%) as a white solid.1H NMR (300 MHz, Chloroform-d) 8 8.61 (d, J = 4.8 Hz, 1H), 7.97 (d, 7= 7.8 Hz, 1H), 7.80 (d, J = 9.6 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.10 -- 6.97 (m, 1H), 6.93 - 6.80 (m, 2H), 5.69 (s, 2H), 3.69 - 3.56 (m, 1H), 3.08 (t, 7 = 12.0 Hz, 1H), 2.89 (t, J = 12.0 Hz, 1H), 2.36 (s, 3H), 2.13 (t, 7 = 9.5 Hz, 4H), 1.84 (d, 7= 13.1 Hz, 2H), 1.51 (q, 7 = 12.6 Hz, 2H), 1.21 - 1.10 (m, 2H), 1.10 - 0.99 (m, 2H). MS m / z: 552.25 [M+H]+.6-(l-(Difluoromethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (19)

[0335] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (30.0 mg, 0.063 mmol, 1.0 equiv) and l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (18.0 mg, 0.076 mmol, 1.2 equiv) as the starting materials to give 6-(l-(difluoromethyl)-177- pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (22.7 mg, 63.8%) as a yellow solid.1H NMR (400 MHz, Chloroform-7) δ 8.62 (d, J= 4.4 Hz, 1H), 8.17 (s, 1H), 8.02 - 7.97 (m, 2H), 7.36 - 7.30 (m, 2H), 7.22 - 6.99 (m, 2H), 6.92 (d, J= 7.5 Hz, 1H), 6.85 (dd, J= 11.6, 7.9 Hz, 1H), 5.71 (s, 2H), 3.10 (t, J = 12.1 Hz, 1H), 2.89 (t, J = 12.3 Hz, 1H), 2.36 (s, 3H), 2.14 (t, J = 11.4 Hz, 4H), 1.85 (d, J = 12.9 Hz, 2H), 1.59 - 1.44 (m, 2H). MS m / z: 562.05 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H)-one (20)

[0336] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H )-one. Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyrazin-2-yl)methyl)pyridazin-3(2H )-one (25 mg, 0.052 mmol, 1.0 equiv) and pyrazin-2-ylboronic acid (9.6 mg, 0.078 mmol, 1.5 equiv) as the starting materials to give 4-(4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrazin-2-yl)-2-((3-(trifluoromethyl)pyrazin- 2-yl)methyl)pyridazin-3(2H )-one (5.3 mg, 19%) as a white solid.1H NMR (300 MHz, Chloroform-6?) δ 9.30 (s, 1H), 8.66 - 8.57 (m, 4H), 8.20 (s, 1H), 7.11 - 6.98 (m, 1H), 6.96 - 6.79 (m, 2H), 5.84 (s, 2H), 3.11 (t, J = 12.1 Hz, 1H), 2.90 (t, J= 12.4 Hz, 1H), 2.36 (s, 3H), 2.15 (d, J= 12.5 Hz, 4H), 1.86 (d, J= 13.2 Hz, 2H), 1.43 (d, J= 13.7 Hz, 2H). MS m / z: 525.20 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (21)

[0337] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the stalling materials to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0338] Step 2: 4-(( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2-methylpyrimidin- 4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / Z)-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-2-methylpyrimidine (26.9 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(2- methylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (28.4 mg, 59.1%) as a white solid.1H NMR (400 MHz, Chloroform-7) δ 8.65 (d, J = 5.2 Hz, 1H), 8.60 (d, J= 4.8 Hz, 1H), 8.26 (s, 1H), 8.04 - 7.95 (m, 1H), 7.82 (d, J = 4.9 Hz, 1H), 7.32 (dd, J= 8.0, 4.9 Hz, 1H), 7.04 (td, 7= 7.8, 5.4 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.85 (dd, 7 = 11.8, 8.1 Hz, 1H), 5.78 (s, 2H), 3.17 - 3.05 (m, 1H), 2.93 (t, 7 = 12.2 Hz, 1H), 2.83 (s, 3H), 2.37 (s, 3H), 2.16 (d, 7 = 11.9 Hz, 4H), 1.92 - 1.80 (m, 2H), 1.68 - 1.52 (m, 2H). MS m / z: 538.20 [M+H]+.6-(2,6-Dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (22)

[0339] Step 1 : (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0340] Step 2 : 6-(2,6-dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-2,6-dimethylpyrimidine (29.4 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 6-(2,6-dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (34.8 mg, 71.6%) as a white solid.1H NMR (300 MHz, Chloroform-ri) δ 8.59 (d, J= 4.9 Hz, 1H), 8.25 (s, 1H), 8.00 (d, J= 7.9 Hz, 1H), 7.77 (s, 1H), 7.36 - 7.29 (m, 1H), 7.08 - 7.00 (m, 1H), 6.95 - 6.80 (m, 2H), 5.78 (s, 2H), 3.10 (t, J= 12.0 Hz, 1H), 3.01 - 2.82 (m, 4H), 2.61 (s, 3H), 2.37 (s, 3H), 2.15 (d, J= 12.2 Hz, 4H), 1.86 (d, J= 12.2 Hz, 2H), 1.26 (s, 2H). MS m / z: 552.20 [M+H]+.6-(2,5-Dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (23)

[0341] Step 1 : (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0342] Step 2 : 6-(2,5-dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-2,5-dimethylpyrimidine (29.4 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 6-(2,5-dimethylpyrimidin-4-yl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (29.8 mg, 61.2%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 8.65 - 8.61 (m, 1H), 8.51 (s, 1H), 8.09 (d, J= 0.8 Hz, 1H), 8.03 - 7.99 (m, 1H), 7.37 - 7.32 (m, 1H), 7.08 - 6.99 (m, 1H), 6.95 - 6.82 (m, 2H), 5.76 (s, 2H), 3.11 (t, J= 12.1 Hz, 1H), 3.01 - 2.81 (m, 4H), 2.36 (d, J= 5.1 Hz, 6H), 2.16 (d, J= 10.5 Hz, 4H), 1.87 (d, J= 12.4 Hz, 2H), 1.59 (d, J= 12.4 Hz, 2H). MS m / z: 552.15 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)pyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (24)

[0343] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0344] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5- (trifluoromethyl)pyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one: Followed the general procedure H using 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (crude, 104 mmol, 1.0 equiv) and 2-chloro-5-(trifluoromethyl)pyrazine (37.7 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5- (trifluoromethyl)pyrazin-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one (41.5 mg, 78.8%) as a white solid. ’H NMR (400 MHz, Chloroform-7) 69.36 (s, 1H), 8.91 (s, 1H), 8.63 (d, 7 = 4.8 Hz, 1H), 8.19 (s, 1H), 8.04 (d, 7= 8.0 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.06 - 7.01 (m, 1H), 6.92 (d, 7= 7.5 Hz, 1H), 6.87- 6.82 (m, 1H), 5.81 (s, 2H), 3.12 (t, 7 = 11.9 Hz, 1H), 2.91 (t, 7= 12.3 Hz, 1H), 2.36 (d, 7= 1.6 Hz, 3H), 2.15 (d, 7= 12.0 Hz, 4H), 1.88 - 1.84 (m, 2H), 1.62 - 1.51 (m, 2H). MS m / z: 592.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-fluoropyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (25)

[0345] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-fluoropyrimidin-4- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-y l)methyl)- 1 ,6-dihydropy ridazin-3-yl)boronic acid (50.0 mg, 0.102 mmol, 1.0 equiv) and 4-chloro-5-fluoropyrimidine (16.3 mg, 0.122 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5- fluoropyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (23.2 mg, 41.9%) as a white solid.NMR (400 MHz, Chloroform- J) 8 9.08 (d, J - 2.5 Hz, 1H), 8.64 (dd, J = 14.3, 4.0 Hz, 2H), 8.09 (s, 1H), 8.04 - 7.94 (m, 1H), 7.33 (dd, 7 = 7.9, 4.9 Hz, 1H), 7.04 (td, 7 = 7.8, 5.4 Hz, 1H), 6.92 (d, 7= 7.4 Hz, 1H), 6.85 (dd, 7 = 11.8, 8.1 Hz, 1H), 5.79 (s, 2H), 3.11 (tt, 7= 12.1, 2.9 Hz, 1H), 2.99 - 2.83 (m, 1H), 2.36 (s, 3H), 2.17 (dd, 7 = 15.0, 11.6 Hz, 4H), 1.96 - 1.79 (m, 2H), 1.64 - 1.49 (m, 2H). MS m / z: 542.20 [M+H]+.6-(5-Fluoro-2-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (26)

[0346] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 nig, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0347] Step 2: 6-(5-fluoro-2-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-chloro-5-fluoro-2-methylpyrimidine (18.2 mg, 0.124 mmol, 1.2 equiv) as the stalling materials to give 6-(5-fluoro-2-methylpyrimidin-4-yl)-4- ((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2 / / )-one (32.6 mg, 57.4%) as a white solid. 'H NMR (400 MHz, Chloroform-7) δ 8.62 (d, 7= 4.8 Hz, 1H), 8.53 (d, 7 = 3.3 Hz, 1H), 8.02 (d, 7= 17.8 Hz, 2H), 7.38 - 7.30 (m, 1H), 7.09 - 6.99 (m, 1H), 6.92 (d, 7= 7.4 Hz, 1H), 6.90 - 6.80 (m, 1H), 5.78 (s, 2H), 3.10 (t, 7= 12.0 Hz, 1H), 2.91 (t, 7= 12.3 Hz, 1H), 2.81 (d, 7= 1.2 Hz, 3H), 2.37 (s, 3H), 2.15 (d, 7 = 11.9 Hz, 4H), 1.86 (d, 7= 12.6 Hz, 2H), 1.59 (t, 7= 12.5 Hz, 2H). MS m / z: 556.15 [M+H]+.4-(( lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-( 1 -methyl- 1H- 1,2, 3-triazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (27)

[0348] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid. Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 nig, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0349] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-lH-l,2,3- triazol-4-yl)-2-((3-(trifluoromcthyl)pyridin-2-yl)mcthyl)pyridazin-3(2 / 7)-onc. Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-bromo-l-methyl-177-l,2,3-triazole (33.6 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l- methyl- 1H- 1 ,2,3-triazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one (44.3 mg, 85.4%) as a white solid.1H NMR (300 MHz, Chlorol'orm-d) δ 8.63 (s, 1H), 8.05 - 7.91 (m, 3H), 7.32 (s, 1H), 7.09 - 6.96 (m, 1H), 6.94 - 6.82 (m, 2H), 5.71 (s, 2H), 4.14 (s, 3H), 3.12 (t, J= 11.6 Hz, 1H), 2.89 (t, J= 12.1 Hz, 1H), 2.36 (s, 3H), 2.14 (d, J= 11.8 Hz, 4H), 1.84 (d, J= 12.4 Hz, 2H), 1.59 (t, J= 12.3 Hz, 2H). MS m / z: 527.25 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (28)

[0350] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 nig, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0351] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrimidin-4-yl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (40.0 mg, 0.082 mmol, 1.0 equiv) and 4-chloropyrimidine (21.0 mg, 0.098 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(pyrimidin-4- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (16.0 mg, 37.2%) as a white solid.1H NMR (400 MHz, Chlorofonn-d) 8 9.28 (d, J = 1.3 Hz, 1H), 8.76 (d, J = 5.4 Hz, 1H), 8.60 (dd, 7= 4.8, 1.6 Hz, 1H), 8.27 (d, J = 0.9 Hz, 1H), 8.06 (dd, 7= 5.4, 1.4 Hz, 1H), 8.01 (dd, 7 = 7.6, 1.5 Hz, 1H), 7.33 (dd, 7= 8.0, 4.9 Hz, 1H), 7.09 - 6.99 (m, 1H), 6.92 (d, 7= 7.4 Hz, 1H), 6.88 - 6.79 (m, 1H), 5.79 (s, 2H), 3.18 - 3.05 (m, 1H), 2.91 (t, 7= 12.5 Hz, 1H), 2.36 (s, 3H), 2.23 - 2.08 (m, 4H), 1.92 - 1.81 (m, 2H), 1.66 - 1.50 (m, 2H). MS m / z: 524.15 [M+H]+.6-(5-(Difhioromethyl)pyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (29)

[0352] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethy l)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-y l)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0353] Step 2: 6-(5-(difluoromethyl)pyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 2-chloro-5-(difluoromethyl)pyrazine (20.7 mg, 0.122 mmol, 1.2 equiv) as the starting materials to give 6-(5-(difluoromethyl)pyrazin-2-yl)-4- ((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (26.0 mg, 44.0%) as a white solid.1H NMR (400 MHz, Chloroform-6?) 39.31 (s, 1H), 8.89 (s, 1H), 8.66 (d, J= 4.9 Hz, 1H), 8.20 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.04 (td, J= 7.8, 5.4 Hz, 1H), 6.95 - 6.71 (m, 3H), 5.81 (s, 2H), 3.12 (t, J= 12.1 Hz, 1H), 2.91 (t, J = 12.3 Hz, 1H), 2.36 (s, 3H), 2.15 (d, J= 12.1 Hz, 4H), 1.89 - 1.84 (m, 2H), 1.59 (t, J= 12.5 Hz, 2H). MS m / z: 574.10 [M+H]+.2-((3-(l,l-Difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(5-methylpyrimidin-4-yl)pyridazin-3(2H)-one (30)

[0354] Step 1: 2-chloro-3-(l,l-difluoroethyl)pyridine: Followed the general procedure I using l-(2-chloropyridin-3-yl)ethan-l-one (5.00 g, 32.1 mmol, 1.0 equiv) as the starting materials to give 2-chloro-3-(l,l-difluoroethyl)pyridine (5.0 g, 87%) as a light yellow oil. MS m / z: 178 [M+H]+.

[0355] Step 2: (3-(l,l-difluoroethyl)pyridin-2-yl)methanol: To a stirred solution of 2- chloro-3-(l,l-difluoroethyl)pyridine (2.5 g, 14.1 mmol, 1.0 equiv) and Pd(PPh3)2Ch (0.99 g, 1.41 mmol, 0.1 equiv) in toluene (20 mL) was added (tributylstannyl)methanol (5.42 g, 16.9 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The reaction was monitored 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 water (2 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 (3-(l,l-difluoroethyl)pyridin-2-yl)methanol (560 mg, 23%) as a light yellow oil. MS m / z: 174 [M+H]+.

[0356] Step 3: 2-(chloromethyl)-3-(l,l-difluoroethyl)pyridine: Followed the general procedure Q using (3-(l,l-difluoroethyl)pyridin-2-yl)methanol (560 mg, 3.23 mmol, 1.0 equiv) and SOCh (3 mL) as the starting materials to give 2-(chloromethyl)-3-(l,l- difluoroethyl)pyridine (550 mg, 89%) as a yellow oil. MS m / z: 192 [M+H]+.

[0357] Step 4: 6-chloro-2-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one: Followed the general procedure V using 2-(chloromethyl)-3-(l,l-difluoroethyl)pyridine (50.0 mg, 0.260 mmol, 1.0 equiv) and 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (100 mg, 0.313 mmol, 1.2 equiv) as the starting materials to give 6-chloro-2-((3-(l,l- difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)pyridazin-3(2H )-one (50.0 mg, 40%) as a light yellow solid. MS m / z: 476 [M+H]+.

[0358] Step 5: (l-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-2-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)- 4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (50.0 mg, 0.105 mmol, 1.0 equiv) as the starting material to give (l-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-5- ((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 486 [M+H]+.

[0359] Step 6: 2-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(5-methylpyrimidin-4-yl)pyridazin-3(2H )-one: Followed the general procedure H using (l-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-5-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-6-oxo- 1 ,6-dihydropyridazin-3-yl)boronic acid (crude, 0.105 mmol, 1.0 equiv) and 4-chloro-5-methylpyrimidine (16.3 mg, 0.126 mmol, 1.2 equiv) as the starting materials to give 2-((3-(l,l-difluoroethyl)pyridin-2-yl)methyl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylpyrimidin-4-yl)pyridazin-3(2H )-one (6.5 mg, 14%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 9.15 (s, 1H), 8.62 (s, 1H), 8.54 (d, J= 4.0 Hz, 1H), 8.15 (d, J= 0.9 Hz, 1H), 7.90 (dd, J= 8.0, 1.6 Hz, 1H), 7.33 (dd, J= 7.9, 4.9 Hz, 1H), 7.04 (td, J= 7.8, 5.5 Hz, 1H), 6.92 (d, J= 7.4 Hz, 1H), 6.84 (dd, J= 11.9, 8.2 Hz, 1H), 5.71 (d, J= 1.6 Hz, 2H), 3.09 (t, J = 12.1 Hz, 1H), 2.90 (t, J= 12.3 Hz, 1H), 2.50 (s, 3H), 2.36 (s, 3H), 2.20 (s, 1H), 2.14 (d, J= 18.5 Hz, 6H), 1.85 (dd, J= 12.7, 3.8 Hz, 2H), 1.64 - 1.49 (m, 2H). MS m / z: 534.20 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylthiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (31)

[0360] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv)as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0361] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methylthiazol-2- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 2-bromo-5-methylthiazole (38.9 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5- methylthiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (25.2 mg, 52.7%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 8.62 - 8.61 (m, 1H), 8.02 - 7.98 (m, 2H), 7.52 (d, J= 1.3 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.05 - 7.00 (m, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.86 - 6.81 (m, 1H), 5.71 (s, 2H), 3.13 - 3.07 (m, 1H), 2.90 - 2.84 (m, 1H), 2.49 (d, J= 1.2 Hz, 3H), 2.35 (s, 3H), 2.17 - 2.09 (m, 4H), 1.85 - 1.81 (m, 2H), 1.60 - 1.50 (m, 2H). MS m / z: 543.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-l,3,4-thiadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (32)

[0362] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2Z7)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0363] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-l,3,4- thiadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followedthe general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 2-bromo-5-methyl-l ,3,4-thiadiazole (27.6 mg, 0.156 mmol, 1.5 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6- (5-methyl-l ,3,4-thiadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )- one (6.9 mg, 12%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.09 (s, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.39 (s, 1H), 7.05 - 7.00 (m, 1H), 6.91 (s, 1H), 6.87 - 6.81 (m, 1H), 5.74 (s, 2H), 3.10 (t, J = 11.9 Hz, 1H), 2.89 (t, J= 12.0 Hz, 1H), 2.82 (s, 3H), 2.37 (s, 3H), 2.13 (d, J= 12.2 Hz, 4H), 1.85 (d, J = 12.8 Hz, 2H), 1.56 (t, J = 12.5 Hz, 2H). MS m / z: 544.10 [M+H]+.6-(3-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4-(( lr,4r)-4-(2-fhioro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (33)

[0364] Step 1: 4-bromo-3-(difluoromethyl)-l-methyl-177-pyrazole hydrogen chloride: Followed the general procedure I using 4-bromo-l -methyl- 177-pyrazole-3-carbaldehy de (500 mg, 2.64 mmol, 1.0 equiv) as the starting material to give 4-bromo-3-(difluoromethyl)-l- methyl-177-pyrazole hydrochloride (310 mg, 55%) as a white solid. MS m / z: 211 [M+H]+.

[0365] Step 2: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0366] Step 3: 6-(3-(difluoromethyl)-l -methyl- 177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-bromo-3-(difluoromethyl)-l-methyl-177-pyrazole hydrochloride (32.7 mg, 0.156 mmol, 1.5 equiv) as the starting materials to give 6-(3- (difluoromethyl)-l -methyl- 177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (36.4 mg, 60.7%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 8.73 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.43 (d, J = 29.4 Hz, 2H), 7.07 - 6.94 (m, 2H), 6.93 - 6.83 (m, 2H), 5.76 (s, 2H), 3.96 (s, 3H), 3.08 (s, 1H), 2.88 (s, 1H), 2.36 (s, 3H), 2.14 (s, 4H), 1.83 (s, 2H). 1.49 (s, 2H). MS m / z: 576.10 [M+H]+.6-(2,4-Dimethylthiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (34)

[0367] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the stalling material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0368] Step 2: 6-(2,4-dimethylthiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 5-bromo-2,4-dimethylthiazole (24.2 mg, 0.124 mmol, 1.2equiv) as the starting materials to give 6-(2,4-dimethylthiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (14.4 mg, 36.8%) as a white solid.1H NMR (400 MHz, Chloroform-d) 6 8.63 (d, J = 4.8 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.36 - 7.28 (m, 2H), 7.09 - 6.99 (m, 1H), 6.92 (d, 7= 7.5 Hz, 1H), 6.89 - 6.80 (m, 1H), 5.70 (s, 2H), 3.08 (t, J = 12.1 Hz, 1H), 2.88 (t, J = 12.2 Hz, 1H), 2.73 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H), 2.14 (t, J = 11.4 Hz, 4H), 1.85 (d, 7 = 13.0 Hz, 2H), 1.51 - 1.42 (m, 2H). MS m / z: 557.10 [M+H]+.6-(l-(2,2-Difluoropropyl)-lH-pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl) -2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (35)

[0369] Step 1: 3-bromo-l-(2,2-difluoropropyl)-177-pyrazole: Followed the general procedure F using 3-bromo-177-pyrazole (300 mg, 2.04 mmol, 1.0 equiv) and 2,2- difluoropropyl trifluoromethanesulfonate (558 mg, 2.44 mmol, 1.2 equiv) as the starting materials to give 3-bromo-l-(2,2-difluoropropyl)-177-pyrazole (80 mg, 17%) as a brown oil. MS m / z: 225 [M+H]+.

[0370] Step 2: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0371] Step 3: 6-(l-(2,2-difluoropropyl)-177-pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl) cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 3-bromo-l-(2,2-difluoropropyl)-177-pyrazole (46.4 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 6-(l-(2,2-difluoropropyl)-177- pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (19.2 mg, 36.9%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J= 4.8 Hz, 1H), 7.98 (d, J= 7.9 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.06 - 7.00 (m, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.87 - 6.81 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.73 (s, 2H), 4.53 - 4.47 (m, 2H), 3.13 - 3.05 (m, 1H), 2.93 - 2.85 (m, 1H), 2.36 (s, 3H), 2.19 - 2.10 (m, 4H), 1.88 - 1.80 (m, 3H), 1.59 (d, J= 18.6 Hz, 4H). MS m / z 590.10 [M+H]+.6-(5-(Difluoromethyl)-l-methyl-LH-pyrazol-4-yl)-4-(( lr,4r)-4-(2-fhioro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (36)

[0372] Step 1: 4-bromo-5-(difluoromethyl)-l-methyl-177-pyrazole: Followed the general procedure I using 4-bromo-l-methyl-177-pyrazole-5-carbaldehyde (500 mg, 2.64 mmol, 1.0 equiv) as the starting material to give 4-bromo-5-(difluoromethyl)-l-methyl-177- pyrazole (260 mg, 46%) as a colorless oil.MS m / z. 211 [M+H]+.

[0373] Step 2: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z. 490 [M+H]+.

[0374] Step 3: 6-(5-(difluoromethyl)-l-methyl-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-bromo-5-(difluoromethyl)-l-methyl-177-pyrazole (26.1 mg, 0.124 mmol, 1.2 equiv) as the starting materials to give 6-(5-(difluoromethyl)-l-methyl- 177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (38.1 mg, 74.0%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.70 - 8.67 (m, 1H), 8.06 - 8.03 (m, 1H), 7.71 (d, J = 1.1 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.30 (d, 7 = 0.9 Hz, 1H), 7.11 - 6.95 (m, 2H), 6.95 - 6.82 (m, 2H), 5.70 (s, 2H), 4.06 (s, 3H), 3.10 (t, J= 12.1 Hz, 1H), 2.89 (t, J= 12.3 Hz, 1H), 2.37 (s, 3H), 2.14 (t, J= 12.5 Hz, 4H), 1.85 (d, J= 11.0 Hz, 2H), 1.51 (d, J= 12.4 Hz, 2H).MS m / z: 576.15 [M+H]+.6-(2,2-Difluoroethyl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (37)

[0375] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0376] Step 2: 6-(2,2-difluorovinyl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104mmol, 1.0 equiv) and 2-bromo- 1,1 -difluoroethene (17.7 mg, 0.124 mmol, 1.2 equiv) as the starting materials to give 6-(2,2-difluorovinyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl) pyridazin-3(2H )-one (19.2 mg, 36%) as a brown oil. MS m / z. 507 [M+H]+.

[0377] Step 3: 6-(2,2-difluoroethyl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure B 6-(2,2-difluorovinyl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (30 mg, 0.059 mmol, 1.0 equiv) as the starting material to give 6-(2,2-difluoroethyl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (6.2 mg, 20%) as a white solid.1!! NMR (400 MHz, Chlorol'orm-d) δ 8.63 (d, J= 5.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.10 - 7.00 (m, 2H), 6.92 (t, J = 7.7 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.22 - 5.91 (m, 1H), 5.66 (s, 2H), 3.20 - 2.86 (m, 4H), 2.36 (d, J = 9.9 Hz, 3H), 2.17 - 2.06 (m, 4H), 1.83 (s, 2H), 1.51 - 1.39 (m, 2H). MS m / z 510.10[M+H]+.6-(Bicyclo[l.l.l]pentan-l-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (38)

[0378] Step 1: 6-(bicyclo[l.l.l]pentan-l-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl) pyridin-2-yl)mcthyl)pyridazin-3(2 / 7)-onc: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and 2-(bicyclo[l.l.l]pentan-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (24.2 mg, 0.125 mmol, 1.2 equiv) as the starting materials to give 6-(l- (2,2-difluoropropyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridine-2-yl) methyl)pyridazin-3(2H )-one (13.7 mg, 25.1%) as a light yellow oil. ’H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J= 4.8 Hz, 1H), 7.97 (d, J= 7.8Hz, 1H), 7.42 (s, 1H), 7.30 (dd, J= 7.9, 4.8 Hz, 1H), 7.08 - 6.98 (m, 1H), 6.91 (d, J= 7.5 Hz, 1H), 6.84 (dd, J= 11.8, 8.1 Hz, 1H), 5.91 - 5.78 (m, 1H), 5.65 (d, J = 20.0 Hz, 3H), 5.33 (s,1H), 5.08 - 4.98 (m, 2H), 3.16 (d, J = 6.8 Hz, 2H), 3.11 - 3.01 (m, 1H), 2.93 - 2.83 (m, 1H),2.36 (s, 3H), 2.20 - 2.06 (m, 4H), 1.88 - 1.79 (m, 2H), 1.55 - 1.43 (m, 2H). MS m / z: 512.15[M+H]+.6-(l-(Difluoromethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H)- one (39)

[0379] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-( trifluoromethoxy )pyridin-2-yl)methyl)pyridazin-3(2H )-one. Followed the general procedure F using 6-chloro-4-(( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (80.0 mg, 0.249 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(trifluoromethoxy)pyridine (68.7 mg, 0.324 mmol, 1.0 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2-fluoro- 6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )- one (50 mg, 40%) as a white solid. MS m / z: 496 [M+H]+.

[0380] Step 2: 6-(l -(difluoromethyl)- 177-pyrazol-4-yl)-4-(( Ir, 4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )-one. Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.101 mmol, 1.0 equiv) and l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-177-pyrazole (24.6 mg, 0.101 mmol, 1.0 equiv) as the starting materials to give 6-(l-(difluoromethyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethoxy)pyridin-2-yl)methyl)pyridazin-3(2H )-one (32.3 mg, 54.8 %) as a yellow solid. ’ H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J= 4.6 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.21 (s, 1H), 7.07 - 7.00 (m, 1H), 6.92 (d, J= 7.4 Hz, 1H), 6.89 - 6.80 (m, 1H), 5.63 (s, 2H), 3.09 (t, J = 12.1 Hz, 1H), 2.87 (t, 7= 10.9 Hz, 1H), 2.36 (s, 3H), 2.20 - 2.10 (m, 4H), 1.85 (d, J = 12.7 Hz, 2H), 1.50 (d, J= 12.6 Hz, 2H).MS m / z: 578.10 [M+H]+.4-(( lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-( 1 -methyl- lH-pyrazol-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (40)

[0381] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-methyl-177- pyrazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one. Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (26.0 mg, 0.125 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(l-methyl-177-pyrazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (48.4 mg, 87.9%) as a white solid.1H NMR (400 MHz, Chloroform-6?) δ 8.62 (s, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.75 (s, 1H), 7.31 (d, 7= 8.6 Hz, 2H), 7.07 - 7.00 (m, 1H), 6.92 (d, 7= 7.4 Hz, 1H), 6.88 - 6.81 (m, 1H), 5.69 (s, 2H), 3.94 (s, 3H), 3.09 (t, 7= 11.9 Hz, 1H), 2.89 (t, 7= 12.4 Hz, 1H), 2.36 (s, 3H), 2.13 (t, 7 = 11.1 Hz, 4H), 1.83 (s, 2H), 1.51 (d, 7 = 12.5 Hz, 2H).MS m / z: 526.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-( 1- (trifluoromethyl) -lH-pyrazol-4- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (41)

[0382] Step 1: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(l-(trifluoromethyl)- 177-pyrazol-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(trifluoromethyl)-177-pyrazole (32.7 mg, 0.125 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(l-(trifluoromethyl)-177-pyrazol-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (43.3 mg, 71.2%) as a white solid.1H NMR (400 MHz, Chloroform-7) δ 8.67 (d, J= 4.8 Hz, 1H), 8.18 (s, 1H), 8.11 - 8.05 (m, 2H), 7.44 - 7.37 (m, 1H), 7.31 (d, J = 0.9 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.92 (d, 7= 7.4 Hz, 1H), 6.89 - 6.82 (m, 1H), 5.74 (s, 2H), 3.09 (t, 7= 12.1 Hz, 1H), 2.89 (t, 7= 12.5 Hz, 1H), 2.36 (s, 3H), 2.14 (t, 7 = 11.1 Hz, 4H), 1.89 - 1.81 (m, 2H), 1.57 - 1.46 (m, 2H).MS m / z: 580.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2-(2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H)-one (42)

[0383] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid. MS m / z: 490 [M+H]+.

[0384] Step 2: 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 2,4-dichloro-5-methylpyrimidine (20.1 mg, 0.124 mmol, 1.2 equiv) as the starting materials to give 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4- (2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (50 mg, 86%) as a colorless oil. MS m / z: 572 [M+H]+.

[0385] Step 3: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2-(2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one: Followed the general procedure K using 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)- 4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)mcthyl)pyridazin-3(2 / 7)-onc (50 mg, 0.087 mmol, 1.0 equiv) as the starting material to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2-(2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )- one (26.5 mg, 44.3%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 8.67 - 8.62 (m, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.40 - 7.34 (m, 1H), 7.07 - 7.00 (m, 1H), 6.92 (d, J= 7.4 Hz, 1H), 6.90 - 6.80 (m, 1H), 5.76 (s, 2H), 4.92 - 4.79 (m, 2H), 3.14 - 3.03 (m, 1H), 2.91 (t, J= 12.3 Hz, 1H), 2.37 (s, 3H), 2.32 - 2.28 (m, 3H), 2.14 (t, J= 11.6 Hz, 4H), 1.89 - 1.84 (m, 2H), 1.63 - 1.51 (m, 2H). MS m / z: 636.15 [M+H]+.6-(l-(2,2-Difluoropropyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl) -2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (43)

[0386] Step 1: 4-bromo-l-(2,2-difluoropropyl)-177-pyrazole: Followed the general procedure F using 4-bromo-177-pyrazole (500 mg, 3.40 mmol, 1.0 equiv) and 2,2- difluoropropyl trifluoromethanesulfonate (931 mg, 4.08 mmol, 1.2 equiv) as the startingmaterials to give 4-bromo-l-(2,2-difluoropropyl)-177-pyrazole (200 mg, 26%) as a brown oil. MS m / z: 225 [M+H]+.

[0387] Step 2: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid. MS m / z: 490[M+H]+.

[0388] Step 3: 6-(l-(2,2-difluoropropyl)-177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl) cyclohexyl) -2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 4-bromo-l-(2,2-difluoropropyl)-177-pyrazole e (39.3 mg, 0.176 mmol, 1.7 equiv) as the stalling materials to give 6-(l-(2,2-difluoropropyl)-177- pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (42 mg, 81%) as a white solid. ’HNMR (400 MHz, Chloroform-ri) δ 8.69 (s, 1H), 8.08 (d, J= 7.6 Hz, 1H), 7.87 (d, J= 2.0 Hz, 2H), 7.41 (s, 1H), 7.30 (s, 1H), 7.06 - 7.00 (m, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.88 - 6.82 (m, 1H), 5.74 (s, 2H), 4.52 - 4.45 (m, 2H), 3.11 - 3.04 (m, 1H), 2.89 (s, 1H), 2.36 (s, 3H), 2.20 - 2.09 (m, 4H), 1.84 (d, J= 12.7 Hz, 2H), 1.64(s, 1H), 1.57 - 1.49 (m, 4H). MS m / z: 590.10[M+H]+.6-(l-(Difluoromethyl)-lH-pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (44)

[0389] Step 1: 6-(l -(difluoromethyl)- 177-pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl) cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl) cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and l-(difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177- pyrazole (38.1 mg, 0.156 mmol, 1.5 equiv) as the starting materials to give 6-(l- (difluoromethyl)-177-pyrazol-3-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl) cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (31.6 mg, 54.0%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.64 - 8.60 (m, 1H), 8.03 - 7.98 (m, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.82 (d, J= 2.7 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.23 (s, 1H), 7.10 - 7.00 (m, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.88 - 6.81 (m, 2H), 5.74 (s, 2H), 3.14 - 3.06 (m, 1H), 2.94 - 2.84 (m, 1H), 2.36 (s, 3H), 2.21 - 2.08 (m, 4H), 1.89 - 1.81 (m, 2H), 1.62 - 1.49 (m, 2H). MS m / z: 562.15[M+H]+.6-(l-(Difluoromethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one (45)

[0390] Step 1: 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-(2- (trifluoromethyl)benzyl) pyridazin-3(2H )-one: Followed the general procedure F using 6- chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)pyridazin-3(2H )-one (50.0 mg, 0.156 mmol, 1.0 equiv) and l-(bromomethyl)-2-(trifluoromethyl)benzene (44.7 mg, 0.187 mmol, 1.2 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-(2-(trifluoromethyl)benzyl) pyridazin-3(2 / 7)-onc (50 mg, 66%)as a white solid. MS m / z: 479 [M+H]+.

[0391] Step 2: 6-(l -(difluoromethyl)- 177-pyrazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl) cyclohexyl) -2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-(2- (trifluoromethyl)benzyl) pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (50.9 mg, 0.208 mmol, 2.0 equiv) as the starting materials to give 6-(l-(difluoromethyl)-177-pyrazol-4- yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-(2- (trifluoromethyl)benzyl)pyridazin-3(2H)-one (44 mg, 75%) as a white solid.1H NMR (400 MHz, Chloroform-ri) δ 8.15 (s, 1H), 7.98 (s, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.46 (t, J= 7.7 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.30 (d, J= 0.9 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J= 7.8 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.93 (d, J= 7.5 Hz, 1H), 6.89 - 6.83 (m, 1H), 5.63 (s, 2H), 3.13 (t, J = 11.9 Hz, 1H), 2.90 (t, J= 12.4 Hz, 1H), 2.37 (s, 3H), 2.15 (t, J= 14.6 Hz, 4H), 1.87 (d, J = 12.7 Hz, 2H), 1.47 (s, 2H). MS m / z: 561.25 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(tetrahydrofuran-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (46)

[0392] Step 1: 6-(2,5-dihydrofuran-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (50.0 mg, 0.104 mmol, 1.0 equiv) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (24.5 mg, 0.125 mmol, 1.2 equiv) as the starting materials to give 6-(2,5- dihydrofuran-3-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (30.0 mg, 56%) as a white solid. MS m / z: 514 [M+H]+.

[0393] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(tetrahydrofuran-3- yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure B using 6-(2,5-dihydrofuran-3-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (30.0 mg, 0.058 mmol, 1.0 equiv) as the starting material to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(tetrahydrofuran-3-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (11.2 mg, 35.4%) as a white solid.1H NMR (400 MHz, Chloroform-6?) δ 8.64 (d, J= 4.8 Hz, 1H), 7.99 (d, J= 7.9 Hz, 1H), 7.33 (dd, J= 7.9, 4.7 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.91 (d, J= 7.5 Hz, 1H), 6.84 (dd, J= 11.8, 8.1 Hz, 1H), 5.64 (s, 2H), 4.11 - 3.96 (m, 2H), 3.91 - 3.80 (m, 2H), 3.47 - 3.35 (m, 1H), 3.03 (t, J = 12.0 Hz, 1H), 2.87 (t, J = 12.3 Hz, 1H), 2.35 (s, 3H), 2.34 - 2.26 (m, 1H), 2.19 - 2.03 (m, 5H), 1.84 (s, 1H), 1.80 (s, 1H), 1.53 - 1.39 (m, 2H). MS m / z: 516.25 [M+H]+.6-(5-Ethyl-l,3,4-thiadiazol-2-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (47)

[0394] Step 1: 2-bromo-5-vinyl-l,3,4-thiadiazole: Followed the general procedure A using 2,5-dibromo-l,3,4-thiadiazole (500 mg, 2.05 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2- vinyl-l,3,2-dioxaborolane (157 mg, 1.02 mmol, 0.5 equiv) as the starting materials to give 2- bromo-5-vinyl-l,3,4-thiadiazole (180 mg, 45%) as a light brown oil. MS m / z: 191 [M+H]+.

[0395] Step 2: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0396] Step 3: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinyl-l,3,4-thiadiazol-2-yl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.104 mmol, 1.0 equiv) and 2-bromo-5-vinyl-l,3,4-thiadiazole (32.0 mg, 0.124 mmol, 1.2 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinyl- 1,3,4- thiadiazol-2-yl)pyridazin-3(2H)-one (20 mg, 35%) as a colorless oil. MS m / z. 556 [M+H]+.

[0397] Step 4: 6-(5-ethyl-l,3,4-thiadiazol-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one: Followed the general procedure B using 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinyl-l,3,4-thiadiazol-2-yl)pyridazin-3(2H )- one (20 mg, 0.036 mmol, 1.0 equiv) as the starting material to give 6-(5-ethyl- 1,3,4- thiadiazol-2-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (8.9 mg, 44%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J= 4.8 Hz, 1H), 8.08 (d, J= 17.8 Hz, 2H), 7.44 - 7.37 (m, 1H), 7.07 - 7.00 (m, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.88 - 6.80 (m, 1H), 5.75 (s, 2H), 3.19 (t, J= 7.6 Hz, 2H), 3.09 (t, J= 12.1 Hz, 1H), 2.91 (d, J= 12.8 Hz, 1H), 2.37 (s, 3H), 2.13 (d, J = 12.9 Hz, 4H), 1.85 (d, J = 12.4 Hz, 2H), 1.55 (d, J = 12.6 Hz, 2H), 1.44 (d, J = 7.6 Hz, 3H).MS m / z 558.10 [M+H]+.4-((lr,4r)-4-(2-Fluoro-6-methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)-l,3,4- thiadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (48)

[0398] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (50.0 mg, 0.104 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z 490 [M+H]+.

[0399] Step 2: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)- l,3,4-thiadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropy- ridazin-3-yl)boronic acid (crude, 0.102 mmol, 1.0 equiv) and 2-chloro-5-(trifluoromethyl)-l,3,4-thiadiazole (38.5 mg, 0.204 mmol, 2.0 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (39.8 mg, 65.1%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J= 4.7 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J= 7.8 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.08 - 6.99 (m, 1H), 6.93 (d, J= 7.4 Hz, 1H), 6.89 - 6.80 (m, 1H), 5.74 (s, 2H), 3.11 (t, J = 12.1 Hz, 1H), 2.90 (t, J= 12.2 Hz, 1H), 2.37 (s, 3H), 2.14 (d, J = 12.1 Hz, 4H), 1.87 (d, J= 12.4 Hz, 2H), 1.52 (d, J= 12.4 Hz, 2H). MS m / z: 598.05 [M+H]+.6-(l-(Difluoromethyl)-lH-imidazol-4-yl)-4-((lr,4r)-4-(2-fhioro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (49)

[0400] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (40.0 mg, 0.083 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0401] Step 2: 6-(l -(difluoromethyl)- 177-imidazol-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.083 mmol, 1.0 equiv) and 4-bromo- l-(difluoromcthyl)- 1 / 7-imidazolc (19.5 mg,0.099 mmol, 1.2 equiv) as the starting materials to give 6-(l-(difluoromethyl)-177-imidazol-4- yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (13.3 mg, 33.4%) as a white solid.1H NMR (400 MHz, Chloroform-ri) δ 8.60 (d, J= 4.2 Hz, 1H), 7.97 (d, J= 7.8 Hz, 1H), 7.88 (d, J= 11.3 Hz, 2H), 7.65 (s, 1H), 7.30 (dd, J= 8.0, 5.0 Hz, 1H), 7.13 - 6.79 (m, 4H), 5.72 (s, 2H), 3.11 (t, J = 12.1 Hz, 1H), 2.88 (t, J = 12.5 Hz, 1H), 2.35 (s, 3H), 2.13 (d, J= 12.1 Hz, 4H), 1.83 (d, J = 12.9 Hz, 2H), 1.56 (q, J= 12.6 Hz, 2H). MS m / z: 562.15[M+H]+.6-(5-Ethylpyrazin-2-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (50)

[0402] Step 1: (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (100 mg, 0.208 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0403] Step 2: 6-(5-chloropyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.208 mmol, 1.0 equiv) and 2-bromo-5-chloropyrazine (47.8 mg, 0.249 mmol, 1.2 equiv) as the starting materials to give 6-(5-chloropyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (60 mg, 51%) as a white solid. MS m / z: 558 [M+H]+.

[0404] Step 3: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinylpyrazin-2-yl)pyridazin-3(2H )-one: Followed the general procedure A using 6-(5-chloropyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (60.0 mg, 0.108 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (18.4 mg, 0.118 mmol, 1.1 equiv) as the starting materials to give 4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinylpyrazin-2- yl)pyridazin-3(2H )-one (40 mg, 71%) as a white solid. MS m / z: 550 [M+H]+.

[0405] Step 4: 6-(5-ethylpyrazin-2-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one: Followed the general Procedure B using 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)-6-(5-vinylpyrazin-2-yl)pyridazin-3(2H )-one (40 mg, 0.073 mmol, 1.0 equiv) as the starting material to give 6-(5-ethylpyrazin-2-yl)-4-((lr,4r)-4- (2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (18.7 mg, 46.6%) as a white solid.1H NMR (400 MHz, Chlorol'orm-d) δ 9.16 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.01 (d, J= 7.5 Hz, 1H), 7.33 (s, 1H), 7.08 - 6.99 (m, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.85 (dd, J= 11.5, 8.4 Hz, 1H), 5.78 (s, 2H), 3.13 (t, J = 12.0 Hz, 1H), 3.00 - 2.85 (m, 3H), 2.36 (s, 3H), 2.15 (d, J= 12.1 Hz, 4H), 1.84 (s, 2H), 1.63 - 1.53 (m, 2H), 1.37 (t, J= 7.2 Hz, 3H). MS m / z: 552.10 [M+H]+.6-(2-Ethyl-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (51)

[0406] Step 1 : (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (100 mg, 0.208 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 490 [M+H]+.

[0407] Step 2 : 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure H using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.208 mmol, 1.0 equiv) and 2,4-dichloro-5-methylpyrimidine (37.1 mg, 0.228 mmol, 1.1 equiv) as the starting materials to give 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4- (2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (55 mg, 54%) as a light green oil. MS m / z. 572 [M+H]+.

[0408] Step 3 : 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2- vinylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure A using 6-(2-chloro-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2- fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (40 mg, 0.070 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (21.5 mg, 0.140 mmol, 2.0 equiv) as the starting materials to give 4-(4-(2- fluoro-6-methylphenyl)cyclohexyl)-6-(5-methyl-2-vinylpyrimidin-4-yl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (30.0 mg, 76.1%) as a colorless oil. MS m / z: 564 [M+H]+.

[0409] Step 4 : 6-(2-ethyl-5-methylpyrimidin-4-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure B using 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-(5-methyl-2-vinylpyrimidin-4-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin- 3(2H )-one (25 mg, 0.044 mmol, 1.0 equiv) as the starting material to give 6-(2-ethyl-5- methylpyrimidin-4-yl)-4-(4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (9.5 mg, 37%) as a white solid.1H NMR (300 MHz, Chloroform-d) δ 8.63 (d, J= 4.8 Hz, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.09 - 7.00 (m, 1H), 6.96 - 6.80 (m, 2H), 5.76 (s, 2H), 3.16 - 3.11 (m, 3H), 2.90 (t, J= 12.1 Hz, 1H), 2.36 (d, 7= 7.9 Hz, 6H), 2.16 (d, J = 12.3 Hz, 4H), 1.87 (d, J= 12.0 Hz, 2H), 1.57 (d, J= 12.7 Hz, 2H), 1.46 (s, 3H). MS m / z 566.20 [M+H]+.6-( l-(Difhioromethyl)- lH-pyrazol-4-yl)-4-(( lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (52)

[0410] Step 1: ethyl 2',6'-difluoro-2,3,4,5-tetrahydro-[l,l'-biphenyl]-4-carboxylate: Followed the general procedure A using ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclohex-3-ene-l -carboxylate (2.0 g, 7.1 mmol, 1.0 equiv) and 2-bromo-l,3- difluorobenzene (1.38 g, 7.1 mmol, 1.0 equiv) as the starting materials to give ethyl 2', 6'- difluoro-2,3,4,5-tetrahydro-[l,l'-biphenyl]-4-carboxylate (1.8 g, 94%) as a yellow oil. MS m / z: 267 [M+H]+.

[0411] Step 2: ethyl 4-(2,6-difluorophenyl)cyclohexane-l -carboxylate: ollowed the general procedure B using ethyl 2',6'-difluoro-2,3,4,5-tetrahydro-[l,l'-biphenyl]-4- carboxylate (1.8 g, 6.7 mmol, 1.0 equiv) as the starting material to give the the crude product ethyl 4-(2,6-difluorophenyl)cyclohexane-l -carboxylate (1.7 g, crude) as a light yellow oil. MS m / z: 269 [M+H]+.

[0412] Step 3: 4-(2,6-difluorophenyl)cyclohexane-l -carboxylic acid: Followed the general procedure C using ethyl 4-(2,6-difluorophenyl)cyclohexane-l -carboxylate (1.7 g, 6.3 mmol, 1.0 equiv) as the starting material to give the crude product 4-(2,6- difluorophenyl)cyclohexane- 1 -carboxylic acid (1.45 g, crude) as a white solid. MS m / z: 239 [M+H]+.

[0413] Step 4: 3,6-dichloro-4-(4-(2,6-difluorophenyl)cyclohexyl)pyridazine: Followed the general procedure D using 4-(2,6-difluorophenyl)cyclohexane-l -carboxylic acid (1.45 g, 6.1 mmol, 1.0 equiv) and 3,6-dichloropyridazine (0.81 g, 5.4 mmol, 0.9 equiv) as the starting materials to give 3,6-dichloro-4-(4-(2,6-difluorophenyl)cyclohexyl)pyridazine (1.1 g, 53%) as a white solid. MS m / z: 343 [M+H]+.

[0414] Step 5: 6 -chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)pyridazin-3(2H )-one: Followed the general procedure E using 3,6-dichloro-4-(4-(2,6- difluorophenyl)cyclohexyl)pyridazine (1.1 g, 3.2 mmol, 1.0 equiv) as the starting material togive 6-chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)pyridazin-3(2H )-one (260 mg, 24%) as a white solid. MS m / z. 325 [M+H]+.

[0415] Step 6: 6-chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure F using 6-chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)pyridazin-3(2H )-one (260 mg, 0.8 mmol, 1.0 equiv) and 2-(chloromethyl)-3-(trifluoromethyl)pyridine (156 mg, 0.8 mmol, 1.0 equiv) as the starting materials to give 6-chloro-4-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (40 mg, 10%) as a white solid. MS m / z. 484 [M+H]+.

[0416] Step 7: 2-(2,2-difluoropropyl)-5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 7-((3-(trifluoromethoxy)pyridin-2-yl)methyl)-2,7-dihydro-677-pyrazolo[3,4-Z>]pyridin-6-one: Followed the general procedure A using 6-chloro-4-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2 / / )-one (40 mg, 0.083 mmol, 1.0 equiv) and l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (24.2 mg, 0.10 mmol, 1.2 equiv) as the starting materials to give 6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2- ((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (21.1 mg, 45.1%) as a white solid. NMR (400 MHz, Chloroform-J) 5 8.61 (d, 7= 4.7 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J = 6.1 Hz, 2H), 7.32 (d, 7 = 7.1 Hz, 2H), 7.22 - 7.03 (m, 2H), 6.82 (t, 7 = 8.6 Hz, 2H), 5.71 (s, 2H), 3.16 - 3.04 (m, 2H), 2.17 - 2.05 (m, 4H), 1.94 - 1.85 (m, 2H), 1.58 - 1.43 (m, 2H). MS m / z: 566.05 [M+H]+.6-(5-(Difluoromethyl)-l,3,4-oxadiazol-2-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (53)

[0417] Step 1: ethyl 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazine-3-carboxylate: Followed the general procedure U using ethyl 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboxylate (150 mg, 0.313 mmol, 1.0 equiv) as the starting material to give ethyl 5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carboxylate (120 mg, 74%) as a white solid. MS m / z: 518 [M+H]+.

[0418] Step 2: 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazine-3-carbohydrazide: Followed the general procedure N using ethyl 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-l- ((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carboxylate (120 mg, 0.232 mmol, 1.0 equiv) as the starting material to give 5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carbohydrazide (100 mg, 85%) as a white solid. MS m / z: 504 [M+H]+.

[0419] Step 3: 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-M-(2,2,2- trifluoroacetyl)- 1 -((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6-dihydropyridazine-3- carbohydrazide: Followed the general procedure O using 5-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-6-oxo-l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6- dihydropyridazine-3-carbohydrazide (100 mg, 0.119 mmol, 1.0 equiv) and 2,2,2- trifluoroacetic anhydride (62.5 mg, 0.298 mmol, 1.5 equiv) as the starting materials to give 5- (( 1 r,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-oxo-M-(2,2,2-trifluoroacetyl)- 1 -((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazine-3-carbohydrazide (80 mg, 67%) as a white solid. MS m / z: 582 [M+H]+.

[0420] Step 4: 4-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)- l,3,4-oxadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general Procedure P using 5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo-M-(2,2,2-tri fluoroacetyl)- 1 -((3-(trifluoromethyl)pyridin-2-yl)methyl)- 1 ,6- dihydropyridazine-3-carbohydrazide (80 mg, 0.133 mmol, 1.0 equiv) as the starting materials to give 4-((l r,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-6-(5-(trifluoromethyl)- 1,3,4- oxadiazol-2-yl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one (40.8 mg, 52.6%) as a white solid.1H NMR (400 MHz, Chloroform-7) δ 8.58 (d, J= 5.1 Hz, 1H), 8.00 (d, J = 8.0 Hz 1H), 7.95 (s, 1H), 7.34 (dd, J = 8.0, 4.9 Hz, 1H), 7.04 (td, J = 7.9, 5.5 Hz, 1H), 6.92 (d, 7= 7.5 Hz, 1H), 6.85 (dd, 7= 11.9, 8.2 Hz, 1H), 5.79 (s, 2H), 3.09 (t, 7= 12.1 Hz, 1H), 2.88 (t, 7= 12 Hz 1H), 2.37 (s, 3H), 2.14 (d, 7= 11.8 Hz, 4H), 1.86 (dd, 7= 13.6, 3.8 Hz, 2H), 1.56 - 1.47 (m, 2H). MS m / z: 582.00 [M+H]+.6-(2-(Difhioromethyl)thiazol-5-yl)-4-((lr,4r)-4-(2-fhioro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (54)

[0421] Step 1: 6-(2-(difluoromethyl)thiazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one: Followed the general procedure A using (5-((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)- 6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (40 mg, 0.082 mmol, 1.0 equiv) and 5-bromo-2-(difluoromethyl)thiazole (21 mg, 0.098 mmol, 1.2 equiv) as the starting materials to give 6-(2-(difluoromethyl)thiazol-5-yl)-4- ((lr,4r)-4-(2-fluoro-6-methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H )-one (34.0 mg, 70.9%) as a white solid.1H NMR (300 MHz, Chloroform-6?) δ 8.64 (d, J= 4.6 Hz, 1H), 8.12 (d, J= 1.6 Hz, 1H), 8.04 (d, J= 7.7 Hz, 1H), 7.47 (s, 1H), 7.38 (t, 7 = 6.4 Hz, 1H), 7.10 - 6.60 (m, 4H), 5.72 (s, 2H), 3.10 (t, J= 12.1 Hz, 1H), 2.90 (t, J = 12.4 Hz, 1H), 2.37 (s, 3H), 2.15 (d, J = 12.3 Hz, 4H), 1.90 - 1.83 (m, 2H), 1.53 (q, J= 12.6 Hz, 2H). MS m / z: 579.05[M+H]+.6-(5-(Difluoromethyl)-l-methyl-lH-pyrazol-4-yl)-4-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (55)

[0422] Step 1: 4-bromo-5-(difluoromethyl)-l-methyl-lH-pyrazole: Followed the general procedure I using 4-bromo-l-methyl-lH-pyrazole-5-carbaldehyde (100 mg, 0.529 mmol, 1.0equiv) as the starting material to give 4-bromo-5-(difluoromethyl)-l-methyl-lH-pyrazole (38 mg, 34%) as a yellow oil. MS m / z: 211 |M+H]+.

[0423] Step 2: (5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid: Followed the general procedure G using 6-chloro-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2-((3- (trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)-one (100 mg, 0.207 mmol, 1.0 equiv) as the starting material to give (5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-6-oxo-l-((3- (trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid which was used directly in next step. MS m / z: 494 [M+H]+.

[0424] Step 3: 6-(5-(difluoromethyl)-l-methyl-177-pyrazol-4-yl)-4-((lr,4r)-4-(2,6- difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H )-one:Followed the general procedure H using (5-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-6-oxo- l-((3-(trifluoromethyl)pyridin-2-yl)methyl)-l,6-dihydropyridazin-3-yl)boronic acid (crude, 0.207 mmol, 1.0 equiv) and 4-bromo-5-(difluoromethyl)-l -methyl- l / / -pyrazole (52.4 mg, 0.248 mmol, 1.2 equiv) as the stalling materials to give 6-(5-(difluoromethyl)-l-methyl-l / / - pyrazol-4-yl)-4-((lr,4r)-4-(2,6-difluorophenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2- yl)methyl)pyridazin-3(2H)-one (13.4 mg, 18.9%) as a white solid.lH NMR (300 MHz, Chloroform-d) 8 8.68 (d, J = 4.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.44 - 7.33 (m, 1H), 7.29 (d, J = 0.9 Hz, 1H), 7.20 - 6.90 (m, 2H), 6.83 (t, J = 8.5 Hz, 2H), 5.70 (s, 2H), 4.06 (s, 3H), 3.10 (t, J = 12.2 Hz, 2H), 2.10 (d, J - 11.1 Hz, 4H), 1.99 - 1.89 (m, 2H), 1.60 - 1.40 (m, 2H). MS m / z.: 580.05 [M+H]+.6-(l-(Difluoromethyl)-lH-pyrazol-5-yl)-4-((lr,4r)-4-(2-fluoro-6- methylphenyl)cyclohexyl)-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyridazin-3(2H)- one (56)

[0425] Step 1: 4-((lr,4r)-4-(2-fluoro...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;R2is optionally substituted carbocyclyl or optionally substituted heterocyclyl;R3is hydrogen, halogen, optionally substituted alkyl, or optionally substituted aryl;R4is hydrogen, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -ORA, -N(RA)2, - C(=O)N(RA)2, -C(=NRA)NRAORA, or -NRAC(=O)RA;Y is -C(R5)2- or a bond; 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, or an oxygen protecting group when attached to an oxygen atom, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

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 R1is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted carbocyclyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl or optionally substituted heteroaryl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted aryl.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1is optionally substituted heteroaryl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R1iswherein 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, 3, or 4.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently haloalkyl or -ORA; and x is 0, 1, 2, 3, or 4.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1iswherein Z1and Z2are each independently CH, CR6, or N; each R6is independently cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1iswherein each R6is independently cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2; and x is 0, 1, 2, 3, or 4.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1iswherein R6is cyclopropyl, -CF3, -CHF2, -CF2CH3, -CH2CF3, -CH2CHF2, -OCF3, or -OCHF2.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R1is16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted carbocyclyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted C3-12 cycloalkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted C3-8 cycloalkyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted cyclohexyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein 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 an optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted aryl; and y is 0, 1, or 2.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R2iswherein R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

22. The compound of any one of claims 1-21, or a tautomer or pharmaceutically acceptable salt thereof, wherein R2iswherein Z3and Z4are each independently -N- or -CR9-; andR8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

23. The compound of any one of claims 1-22, or a tautomer or pharmaceutically acceptable salt thereof, wherein R2is24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R2is25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R2iswherein R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

26. The compound of any one of claims 1-25, or a tautomer or pharmaceutically acceptable salt thereof, wherein R2iswherein Z3and Z4are each independently -N- or -CR9; andR8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

27. The compound of any one of claims 1-26, or a tautomer or pharmaceutically acceptable salt thereof, wherein R2iswherein R8, R9, and R10are each independently hydrogen, halogen, optionally substituted alkyl, or -ORA.

28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R2is29. The compound of any one of claims 1-28, or a tautomer or pharmaceutically acceptable salt thereof, wherein R2is30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or optionally substituted aryl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or optionally substituted phenyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6-membered heterocyclyl, optionally substituted 5-6- membered heteroaryl, -ORA, -N(RA)2, -C(=O)N(RA)2, -C(=NRA)NRAORA, or - NRAC(=O)RA34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein:R4is hydrogen, haloalkyl, optionally substituted alkyl, optionally substituted C4-6 cycloalkyl, optionally substituted 4-6-membered heterocyclyl, optionally substituted 5-6- membered heteroaryl, -ORA, -N(RA)2, -C(=O)N(RA)2, -C(=NRA)NRAORA, or - NRAC(=O)RA; and each RAis independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, or two instances of RAtogether with the atoms to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted 5-6-membered heteroaryl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted 5-membered heteroaryl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R4is optionally substituted thiazole, optionally substituted pyrazole, optionally substituted triazole, optionally substituted dithiazole, optionally substituted imidazole, optionally substituted oxadiazole, or optionally substituted oxazole.

38. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R4is:

39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R4is40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein R4is41. The compound of claim 1, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

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

43. The compound of claim 1, wherein the compound is of Formula (I-c):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.

44. The compound of claim 1, wherein the compound is of Formula (I-d):or a pharmaceutically acceptable salt thereof, wherein:R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

45. The compound of claim 1, wherein the compound is of Formula (I-e):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;R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl; and x is 0, 1, or 2.

46. The compound of claim 1, wherein the compound is of Formula (I-f):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH, CR6, or N; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA;R7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl; and x is 0, 1, or 2.

47. The compound of claim 1, wherein the compound is of Formula (I-f-1):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH, CR6, or N;Z3and Z4are each independently -N- or -CR9-; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA;each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA; and x is 0, 1, or 2.

48. The compound of claim 1, wherein the compound is of Formula (I-f-2):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH, CR6, or N;Z3and Z4are each independently -N- or -CR9-; each R6is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA; and x is 0, 1, or 2.

49. The compound of claim 1, wherein the compound is of Formula (I-g):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH or N;R6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; andR7is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl.

50. The compound of claim 1, wherein the compound is of Formula (I-g-1):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH or N;Z3and Z4are each independently -N- or -CR9-; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA51. The compound of claim 1 , wherein the compound is of Formula (I-g-2):or a pharmaceutically acceptable salt thereof, wherein:Z2is CH or N;Z3and Z4are each independently -N- or -CR9-; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA52. The compound of claim 1, wherein the compound is of Formula (I-g-3):or a tautomer or pharmaceutically acceptable salt thereof, wherein:Z2is CH or N; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORA53. The compound of claim 1, wherein the compound is of Formula (I-g-4):or a tautomer or pharmaceutically acceptable salt thereof, wherein:Z2is CH or N; andR6is halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or -ORA; and each R8, R9, and R10is independently hydrogen, halogen, optionally substituted alkyl, or -ORAor a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound of any of claims 1-54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

56. 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 1-54, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 55.

57. The method of claim 56, wherein the disease or disorder is associated with C5aRl.

58. The method of claim 56 or 57, 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.

59. The method of any one of claims 56-58, wherein the disease or disorder is a neurological disease or disorder.

60. A method of antagonizing C5aRl, the method comprising contacting C5aRl with a compound of any of claims 1-54, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 55.

61. The method of claim 60, wherein the contacting is in vitro.

62. The method of claim 60, wherein the contacting is in vivo.

63. A kit comprising a compound of any of claims 1-54, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 55, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.