Imidazopyridazine il-17 inhibitor compounds

Abstract

The present application discloses compounds having the following formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, X, n, and m are as defined in the specification, as well as methods of making and using the compounds disclosed herein for treating or ameliorating an IL- 17 mediated syndrome, disorder and / or disease.

Description

[0001] IMIDAZOPYRID AZINE IL-17 INHIBITOR COMPOUNDS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priorities to and the benefits of U.S. Provisional Application No. 63 / 570,450, filed on March 27, 2024, and U.S. Provisional Application No. 63 / 699,846, filed on March 27, 2024, the entire disclosure of each of which, except for any definitions, disclaimers, disavowals, and inconsistencies, is incorporated herein by reference.

[0004] BACKGROUND

[0005] Interleukin- 17 (“IL- 17”), also known as IL-17A and CTLA-8, is produced mainly by CD4+ Thl7 cells, and also by other immune cells such as CD8+ T cells, yb T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A / A) or as a heterodimer (A / F) with IL-17F and signals through binding to dimeric receptor complex IL-17RA and IL-17RC. IL- 17RA is ubiquitously expressed at particularly high levels by haematopoietic cell types, whereas IL-17RC is preferentially expressed by non-haematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A4L-17R signaling induces de novo gene transcription by triggering NF-kB, C / EBP and MAPK pathways through ACT1-TRAF6-TRAF4. It can also stabilize target mRNA transcripts through the ACT1- TRAF2-TRAF5 complex (Amatya N. et al., Trends in Immunology, 2017, 38, 310-322). IL-17A stimulates the release of inflammatory mediators including IL-6, IL-8, G-CSF, TNF-a, and IL- 1 that recruit and activate lymphocytes to the site of injury or inflammation and maintain a proinflammatory state.

[0006] Preclinical and clinical data have demonstrated the significant pathological role of IL-17A in multiple autoimmune and inflammatory diseases.

[0007] Animal and human studies have shown that IL-17A plays a crucial role in pathogenesis of the multiple diseases and / or conditions discussed above. The significance of targeting IL-17A has been demonstrated by the transformational efficacy of injectable IL-17A neutralizing antibodies in patients.

[0008] Despite the advances achieved with injectable IL-17A antagonist antibodies, there is a long-felt need for the development of an oral small molecule IL-17A inhibitor as it may broaden treatment options for many patients without access to biologies. In addition, a safe and efficacious small molecule IL-17A inhibitor may offer significant benefits to patients over the injectable IL- 17A neutralizing antibodies such as convenient dosing regimens and cost savings, which in turn may provide effective long-term disease management.

[0009] However, the development of an oral small molecule treatment has remained challenging and no oral small molecule IL-17A inhibitors have progressed into late-stage clinical trials yet. Accordingly, there is a need for new small molecule IL-17A modulators (e.g., inhibitors). The present disclosure is directed at overcoming such need and other problems encountered in the art.

[0010] SUMMARY

[0011] The present application discloses compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, X, n, and m are as defined herein.

[0012] The present application also discloses pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] The present application also discloses methods for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus. DETAILED DESCRIPTION

[0014] Definitions

[0015] Discussion of documents, acts, materials, devices, articles, or the like which has been included in the present specification is for the purpose of providing context. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any compounds or methods disclosed or claimed.

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

[0017] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0018] In an attempt to help the reader of the application, the description has been separated into various paragraphs or sections or is directed to various embodiments of the application. These separations should not be considered as disconnecting the substance of a paragraph or section or embodiments from the substance of another paragraph or section or embodiments. On the contrary, one skilled in the art will understand that the description has broad application and encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated. The discussion of any embodiment is meant only to be exemplary and is not intended to suggest that the scope of the disclosure, including the claims, is limited to these examples.

[0019] The term “administering” with respect to the methods of the present disclosure, means a method for therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include but not limited to administering a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.

[0020] The term “subject” refers to a patient, which may be an animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human. The term “therapeutically effective amount” or “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes but not limited to preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.

[0021] The term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0022] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound disclosed herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G.S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of the disclosure may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0023] As used herein, “IL- 17” or “IL-17A” refers to interleukin 17A. It is also named IL 17, CTLA8, CTLA-8. Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by a group of immune cells in response to their stimulation. An exemplary amino acid sequence of human IL-17 is represented in GenBank Accession No. NP 002181.1, which can be encoded by a nucleic acid sequence such as that of GenBank Accession No. NM_002190.3.

[0024] The term “modulator” as used herein refers to any agents or molecules that can bind to IL- 17, including small molecule compounds.

[0025] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. As used herein, the term “treat,” “treating,” or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome, or disorder, including those which may not be discernible by the patient. In a further embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease, condition, syndrome, or disorder either physically (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

[0026] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. In an embodiment, “prevent” or “prevention” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

[0027] The term “alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., (Ci-Ci2)alkyl) or 1 to 6 carbon atoms (i.e., (Ci-Ce)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (»-Pr, / ?-propyl, -CH2CH2CH3), isopropyl (z-Pr, z-propyl, -CH(CH3)2), 1 -butyl (zz-bu, n- butyl, -CH2CH2CH2CH3), 2-butyl (.s-bu, .s-butyl, -CH(CH3)CH2CH3), / c / 7-butyl ( / -bu, / -butyl, - CH(CH3)3), 1 -pentyl (zz-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3) CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-

[0028] CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-tnmethylpentyl (- CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)sCH3), decyl (-(CH2)9CH3), undecyl (-(CH2)IOCH3), and dodecyl (-(CH2)IICH3)..

[0029] The term “C(«. / > / ’ (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C(i-4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.

[0030] The term “alkylene” refers to a linear or branched saturated divalent hydrocarbon moiety derived from an alkane having 1 to 12 carbon atoms (i.e., (Ci-Ci2)alkylene), 1 to 6 carbon atoms (i.e., (Ci-Ce)alkylene), 1 to 4 carbon atoms (i.e., (Ci-C4)alkylene), or 1 to 3 carbon atoms (i.e., (Ci- C3)alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), -C(CH3)H-, propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and -CH2CH(CH3)-. In an embodiment, alkylene refers to C(i-4)alkylene. In an embodiment, alkylene refers to C(i-3)alkylene. In another embodiment, alkylene refers to C(i-2)alkylene.

[0031] The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon ring system having, for example, 3 to 12 carbon atoms (i.e., C(3-i2)cycloalkyl), 3 to 10 carbon atoms (i.e., C(3- io)cycloalkyl), 3 to 8 carbon atoms (i.e., C(3-8)cycloalkyl), or 3 to 6 carbon atoms (i.e., C(3- 6)cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be unsubstituted or substituted. Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for example and without limitation, an example of a spiropentyl group for example and without limitation, examples of spirohexyl groups include • forexample and without limitation examples of cycloheptyl groups include otherwise stated specifically in the specification, a spirocycloalkyl group may be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include

[0032] The term “aryl,” unless otherwise stated, refers to a polyunsaturated, aromatic hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Examples of aryl groups include but not limited to phenyl, naphthyl, anthracenyl, 2-phenylfuran, 2-phenylimidazole, and 1 -phenylpyrazole. The term “heterocyclyl” refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members and which contains carbon atoms and at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of N, O, and S. Exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise noted, the heterocyclyl group is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In an embodiment, heterocyclyl refers to 3- to 10-membered heterocyclyl. In another embodiment, heterocyclyl refers to 3- to 8-membered heterocyclyl. In another embodiment, heterocyclyl refers to 3- to 6-membered heterocyclyl.

[0033] The term “heteroaryl” refers to a single-ring or multi-ring aromatic compound that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term “heteroaryl” includes but not limited to single aromatic rings of from 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The term “heteroaryl” also includes but not limited to multi-ring aromatic compounds such as 8- to 10-membered heteroaryl which contains from 4 to 9 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples of heteroaryl includes azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2- onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. Exemplary 8- to 10-membered heteroaryls include but are not limited to quinolinyl, and triazolopyridyl.

[0034] The term “halogen” or “halo” refers to bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1).

[0035] The term “oxo” refers to an oxygen atom connected to its pendant group by a double bond. Oxo can be represented "=O."

[0036] Where the compounds disclosed herein have at least one stereocenter, they may accordingly exist as enantiomers or diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present disclosure.

[0037] “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0038] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A “racemic” mixture is a 1 : 1 mixture of a pair of enantiomers. A “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1:1.

[0039] Where the processes for the preparation of the compounds according to the present disclosure give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, a scalemic mixture, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di- / ?-toluoyl-D-tartaric acid and / or (+)-di- / ?-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral column via HPLC or SFC. In some instances, retainers of compounds may exist which are observable by NMR leading to complex multiplets and peak integration in the NMR spectrum.

[0040] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence- rule procedure, and preceded, when necessary, by the appropriate locants (Pure & Appl. Chem. 45, 1976, 11-30). Certain examples contain chemical structures that are depicted or labelled as an (R*) or (5*). When (R*) or (5*) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established. Thus, a compound designated as (R*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S)', and a compound designated as (5*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (5). For example, W((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((J?*)-l-(5-methyl-l,3,4-oxadiazol-2-yl)ethyl)-2- oxo-5-(trifhioromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-4-methyl- 1 ,2, 5-oxadiazole-3 -carboxamide: , refers to a compound that is either:

[0041] During any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0042] Furthermore, it is intended that within the scope of the present disclosure, any element, in particular when mentioned in relation to a compound of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen (“H”) includes within its scope1H,2H (i.e., deuterium or D), and3H (i.e., tritium or T). In some embodiments, the compounds described herein include a2H (i.e., deuterium) isotope. By way of example, the group denoted -C(i-6)alkyl includes not only -CH3, but also -CD3; not only -CH2CH3, but also -CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and15O and16O and17O and18O. The isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the disclosure may include but not limited to a radioactive isotope selected from the group comprising3H,nC,18F,35S,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,nC and18F.

[0043] Compounds

[0044] The present application discloses compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0045] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl;

[0046] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0047] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0048] R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;

[0049] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0050] R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3 ; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

[0051] The present application discloses compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0052] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl;

[0053] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, oxo, -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0054] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0055] R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;

[0056] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0057] R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3 ; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

[0058] The present application also discloses compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each R1is independently halo or -C(l-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0059] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl;

[0060] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0061] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0062] R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;

[0063] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0064] R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3 ; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

[0065] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has a formula according to Formula (1-1):

[0066] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has a formula according to Formula (1-2):

[0067] (1-2)

[0068] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R1is independently halo. In some embodiments, each R1is -F. In some embodiments, each R1is -Cl. In some embodiments, each R1is -Br. In some embodiments, each R1is -I. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R1is independently -C(i)alkyl that is substituted with one to three Rlagroups. In some embodiments, each R1is independently - palkyl that is substituted with one Rlagroup. In some embodiments, each R1is independently -C( palkyl that is substituted with two Rlagroups. In some embodiments, each R1is independently - palkyl that is substituted with three Rlagroups. In some embodiments, each R1is independently - palkyl that is substituted with one to three fluorine atoms. In some embodiments, each R1is -CF3.

[0069] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each Rlais fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1). In some embodiments, each Rlais fluoro. In some embodiments, each Rlais chloro. In some embodiments, each Rlais bromo. In some embodiments, each Rlais iodo.

[0070] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is absent.

[0071] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is a -C(i-3)alkylene, wherein the -C(i-

[0072] 3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -CH2-. In some embodiments, X is a -C(2)alkylene. In some embodiments, X is a -C(3)alkylene.

[0073] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is -CH2- that is substituted with one group selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -CH2-. In some embodiments, X is -CH2- that is substituted with two groups selected from halo, -OH, -C(i-

[0074] 4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -CH2- that is substituted with one to two halo groups. In some embodiments, X is -CH2- that is substituted with one to two fluorine atoms. In some embodiments, X is -CH2- that is substituted with one to two chlorine atoms. In some embodiments, X is -CH2- that is substituted with one to two bromine atoms. In some embodiments, X is -CH2- that is substituted with one to two iodine atoms. In some embodiments, X is -CH2- that is substituted with one to two -OH groups. In some embodiments, X is -CH2- that is substituted with one to two -C(i-4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(i) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(2) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(3) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(i-4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(i) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(2) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(3) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(4) alkyl groups.

[0075] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10- membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups. In some embodiments, R2is a 4- to 10-membered heterocyclyl. In some embodiments, R2is a 4- membered heterocyclyl. In some embodiments, R2is a 5-membered heterocyclyl. In some embodiments, R2is a 6-membered heterocyclyl. In some embodiments, R2is a 7-membered heterocyclyl. In some embodiments, R2is an 8-membered heterocyclyl. In some embodiments, R2is a 9-membered heterocyclyl. In some embodiments, R2is a 10-membered heterocyclyl. In some embodiments, R2is a -C(6)aryl. In some embodiments, R2is a -C(7)aryl. In some embodiments, R2is a -C(8)aryl. In some embodiments, R2is a -C(9)aryl. In some embodiments, R2is a -C(io)aryl. In some embodiments, R2is a 5- to 10-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 7-membered heteroaryl. In some embodiments, R2is an 8-membered heteroaryl.

[0076] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2is a 5-membered heterocyclyl. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with six R2agroups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2is a 6-membered heterocyclyl. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with six R2agroups.

[0077] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 5- membered heteroaryl. In some embodiments, R2is a 5-membered heteroaryl that is substituted with one to three R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is substituted with one R2agroup. In some embodiments, R2is a 5 -membered heteroaryl that is substituted with two R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is substituted with three R2agroups.

[0078] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 6- membered heteroaryl. In some embodiments, R2is a 6-membered heteroaryl that is substituted with one to three R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is substituted with one R2agroup. In some embodiments, R2is a 6-membered heteroaryl that is substituted with two R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is substituted with three R2agroups.

[0079] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2ais halo. In some embodiments, R2ais a fluorine atom. In some embodiments, R2ais a chlorine atom. In some embodiments, R2ais a bromine atom. In some embodiments, R2ais an iodine atom. In some embodiments, R2ais an oxo group. In some embodiments, R2ais a -C(i-6)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a methyl group. In some embodiments, R2ais a methyl group that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R2ais a methyl group that is substituted with one to three fluorine atoms. In some embodiments, R2ais -CFH2. In some embodiments, R2ais -CF2H. In some embodiments, R2ais -CF3. In some embodiments, R2ais a -C(2)alkyl group that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R2ais an ethyl group. In some embodiments, R2ais a -C(3)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a propyl group. In some embodiments, R2ais an isopropyl group. In some embodiments, R2ais a -C(4)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a tert-butyl group. In some embodiments, R2ais a -C(i-3)alkyl-O-C(i-4)alkyl group. In some embodiments, R2ais a -C(i-3)alkyl-O-C(i-4)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a -CH2-O-C(i-4)alkyl group. In some embodiments, R2ais a -CH2OCH3 group. In some embodiments, R2ais a -C(3-6)cycloalkyl group. In some embodiments, R2ais a -C(3-6)cycloalkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a -C(3-6)cycloalkyl group. In some embodiments, R2ais cyclopropyl group. In some embodiments, R2ais cyclobutyl group.

[0080] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R3ais H, -OH, or -C(i-3)alkyl. In some embodiments, R3ais H, -OH, or -CH2. In some embodiments, R3ais H. In some embodiments, R3ais -OH. In some embodiments, R3ais -C(i-3)alkyl. In some embodiments, R3ais - palkyl. In some embodiments, R3ais -C(2)alkyl. In some embodiments, R3ais -C(3)alkyl. In some embodiments, R3ais -C(i-3)alkyl-O-C(i-3)alkyl. In some embodiments, R3ais -CH2-O-C(i-3)alkyl. In some embodiments, R3ais -CH2OCH3.

[0081] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R3bis H, -OH, or -C(i-3)alkyl. In some embodiments, R3bis H, -OH, or -CH2. In some embodiments, R3bis H. In some embodiments, R3bis -OH. In some embodiments, R3bis -C(i-3)alkyl. In some embodiments, R3bis -C(i)alkyl. In some embodiments, R3bis -C(2)alkyl. In some embodiments, R3bis -C(3)alkyl. In some embodiments, R3bis -C(i-3)alkyl-O-C(i-3)alkyl. In some embodiments, R3bis -CH2-O-C(i-3)alkyl. In some embodiments, R3bis -CH2OCH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-io)alkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-io)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4- io)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4-8)alkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R4is a - palkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R4is a -C(2)alkyl that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R4is a -C(3)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(5)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a - C(6)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(7)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(8)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(9)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(io)alkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0082] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-6)alkyl-O-C(i-6)alkyl, which is unsubstituted or substituted with one to six halo atoms.

[0083] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-6)alkyl-O-C(3-5)cycloalkyl, which is unsubstituted or substituted with one to six halo atoms.

[0084] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-6)alkyl-O-C(3-5)cycloalkyl-C(i- 3)alkyl, which is unsubstituted or substituted with one to six halo atoms.

[0085] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, which is unsubstituted or substituted with one to six halo atoms. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a - C(3)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(5)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(6)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a cyclohexyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a - C(7)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(8)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0086] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5is a -C(3-6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a - C(4)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(5)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a cyclopropyl or a spirocyclopentyl, each of which is unsubstituted or substituted with one to two R5agroups. In some embodiments, each R5ais independently a halo, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three halo atoms. In some embodiments, each R5ais independently a fluorine, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three fluorine atoms. In some embodiments, each R5ais a halo. In some embodiments, each R5ais a fluorine. In some embodiments, each R5ais a chlorine. In some embodiments, each R5ais a bromine. In some embodiments, each R5ais iodine. In some embodiments, each R5ais a -C(i-6)alkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(i-6)alkyl. In some embodiments, each R5ais a - palkyl. In some embodiments, each R5ais a -C(2)alkyl. In some embodiments, each R5ais a -C(3)alkyl. In some embodiments, each R5ais a -C(4)alkyl. In some embodiments, each R5ais a -C(5)alkyl. In some embodiments, each R5ais a -Chalky 1. In some embodiments, each R5ais a -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, - CH3, -CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(3-6)cycloalkyl. In some embodiments, each R5ais a -C(3)cycloalkyl. In some embodiments, each R5ais a -C(4)cycloalkyl. In some embodiments, each R5ais a -C(5)cycloalkyl. In some embodiments, each R5ais a - C(6)cycloalkyl.

[0087] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5is a -O-C(3-6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -O-C(3)cycloalkyl. In some embodiments, R5is a -O-C(4)cycloalkyl. In some embodiments, R5is a -O-C(5)cycloalkyl. In some embodiments, R5is a -O-C(6)cycloalkyl. In some embodiments, each R5ais independently a halo, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three halo atoms. In some embodiments, each R5ais independently a fluorine, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three fluorine atoms. In some embodiments, each R5ais a halo. In some embodiments, each R5ais a fluorine. In some embodiments, each R5ais a chlorine. In some embodiments, each R5ais a bromine. In some embodiments, each R5ais iodine. In some embodiments, each R5ais a -C(i-6)alkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(i-6)alkyl. In some embodiments, each R5ais a - palkyl. In some embodiments, each R5ais a -C(2)alkyl. In some embodiments, each R5ais a -C(3)alkyl. In some embodiments, each R5ais a -C(4)alkyl. In some embodiments, each R5ais a -C(5)alkyl. In some embodiments, each R5ais a -Chalky 1. In some embodiments, each R5ais a -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, - CH3, -CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(3-6)cycloalkyl. In some embodiments, each R5ais a -C(3)cycloalkyl. In some embodiments, each R5ais a -C(4)cycloalkyl. In some embodiments, each R5ais a -C(5)cycloalkyl. In some embodiments, each R5ais a - C(6)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5is a 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5- to 6- membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heteroaryl that is substituted with one R5bgroup. In some embodiments, R5is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O, wherein the 5-membered heteroaryl is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O, wherein the 5-membered heteroaryl is substituted with one R5bgroup. In some embodiments, R5is a 6-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 7-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is an 8-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 9-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups.

[0088] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5bis a halo. In some embodiments, R5bis a fluorine atom. In some embodiments, R5bis a chlorine atom. In some embodiments, R5bis a bromine atom. In some embodiments, R5bis an iodine atom. In some embodiments, R5bis a -C(i- 6)alkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, R5bis a -C(i-6)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a - Ccpalkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R5bis a -Ccpalkyl. In some embodiments, R5bis a -C(2)alkyl that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R5bis a -C(2)alkyl. In some embodiments, R5bis a -C(3)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(3)alkyl. In some embodiments, R5bis a -Ccpalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a - Ccpalkyl. In some embodiments, R5bis a -C(5)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(5)alkyl. In some embodiments, R5bis a - C(6)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(6)alkyl. In some embodiments, R5bis a -O-C(i-6)alkyl. In some embodiments, R5bis a -O-C(i)alkyl. In some embodiments, R5bis a -O-C(2)alkyl. In some embodiments, R5bis a -O-C(3)alkyl. In some embodiments, R5bis a -O-C(4)alkyl. In some embodiments, R5bis a -O-C(5)alkyl. In some embodiments, R5bis a -O-C(6)alkyl. In some embodiments, R5bis-C(i-6)alkyl-O-C(i-6)alkyl. In some embodiments, R5bis-CH2-O-CH2. In some embodiments, R5bis a -C(o-2)alkyl-C(3-6)cycloalkyl. In some embodiments, R5bis a -C(3- 6)cycloalkyl. In some embodiments, R5bis a -C(3)cycloalkyl. In some embodiments, R5bis a - C(4)cycloalkyl. In some embodiments, R5bis a -C(5)cycloalkyl. In some embodiments, R5bis a - C(6)cycloalkyl.

[0089] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0090] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is i.

[0091] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0092] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0093] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 4.

[0094] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0095] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0096] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 3.

[0097] In some embodiments, the compound of Formula I has a formula according to Formula la: or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0098] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl;

[0099] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0100] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0101] R3bis a H or -C(i-3)alkyl;

[0102] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0103] R5is a 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; and n is 0, 1, 2, 3, or 4. In some embodiments, the compound of Formula I has a formula according to Formula la: or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0104] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl;

[0105] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, oxo, -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0106] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0107] R3bis a H or -C(i-3)alkyl;

[0108] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0109] R5is a 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; and n is 0, 1, 2, 3, or 4. In some embodiments, disclosed herein is a compound of Formula la, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula la has a formula according to Formula (la- 1):

[0110] (la-1).

[0111] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has a formula according to Formula (la-2):

[0112] In some embodiments, the compound of Formula I has a formula according to Formula lb: or a pharmaceutically acceptable salt thereof, wherein:

[0113] R1is -C(i-3)alkyl, wherein the -C(i-3)alkyl is unsubstituted or substituted with one to six

[0114] Rlagroups; each Rlais independently fluoro; R2is an oxazolidinyl, imidazolidinyl, morpholinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; wherein the oxazolidinyl, imidazolidinyl, and morpholinyl are unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups; and wherein the pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted or substituted with one to three groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, -O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms;

[0115] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms;

[0116] R5is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3.

[0117] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has a formula according to Formula (Ib-a):

[0118] (Ib-a).

[0119] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has a formula according to Formula (Ib-b): In some embodiments, the compound of Formula I has a formula according to Formula lb: or a pharmaceutically acceptable salt thereof, wherein:

[0120] R1is -C(i-3)alkyl, wherein the -C(i-3)alkyl is unsubstituted or substituted with one to six Rlagroups; each Rlais independently fluoro;

[0121] X is a -CH2- or absent;

[0122] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0123] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms;

[0124] R5is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3.

[0125] In some embodiments, the compound of Formula I has a formula according to Formula lb: (Ib) or a pharmaceutically acceptable salt thereof, wherein:

[0126] R1is -C(i-3)alkyl, wherein the -C(i-3)alkyl is unsubstituted or substituted with one to six Rlagroups; each Rlais independently fluoro;

[0127] X is a -CH2- or absent;

[0128] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, oxo, -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3- 4)cycloalkyl wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0129] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms;

[0130] R5is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3.

[0131] In some embodiments, each R1is independently -Gnalkyl that is unsubstituted or substituted with one to three Rlagroups. In some embodiments, each R1is independently -Qpalkyl that is unsubstituted or substituted with one to three fluorine atoms.

[0132] In some embodiments, each R1is independently -Qpalkyl that is substituted with one to three Rlagroups. In some embodiments, each R1is independently -Qpalkyl that is substituted with one Rlagroup. In some embodiments, each R1is independently -C( palkyl that is substituted with two Rlagroups. In some embodiments, each R1is independently -Qpalkyl that is substituted with three Rlagroups. In some embodiments, each R1is independently -Qpalkyl that is substituted with one to three fluorine atoms.

[0133] In some embodiments, each R1is -CF3. In some embodiments, each R1is independently -C(2)alkyl that is unsubstituted or substituted with one to five Rlagroups. In some embodiments, each R1is independently -C(2)alkyl that is substituted with one to five Rlagroups. In some embodiments, each R1is independently - C(2)alkyl that is substituted with one Rlagroup. In some embodiments, each R1is independently - C(2)alkyl that is substituted with two Rlagroups. In some embodiments, each R1is independently -C(2)alkyl that is substituted with three Rlagroups. In some embodiments, each R1is independently -C(2)alkyl that is substituted with four Rlagroups. In some embodiments, each R1is independently -C(2)alkyl that is substituted with five Rlagroups.

[0134] In some embodiments, each R1is independently -C(3)alkyl that is unsubstituted or substituted with one to six Rlagroups. In some embodiments, each R1is independently -C(3)alkyl that is substituted with one to six Rlagroups. In some embodiments, each R1is independently - C(3)alkyl that is substituted with one Rlagroup. In some embodiments, each R1is independently - C(3)alkyl that is substituted with two Rlagroups. In some embodiments, each R1is independently -C(3)alkyl that is substituted with three Rlagroups. In some embodiments, each R1is independently -C(3)alkyl that is substituted with four Rlagroups. In some embodiments, each R1is independently -C(3)alkyl that is substituted with five Rlagroups. In some embodiments, each R1is independently -C(3)alkyl that is substituted with six Rlagroups.

[0135] In some embodiments, each Rlais fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1). In some embodiments, each Rlais fluoro. In some embodiments, each Rlais chloro. In some embodiments, each Rlais bromo. In some embodiments, each Rlais iodo.

[0136] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0137] In some embodiments, X is -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one -OH, -CH3, or -OCH3 group or with one to two fluorine atoms. In some embodiments, X is -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one -OH or -CH3 group or with one to two fluorine atoms. In some embodiments, X is -C(i-3)alkylene or absent. In some embodiments, X is a -CH2-, -CH2CH2-, CH2CH2-, orabsent. In some embodiments, X is -CH2- or absent.

[0138] In some embodiments, X is -C(i-3)alkylene that is optionally substituted with one to four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(i- 3)alkylene that is optionally substituted with one to four groups selected from halo, -OH, or -C(i-4) alkyl. In some embodiments, X is -C(i-3)alkylene that is optionally substituted with one -OH, - CH3, or -OCH3 group or with one to two fluorine atoms. In some embodiments, X is -C(i-

[0139] 3)alkylene that is optionally substituted with one -OH or -CH3 group or with one to two fluorine atoms.

[0140] In some embodiments, X is -C(i-3)alkylene. In some embodiments, X is -C(i-3)alkylene that is substituted with one group selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(i-3)alkylene that is substituted with two groups selected from halo, -OH, - C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(i-3)alkylene that is substituted with three groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is - C(i-3)alkylene that is substituted with four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-

[0141] 4) alkyl. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four halo groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four fluorine atoms. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four chlorine atoms. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four bromine atoms. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four iodine atoms. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -OH groups.

[0142] In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -C(i-4) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -C(i) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -C(2) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -C(3) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -C(4) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -OC(i-4) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -OC(i) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four - OC(2) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -0C(3) alkyl groups. In some embodiments, X is -C(i-3)alkylene that is substituted with one to four -OC(4) alkyl groups.

[0143] In some embodiments, X is -CH2-. In some embodiments, X is -CH2- that is substituted with one group selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -CH2- that is substituted with two groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -CH2- that is substituted with one to two halo groups. In some embodiments, X is -CH2- that is substituted with one to two fluorine atoms. In some embodiments, X is -CH2- that is substituted with one to two chlorine atoms. In some embodiments, X is -CH2- that is substituted with one to two bromine atoms. In some embodiments, X is -CH2- that is substituted with one to two iodine atoms. In some embodiments, X is -CH2- that is substituted with one to two -OH groups. In some embodiments, X is -CH2- that is substituted with one to two -C(i-4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(i) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(2) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(3) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -C(4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(i-4) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(i) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(2) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(3) alkyl groups. In some embodiments, X is -CH2- that is substituted with one to two -OC(4) alkyl groups.

[0144] In some embodiments, X is -CH2- that is optionally substituted with one -OH, -C(i-4) alkyl, or -OC(i -4) alkyl group or with one to two halo groups. In some embodiments, X is -CH2- that is optionally substituted with one -OH or -C(i-4) alkyl group or with one to two halo groups. In some embodiments, X is -CH2- that is optionally substituted with one -OH, -CH3, or -OCH3 group or with one to two fluorine atoms in some embodiments, X is -CH2- that is optionally substituted with one -OH or -CH3 group or with one to two fluorine atoms.

[0145] In some embodiments, X is -C(2)alkylene. In some embodiments, X is -C(2)alkylene that is substituted with one group selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(2)alkylene that is substituted with two groups selected from halo, -OH, - C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(2)alkylene that is substituted with three groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is - C(2)alkylene that is substituted with four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(2)alkylene that is substituted with one to four halo groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four fluorine atoms. In some embodiments, X is -C(2)alkylene that is substituted with one to four chlorine atoms. In some embodiments, X is -C(2)alkylene that is substituted with one to four bromine atoms. In some embodiments, X is -C(2)alkylene that is substituted with one to four iodine atoms. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OH groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -C(i-4) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -C(i) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -C(2) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -C(3) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -C(4) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OC(i-4) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OC(i) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OC(2) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OC(3) alkyl groups. In some embodiments, X is -C(2)alkylene that is substituted with one to four -OC(4) alkyl groups.

[0146] In some embodiments, X is -C(3)alkylene. In some embodiments, X is -C(3)alkylene that is substituted with one group selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(3)alkylene that is substituted with two groups selected from halo, -OH, - C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(3)alkylene that is substituted with three groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is - C(3)alkylene that is substituted with four groups selected from halo, -OH, -C(i-4) alkyl, or -OC(i-4) alkyl. In some embodiments, X is -C(3)alkylene that is substituted with one to four halo groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four fluorine atoms. In some embodiments, X is -C(3)alkylene that is substituted with one to four chlorine atoms. In some embodiments, X is -C(3)alkylene that is substituted with one to four bromine atoms. In some embodiments, X is -C(3)alkylene that is substituted with one to four iodine atoms. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OH groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -C(i-4) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -C(i) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -C(2) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -C(3) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -C(4) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OC(i-4) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OC(i) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OC(2) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OC(3) alkyl groups. In some embodiments, X is -C(3)alkylene that is substituted with one to four -OC(4) alkyl groups.

[0147] In some embodiments, X is -CH2-. In some embodiments, X is -CH2CH2-. In some embodiments, X is . In some embodiments, X is . In some embodiments, X is , . In some embodiments, X is absent.

[0148] In some embodiments, the compound of Formula I has a formula according to Formula Ib- 1:

[0149] (Ib-1), or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of Formula I has a formula according to Formula Ib-

[0151] 2:

[0152] (Ib-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Ic:

[0153] (Ic), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Ic-

[0154] 1:

[0155] (Ic-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Ic-

[0156] 2:

[0157] (Ic-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Id:

[0158] (Id), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Id-

[0159] 1:

[0160] (Id-1), or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound of Formula I has a formula according to Formula Id-

[0162] 2:

[0163] (Id-2), or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound of Formula I has a formula according to Formula le:

[0165] (le), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula le-

[0166] 1:

[0167] (Ie-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula le-

[0168] 2:

[0169] (Ie-2), or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of Formula I has a formula according to Formula If:

[0171] (If), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula If-

[0172] 1:

[0173] (If-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula If-

[0174] 2: or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound of Formula I has a formula according to Formula Ig:

[0176] (Ig), or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the compound of Formula I has a formula according to Formula Ig-

[0178] 1:

[0179] (Ig-1), or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the compound of Formula I has a formula according to Formula Ig-

[0181] 2:

[0182] (Ig-2), or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the compound of Formula I has a formula according to Formula Ih: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula Ih-

[0184] 1:

[0185] (Ih-1), or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound of Formula I has a formula according to Formula Ih-

[0187] 2:

[0188] (Ih-2), or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the compound of Formula I has a formula according to Formula li:

[0190] (Ii), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula li-

[0191] 1:

[0192] (Ii-l), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula li-

[0193] 2: or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound of Formula I has a formula according to Formula li-

[0195] 2a:

[0196] (Ii-2a), or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, R2is 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups. In some embodiments, R2is 4- to 10-membered heterocyclyl that is unsubstituted or substituted with one to six R2agroups. In some embodiments, R2is -C(6-io)aryl that is unsubstituted or substituted with one to six R2agroups. In some embodiments, R2is 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to six R2agroups.

[0198] In some embodiments, R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O- C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0199] In some embodiments, R2is oxazolidinyl, imidazolidinyl, morpholinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; wherein the oxazolidinyl, imidazolidinyl, and morpholinyl are unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups; and wherein the pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted or substituted with one to three groups selected from fluorine, - C(i-4)alkyl, -CH2-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0200] In some embodiments, R2is 4- to 10-membered heterocyclyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is 4- to 10-membered heterocyclyl that is unsubstituted or substituted with one to three oxo or -C(i-4)alkyl groups. In some embodiments, R2is a 4- to 7-membered heterocyclyl that is unsubstituted or substituted with one to three oxo or -C(i-4)alkyl groups. In some embodiments, R2is 4- to 7-membered heterocyclyl that is unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups. In some embodiments, R2is 4- to 7-membered heterocyclyl that is substituted with one oxo group and / or one or two -C(i-4)alkyl groups.

[0201] In some embodiments, R2is a 4-membered heterocyclyl. In some embodiments, R2is a 4- membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 4-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a

[0202] 4-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 4- membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 4- membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 4- membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 4- membered heterocyclyl that is substituted with six R2agroups. In some embodiments, R2ais oxo or -C(i-4)alkyl. In some embodiments, R2ais oxo or - palkyl. In some embodiments, R2ais oxo or -C(2)alkyl. In some embodiments, R2ais oxo or -C(3)alkyl. In some embodiments, R2ais oxo or - C(4)alkyl.

[0203] In some embodiments, R2is a 5-membered heterocyclyl. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 5-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a

[0204] 5-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 5- membered heterocyclyl that is substituted with six R2agroups. In some embodiments, R2ais oxo or -C(i-4)alkyl. In some embodiments, R2ais oxo or - palkyl. In some embodiments, R2ais oxo or -C(2)alkyl. In some embodiments, R2ais oxo or -C(3)alkyl. In some embodiments, R2ais oxo or - C(4)alkyl.

[0205] In some embodiments, R2is a 6-membered heterocyclyl. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 6-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a

[0206] 6-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 6- membered heterocyclyl that is substituted with six R2agroups. In some embodiments, R2ais oxo or -C(i-4)alkyl. In some embodiments, R2ais oxo or - palkyl. In some embodiments, R2ais oxo or -C(2)alkyl. In some embodiments, R2ais oxo or -C(3)alkyl. In some embodiments, R2ais oxo or - C(4)alkyl.

[0207] In some embodiments, R2is a 7-membered heterocyclyl. In some embodiments, R2is a 7- membered heterocyclyl that is substituted with one to six R2agroups. In some embodiments, R2is a 7-membered heterocyclyl that is substituted with one R2agroup. In some embodiments, R2is a

[0208] 7-membered heterocyclyl that is substituted with two R2agroups. In some embodiments, R2is a 7- membered heterocyclyl that is substituted with three R2agroups. In some embodiments, R2is a 7- membered heterocyclyl that is substituted with four R2agroups. In some embodiments, R2is a 7- membered heterocyclyl that is substituted with five R2agroups. In some embodiments, R2is a 7- membered heterocyclyl that is substituted with six R2agroups. In some embodiments, R2ais oxo or -C(i-4)alkyl. In some embodiments, R2ais oxo or - palkyl. In some embodiments, R2ais oxo or -C(2)alkyl. In some embodiments, R2ais oxo or -C(3)alkyl. In some embodiments, R2ais oxo or - C(4)alkyl.

[0209] In some embodiments, R2is oxazolidinyl, imidazolidinyl, or morpholinyl, each of which is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is oxazolidinyl, imidazolidinyl, or morpholinyl, each of which is unsubstituted or substituted with one to three oxo or -C(i-4)alkyl groups. In some embodiments, R2is oxazolidinyl, imidazolidinyl, or morpholinyl, each of which is unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups. In some embodiments, R2is oxazolidinyl, imidazolidinyl, or morpholinyl, each of which is substituted with one oxo group and / or one or two -C(i-4)alkyl groups.

[0210] In some embodiments, R2is oxazolidinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is imidazolidinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is morpholinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2ais oxo or -C(i-4)alkyl. In some embodiments, R2ais oxo or - palkyl. In some embodiments, R2ais oxo or -C(2)alkyl. In some embodiments, R2ais oxo or -C(3)alkyl. In some embodiments, R2ais oxo or -C(4)alkyl.

[0211] In some embodiments, R2is each of which is unsubstituted or substituted with one or two groups selected from halo, -C(i- 6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i- 3)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0212] In some embodiments, R2is each of which is unsubstituted or substituted with one or two -C(i-4)alkyl groups.

[0213] In some embodiments, R2is each of which is unsubstituted or substituted with one or two -CH3 groups.

[0214] In some embodiments, R2is In some embodiments,

[0215] In some embodiments,

[0216] In some embodiments,

[0217] In some embodiments, R2is a -C(6-io)aryl that is unsubstituted or substituted with one to six R2agroups. In some embodiments, R2is a -C(6)aryl that is unsubstituted or substituted with one to five R2agroups. In some embodiments, R2is a -C(6)aryl. In some embodiments, R2is a -C(6)aryl that is substituted with one to five R2agroups. In some embodiments, R2is a -C(6)aryl that is substituted with one R2agroup. In some embodiments, R2is a -C(6)aryl that is substituted with two R2agroups, n some embodiments, R2is a -C(6)aryl that is substituted with three R2agroups, n some embodiments, R2is a -C(6)aryl that is substituted with four R2agroups. In some embodiments, R2is a -C(6)aryl that is substituted with five R2agroups.

[0218] In some embodiments, R2is 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, - C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-3)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is 5- to 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is 5- to 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0219] In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0220] In some embodiments, R2is 8- to 10-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is 8- to 10-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from halo, CN, oxo, -C(i- 6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O- C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl. In some embodiments, R2is 8- to 9-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, - C(i-3)alkyl-O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i- 4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl. In some embodiments, R2is 9- to 10-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl.

[0221] In some embodiments, R2is 8- to 10-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is 8- to 10-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, - C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-3)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is 8- to 9-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is 9- to 10-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0222] In some embodiments, R2is azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2- onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, or tetrahydrothienyl, and N-oxides. In some embodiments, the 8- to 10-membered heteroaryl is triazolyl or pyridyl.

[0223] In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from halo, CN, oxo, -C(i-6)alkyl, -O- C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3- 6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=0)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl. In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and - C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0224] In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5-membered heteroaryl that is substituted with one to three R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is substituted with one R2agroup. In some embodiments, R2is a 5-membered heteroaryl that is substituted with two R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is substituted with three R2agroups. In some embodiments, R2ais fluorine. In some embodiments, R2ais -C(i-4)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais -C(i-4)alkyl. In some embodiments, R2ais -C(i)alkyl. In some embodiments, R2ais -C(2)alkyl. In some embodiments, R2ais -C(3)alkyl. In some embodiments, R2ais -C(4)alkyl. In some embodiments, R2ais -C(i-4)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais - palkyl that is substituted with one to three fluorine atoms. In some embodiments, R2ais -C(2)alkyl that is substituted with one to five fluorine atoms. In some embodiments, R2ais -C(3)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais -C(4)alkyl that is substituted with one to six fluorine atoms.

[0225] In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl group, -C(i- 3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and - C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is a 5-membered heteroaryl that is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the - C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0226] In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is pyrazolyl, imidazolyl, triazolyl, or tetrazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0227] In some embodiments, R2is oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0228] In some embodiments, R2is thiazolyl, isothiazolyl, or thiadiazolyl, each of which is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is thiazolyl, isothiazolyl, or thiadiazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is thiazolyl, isothiazolyl, or thiadiazolyl, each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0229] In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6-membered heteroaryl that is substituted with one to three R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is substituted with one R2agroup. In some embodiments, R2is a 6-membered heteroaryl that is substituted with two R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is substituted with three R2agroups. In some embodiments, R2ais fluorine. In some embodiments, R2ais -C(i-4)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais -C(i-4)alkyl. In some embodiments, R2ais -C(i)alkyl. In some embodiments, R2ais -C(2)alkyl. In some embodiments, R2ais -C(3)alkyl. In some embodiments, R2ais -C(4)alkyl. In some embodiments, R2ais -C(i-4)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais -C(i)alkyl that is substituted with one to three fluorine atoms. In some embodiments, R2ais -C(2)alkyl that is substituted with one to five fluorine atoms. In some embodiments, R2ais -C(3)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais -C(4)alkyl that is substituted with one to six fluorine atoms.

[0230] In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from halo, CN, oxo, -C(i-6)alkyl, -O- C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3- 6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl. In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and - C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0231] In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl group, - C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is a 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the - C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0232] In some embodiments, R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3- 4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0233] In some embodiments, R2is pyrazolyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is imidazolyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is triazolyl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is tetrazolyl that is unsubstituted or substituted with one R2agroup. In some embodiments, R2is oxazolyl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is isoxazolyl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is oxadiazolyl that is unsubstituted or substituted with one R2agroup. In some embodiments, R2is thiazolyl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is isothiazolyl that is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is thiadiazolyl that is unsubstituted or substituted with one R2agroup. In some embodiments, R2is pyridinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is pyridazinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is pyrimidinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2is pyrazinyl that is unsubstituted or substituted with one to three R2agroups. In some embodiments, R2ais fluorine. In some embodiments, R2ais -C(i-4)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais -C(i-4)alkyl. In some embodiments, R2ais - Ccpalkyl. In some embodiments, R2ais -C(2)alkyl. In some embodiments, R2ais -C(3)alkyl. In some embodiments, R2ais -C(4)alkyl. In some embodiments, R2ais -C(i-4)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais -Ccpalkyl that is substituted with one to three fluorine atoms. In some embodiments, R2ais -C(2)alkyl that is substituted with one to five fluorine atoms. In some embodiments, R2ais -C(3)alkyl that is substituted with one to six fluorine atoms. In some embodiments, R2ais -C(4)alkyl that is substituted with one to six fluorine atoms.

[0234] In some embodiments, R2is

[0235] each of which is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is each of which is unsubstituted or substituted with one to two R2agroups.

[0236] In some embodiments, R2is each of which is unsubstituted or substituted with one to two R2agroups.

[0237] In some embodiments, R2is each of which is unsubstituted or substituted with one to two R2agroups. In some embodiments, R2is each of which is unsubstituted or substituted with one to two R2agroups.

[0238] In some embodiments, R2is

[0239] each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl- O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0240] In some embodiments, R2is t H nf ,'N orN-N , each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl- O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0241] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl- O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0242] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl- O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0243] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl group, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl- O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0244] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0245] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0246] In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is each of which is unsubstituted or substituted with one to two groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2is

[0247]

[0248] In some embodiments, R2is

[0249] In some embodiments, R2is

[0250] In some embodiments, R2ais independently a fluorine, oxo, -C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais independently a fluorine, oxo, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the - C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais independently a fluorine, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2OCH3, or cyclopropyl, wherein the methyl is unsubstituted or substituted with one to three fluorine atoms.

[0251] In some embodiments, R2ais halo. In some embodiments, R2ais a fluorine atom. In some embodiments, R2ais a chlorine atom. In some embodiments, R2ais a bromine atom. In some embodiments, R2ais an iodine atom. In some embodiments, R2ais an oxo group. In some embodiments, R2ais a -C(i-4)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a methyl group. In some embodiments, R2ais a methyl group that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R2ais a methyl group that is substituted with one to three fluorine atoms. In some embodiments, R2ais - CFH2. In some embodiments, R2ais -CF2H. In some embodiments, R2ais -CF3. In some embodiments, R2ais a -C(2)alkyl group that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R2ais an ethyl group. In some embodiments, R2ais a -C(3)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a propyl group. In some embodiments, R2ais an isopropyl group. In some embodiments, R2ais a - C(4)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a tert-butyl group. In some embodiments, R2ais a -C(i-3)alkyl-O-C(i-4)alkyl group. In some embodiments, R2ais a -C(i-3)alkyl-O-C(i-4)alkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a -CH2-O-C(i-4)alkyl group. In some embodiments, R2ais a -CH2OCH3 group. In some embodiments, R2ais a -C(3-6)cycloalkyl group. In some embodiments, R2ais a -C(3-6)cycloalkyl group that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R2ais a -C(3-4)cycloalkyl group. In some embodiments, R2ais cyclopropyl group. In some embodiments, R2ais cyclobutyl group.

[0252] In some embodiments, the compound of Formula I has a formula according to Formula Ij:

[0253] (Ij), or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the compound of Formula I has a formula according to Formula Ij- 1:

[0255] (Ij-1), or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the compound of Formula I has a formula according to Formula Ij- 2:

[0257] (Ij-2), or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the compound of Formula I has a formula according to Formula Ik:

[0259] (Ik), or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the compound of Formula I has a formula according to Formula Ik-

[0261] (Ik-1), or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the compound of Formula I has a formula according to Formula Ik-

[0263] 2:

[0264] (Ik-2), or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, R3ais H, -OH, or -C(i-3)alkyl. In some embodiments, R3ais H, -OH, or -CH2. In some embodiments, R3ais H. In some embodiments, R3ais -OH. In some embodiments, R3ais -C(i-3)alkyl. In some embodiments, R3ais - palkyl. In some embodiments, R3ais -C(2)alkyl. In some embodiments, R3ais -C(3)alkyl. In some embodiments, R3ais -C(i-3)alkyl-O-C(i-3)alkyl. In some embodiments, R3ais -CH2-O-C(i-3)alkyl. In some embodiments, R3ais -CH2OCH3.

[0266] In some embodiments, R3bis H, -OH, or -C(i-3)alkyl. In some embodiments, R3bis H, -OH, or -CH2. In some embodiments, R3bis H. In some embodiments, R3bis -OH. In some embodiments, R3bis -C(i-3)alkyl. In some embodiments, R3bis - palkyl. In some embodiments, R3bis -C(2)alkyl. In some embodiments, R3bis -C(3)alkyl. In some embodiments, R3bis -C(i-3)alkyl-O-C(i-3)alkyl. In some embodiments, R3bis -CH2-O-C(i-3)alkyl. In some embodiments, R3bis -CH2OCH3.

[0267] In some embodiments, R3ais H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl, and R3bis H. In some embodiments, R3ais H, -OH, or -CH3, and R3bis H. In some embodiments, R3ais H, and R3bis H. In some embodiments, R3ais -CH2, and R3bis H. In some embodiments, R3ais -OH, and R3bis H.

[0268] In some embodiments, the compound of Formula I has a formula according to Formula II: or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the compound of Formula I has a formula according to Formula II-

[0270] 1: or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound of Formula I has a formula according to Formula II-

[0272] 2:

[0273] (H-2), or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3- 5)cycloalkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3- 5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six fluorine atoms.

[0275] In some embodiments, R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3- 5)cycloalkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(cyclopropyl)i-2each of which is unsubstituted or substituted with one to six fluorine atoms.

[0276] In some embodiments, R4is a -C(i-io)alkyl or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i- io)alkyl or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4-io)alkyl or cyclohexyl, each of which is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(4-io)alkyl or cyclohexyl, each of which is unsubstituted or substituted with one to six fluorine atoms.

[0277] In some embodiments, R4is a -C(4-8)alkyl or cyclohexyl, each of which is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(4-8)alkyl or cyclohexyl, each of which is unsubstituted or substituted with one to six fluorine atoms.

[0278] In some embodiments, R4is -C(4-8)alkyl substituted with one to three fluorine atoms or ,

[0279] In some embodiments, R4is a -C(i-io)alkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-io)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4-io)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(4-8)alkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R4is a -

[0280] C(i)alkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -Coalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -

[0281] C(9)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(io)alkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0282] In some embodiments, R4is VX-^CF3 In some embodiments, R4is a -C(i-6)alkyl-O-C(i-6)alkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-6)alkyl-O-C(i-6)alkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0283] In some embodiments, R4is a -C(i-6)alkyl-O-C(3-5)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-6)alkyl-O-C(3-5)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0284] In some embodiments, R4is a -C(i-6)alkyl-O-C(3-5)cycloalkyl-C(i-3)alkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0285] In some embodiments, R4is a -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(3)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(3)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a - C(4)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(4)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(5)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(5)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(6)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a cyclohexyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a cyclohexyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(7)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(7)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(8)cycloalkyl that is unsubstituted or substituted with one to six fluorine atoms.

[0286] In some embodiments, In some embodiments, R4is a -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2 that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R4is a -C(i-3)alkyl-(C(3- 5)cycloalkyl)i-2 that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R4is a -C(i-3)alkyl-(cyclopropyl)i-2 that is unsubstituted or substituted with one to six fluorine atoms.

[0287] In some embodiments,

[0288] In some embodiments, the compound of Formula I has a formula according to Formula Im: or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compound of Formula I has a formula according to Formula

[0290] Im-1: or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the compound of Formula I has a formula according to Formula

[0292] Im-2:

[0293]

[0294] (Im- 2), or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, R5is a -C(3-6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(4)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a -C(5)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a - C(6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups. In some embodiments, R5is a cyclopropyl or a spirocyclopentyl, each of which is unsubstituted or substituted with one to two R5agroups.

[0296] In some embodiments, each R5ais independently a halo, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three halo atoms. In some embodiments, each R5ais independently a fluorine, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three fluorine atoms. In some embodiments, each R5ais a halo. In some embodiments, each R5ais a fluorine. In some embodiments, each R5ais a chlorine. In some embodiments, each R5ais a bromine. In some embodiments, each R5ais iodine. In some embodiments, each R5ais a -C(i-6)alkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, - CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(i-6)alkyl. In some embodiments, each R5ais a - palkyl. In some embodiments, each R5ais a -C(2)alkyl. In some embodiments, each R5ais a -C(3)alkyl. In some embodiments, each R5ais a -C(4)alkyl. In some embodiments, each R5ais a -C(5)alkyl. In some embodiments, each R5ais a -C(6)alkyl. In some embodiments, each R5ais a -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. In some embodiments, each R5ais a -C(3- 6)cycloalkyl. In some embodiments, each R5ais a -C(3)cycloalkyl. In some embodiments, each R5a is a -C(4)cycloalkyl. In some embodiments, each R5ais a -C(5)cycloalkyl. In some embodiments, each R5ais a -C(6)cycloalkyl.

[0297] In some embodiments, R5is:

[0298] In some embodiments, R5is a -O-C(3-6)cycloalkyl. In some embodiments, R5is a -O- C(3)cycloalkyl. In some embodiments, R5is a -O-C(4)cycloalkyl. In some embodiments, R5is a - O-C(5)cycloalkyl. In some embodiments, R5is a -O-C(6)cycloalkyl.

[0299] In some embodiments,

[0300] In some embodiments, R5is a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to two R5bgroups.

[0301] In some embodiments, R5is a 5- to 10-membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 6- membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 7-membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is an 8-membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 9-membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 10- membered heterocyclyl that is unsubstituted or substituted with one to two R5bgroups.

[0302] In some embodiments, R5is a 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5- to 6-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5- membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heteroaryl that is substituted with one R5bgroup. In some embodiments, R5is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O, wherein the 5-membered heteroaryl is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from N and O, wherein the 5 -membered heteroaryl is substituted with one R5bgroup. In some embodiments, R5is a 6-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 7-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is an 8- membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 9-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups. In some embodiments, R5is a 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups.

[0303] In some embodiments, R5is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which is substituted with one R5bgroup.

[0304] In some embodiments, R5is pyrazolyl or oxadiazolyl, each of which is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is pyrazolyl or oxadiazolyl, each of which is substituted with one R5bgroup.

[0305] In some embodiments, R5is pyrrolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is pyrrolyl that is substituted with one R5bgroup.

[0306] In some embodiments, R5is pyrazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is pyrazolyl that is substituted with one R5bgroup.

[0307] In some embodiments, R5is imidazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is imidazolyl that is substituted with one R5bgroup.

[0308] In some embodiments, R5is triazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is triazolyl that is substituted with one R5bgroup.

[0309] In some embodiments, R5is oxazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is oxazolyl that is substituted with one R5bgroup.

[0310] In some embodiments, R5is isoxazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is isoxazolyl that is substituted with one R5bgroup.

[0311] In some embodiments, R5is oxadiazolyl that is unsubstituted or substituted with one R5bgroup. In some embodiments, R5is oxadiazolyl that is substituted with one R5bgroup. In some embodiments,

[0312] In some embodiments, R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl- O-C(i-6)alkyl, or -C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O- C(i-6)alkyl, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3;

[0313] In some embodiments, R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl- O-C(i-6)alkyl, or -C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0314] In some embodiments, R5bis independently a -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis independently a -C(i-3)alkyl, -O-C(i-3)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-3)alkyl is unsubstituted or substituted with one to three fluorine atoms.

[0315] In some embodiments, R5bis a halo. In some embodiments, R5bis a fluorine atom. In some embodiments, R5bis a chlorine atom. In some embodiments, R5bis a bromine atom. In some embodiments, R5bis an iodine atom. In some embodiments, R5bis a -C(i-6)alkyl that is unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, - CH2F, -CHF2, and -CF3. In some embodiments, R5bis a -C(i-6)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -Qpalkyl that is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, R5bis a - Ccpalkyl. In some embodiments, R5bis a -C(2)alkyl that is unsubstituted or substituted with one to five fluorine atoms. In some embodiments, R5bis a -C(2)alkyl. In some embodiments, R5bis a - C(3)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(3)alkyl. In some embodiments, R5bis a -C(4)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(4)alkyl. In some embodiments, R5bis a -C(5)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(5)alkyl. In some embodiments, R5bis a -C(6)alkyl that is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, R5bis a -C(6)alkyl. In some embodiments, R5bis a -O-C(i-6)alkyl. In some embodiments, R5bis a -O-C(i)alkyl. In some embodiments, R5bis a -O-C(2)alkyl. In some embodiments, R5bis a -O-C(3)alkyl. In some embodiments, R5bis a -O-C(4)alkyl. In some embodiments, R5bis a -O-C(5)alkyl. In some embodiments, R5bis a -O-C(6)alkyl. In some embodiments, R5bis-C(i-6)alkyl-O-C(i-6)alkyl. In some embodiments, R5bis-CH2-O-CH2. In some embodiments, R5bis a -C(o-2)alkyl-C(3-6)cycloalkyl. In some embodiments, R5bis a -C(3-6)cycloalkyl. In some embodiments, R5bis a -C(3)cycloalkyl. In some embodiments, R5bis a -C(4)cycloalkyl. In some embodiments, R5bis a -C(5)cycloalkyl. In some embodiments, R5bis a -C(6)cycloalkyl.

[0316] In some embodiments, R5bis independently -CH3, -CHF2, -CF2CH3, -OCH3, or cyclopropyl.

[0317] In some embodiments,

[0318] In some embodiments,

[0319] In some embodiments,

[0320] In some embodiments,

[0321] In some embodiments,

[0322] In some embodiments,

[0323] In some embodiments, the compound of Formula I has a formula according to Formula In:

[0324]

[0325] (In), or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of Formula I has a formula according to Formula In-

[0327] 1:

[0328] (In-1), or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula I has a formula according to Formula In- la:

[0330] (In- la), or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound of Formula I has a formula according to Formula In-

[0332] 2:

[0333] (In-2), or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the compound of Formula I has a formula according to Formula In- 2a:

[0335] (In-2a), or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0337] In some embodiments, the compound of Formula I has a formula according to Formula Io:

[0338] (Io), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I has a formula according to Formula lo-

[0339] 1:

[0340]

[0341] (lo-l), or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the compound of Formula I has a formula according to Formula lo-

[0343] 2:

[0344] (Io-2), or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, disclosed herein is a compound of Formula In-la or In-2a, or a pharmaceutically acceptable salt thereof, wherein:

[0346] X is a -CH2- or absent;

[0347] R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7- membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i- 4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms;

[0348] R4is a -C(4-8)alkyl or cyclohexyl, each of which is unsubstituted or substituted with one to six fluorine atoms; and

[0349] R5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms. In some embodiments, disclosed herein is a compound of Formula In-la or In-2a, or a pharmaceutically acceptable salt thereof, wherein:

[0350] X is a -CH2- or absent;

[0351] R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7- membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i- 4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms;

[0352] R5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0353] In some embodiments, disclosed herein is a compound of Formula lo-l or Io-2, or a pharmaceutically acceptable salt thereof, wherein:

[0354] X is a -CH2- or absent;

[0355] R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7- membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i- 4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms; and

[0356] R5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0357] In some embodiments, disclosed herein is a compound of Formula lo-l or Io-2, or a pharmaceutically acceptable salt thereof, wherein: absent;

[0358] R2is an oxazolidinyl, imidazolidinyl, morpholinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; wherein the oxazolidinyl, imidazolidinyl, and morpholinyl are unsubstituted or substituted with one oxo group and / or one or two -C(i-4)alkyl groups; and wherein the pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted or substituted with one to three groups selected from fluorine, -C(i- 4)alkyl, -CH2-O-C(i-4)alkyl, -O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms; and

[0359] R5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0360] In some embodiments, the present disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, that is a deuterated isotope comprising one to thirty deuterium atoms. In some embodiments, the present disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, that is a deuterated isotope comprising one to fifteen deuterium atoms. In some embodiments, the present disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, that is a deuterated isotope comprising one to seven deuterium atoms. In some embodiments, the present disclosure provides a compound having a formula as shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0361] Table 1.

[0362]

[0363] In some embodiments, the present disclosure provides a compound having a formula as shown in Table 2, or a pharmaceutically acceptable salt thereof. Table 2.

[0364]

[0365] In some embodiments, the present disclosure provides a compound having a formula as shown in Table 3, or a pharmaceutically acceptable salt thereof.

[0366] Table 3.

[0367]

[0368] In some embodiments, disclosed herein is a compound having a formula selected from the

[0369] or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound having a formula selected from the group consisting of:

[0370]

[0371] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0372] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound having the following formula:

[0373] or a pharmaceutically acceptable salt thereof.

[0374] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, disclosed herein is a compound having the following formula:

[0378] or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0380] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments, disclosed herein is a compound having the following formula: or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, disclosed herein is a pharmaceutical composition, comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule). In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0385] In some embodiments, disclosed herein is a process for making a pharmaceutical composition comprising mixing a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0386] Therapeutic Use

[0387] Preclinical and clinical data have demonstrated the significant pathological role of IL-17A in multiple autoimmune and inflammatory diseases.

[0388] For psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesional skin and blood of patients with psoriasis and correlate with disease severity. IL-17A acts directly in synergy with other cytokines (such as TNFa, IFNy or IL- 22) on keratinocytes triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriatic plaques. The blockade of IL-17A by means of antibodies to IL-17A or IL-23 results in complete reversal of the molecular and clinical disease features in the majority of psoriasis patients, manifesting the significant role of IL-17A and IL-17-producing T-cells in the immunopathogenesis of psoriasis. (Hawkes et al., Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies. J Allergy Clin Immunol. 2017, 140(3): 645-653). The development and approval of IL- 17 monoclonal antibodies such as secukinumab, ixekizumab, and brodalumab and their transformational efficacy for psoriasis have demonstrated IL-17A as a valid target for psoriasis treatments. (Blauvelt A. and Chiricozzi A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis. Clin Rev Allergy Immunol. 2018, 55(3):379-390).

[0389] For psoriatic arthritis (PsA): IL-17A is mechanistically relevant to PsA through NFKB activation that triggers transcription of several PsA related genes including the receptor activator of nuclear factor KB ligand (RANKL). RANKL triggers the differentiation of osteoclast precursor cells into activated osteoclasts, resulting in bone resorption and subsequently joint deformity in PsA (Adamopoulos I. and Mellins E. Nature reviews Rheumatology 2015; 11:189-94). PsA joint is enriched for IL-17+CD8+ T cells, and the levels of this T cell subset are correlated with disease activity (Menon B. et al., Arthritis & Rheumatology 2014; 66: 1272-81). Synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression and secrete increased IL-6, CXCL8 and MMP3 ex vivo compared to osteoarthritis patients. Both secukinumab and ixekizumab are FDA approval drugs for PsA. In matching-adjusted indirect comparison analysis, secukinumab was associated with higher ACR 20 / 50 / 70 response rates in patients with active PsA than anti- TNFoc antibodies (Mease P. et al., Eur. J. Rheumatol. 2019 Jul 1 ;6(3): 113-121 ; Strand V. et al., J. Comp. Eff. Res. 2019, 8(7):497-510; Nash P. et al., Rheumatol. Ther. 2018, 5(1):99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in achieving simultaneous improvement of joint and skin disease (ACR50 and PASH 00) in patients with PsA and inadequate response to conventional synthetic disease-modifying antirheumatic drug (Mease, P. et al. Ann Rheum Diss 2020; 79:123-131). By hitting the same target, IL-17A small molecule inhibitor compounds may exert similar or better efficacy than biologies considering that small molecules generally have better tissue penetration.

[0390] For rheumatoid arthritis (RA): IL-17A has been recognized as critical to the progression of rheumatoid arthritis. “The recognition of IL- 17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date through which T cells can capture and localize macrophage effector functions in rheumatoid arthritis” Stamp, L. etal., Immunol. Cell Biol. 2004, 82(1): 1-9. Moreover, in rheumatoid arthritis IL-17A acts locally on synoviocytes and osteoblasts contributing to synovitis and joint destruction. Robert and Miossec have proposed the use of synovial biopsies and / or biomarkers to precisely identify patients that would respond to IL-17A inhibition. Their work concludes that IL- 17 inhibitors should now be considered in the development of precision medicine in RA. (Robert M. and Miossec P., Front. Med., 2019, 5:364).

[0391] For Ankylosing Spondylitis (AS): Various studies have reported elevated IL-17A and Thl7 and other cells producing IL-17 in AS blood samples (Wendling D. etal., Joint Bone Spine. 2007;74:304-305; Shen H. et al., Arthritis Rheum. 2009;60(6): 1647-56; Zhang L. et al., PLoS One. 2012;7(4):e31000; Jansen D. etal., Rheumatology (Oxford). 2015 Apr; 54(4) : 728-735). In situ analysis of AS spine has revealed increased IL-17A-producing cells in bone of facet (zygapophyseal) joints (Appel H. et al., Arthritis Res. Ther. 2011 ; 13(3):R95). Two advanced IL- 17A neutralizing antibodies, secukinumab, approved by FDA for AS, and ixekizumab, have demonstrated efficacy over placebo even in anti-TNF inadequate responders. In contrast, anti-IL- 23 p40 and pl 9 biologies failed to demonstrate beneficial effect (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. et al., Ann. Rheum. Dis. 2018,77(9):1295-1302), indicating the differential underling mechanism along IL-23 / IL-17 pathway in AS and providing strong evidence to support continuing developing IL-17A inhibitors.

[0392] For hidradenitis suppurativa (HS): Increased IL-17 and IL-17-producing T helper cells in the skin lesions of HS patients were reported and molecular proteomics and gene expression data indicate that the IL-23 / Thl7 pathway is upregulated in HS lesions (Schlapbach C. et al., J. Am. Acad. Dermatol. 2011;65(4):790; Kelly G. et al., British J. Dermatol. 2015 Dec; 173(6): 1431-9; Moran B. et al., J. Invest. Dermatol. 2017;137(l l):2389; Thomi R. et al., JAMA Dermatol. 2018; 154(5): 592). Seven of nine (78%) patients with moderate-to-severe HS achieved HiSCR in an open-label pilot- trial with Secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep;181(3):609-611), and more clinical trials with anti-IL-17 mAbs in HS are on-going.

[0393] For bullous pemphigoid (BP): IL- 17 is elevated in the blister fluid and perilesional skin of BP patients. (Le Jan S. et al., J. Invest. Dermatol. 2014;134 (12):2908-2917.; Chakievska L. J Autoimmun. 2019, 96: 104-112). Exome sequencing of BP patients revealed mutations in twelve IL-17-related genes in one third of patients, providing the genetic link between IL- 17 pathway and BP (Chakievska L. J Autoimmun. 2019, 96:104-112). In experimental murine BP, IL-17A- / - mice are protected, and anti-IL-17A treatment significantly reduced skin lesions in wild type (Chakievska L. J Autoimmun. 2019, 96:104-112). Ixekizumab Phase 2 of treatment naive and refractory BP patients is on-going (NCT03099538).

[0394] For atopic dermatitis (AD): IL-17 was found to be elevated in peripheral blood and lesions in AD patients and Thl7 cells infiltrated more markedly in acute than chronic lesions, suggesting its role in acute phase of AD (Koga C. et al., J. Invest. Dermatol. 2008, 128, 2625-2630). Molecular profile analysis from ustekinumab Phase II suggest likely contribution of IL- 23 / Thl7 / IL-17 pathway in AD (Khattri S. et al., Exp. Dermatol. 2017 Jan;26(l):28-35).

[0395] For vitiligo: Many studies in vitiligo patients have demonstrated an increased frequency of Thl7 cells and higher levels of IL- 17 in both circulation and lesions that positively correlates with disease duration, extent, and activity (Singh R. etal., Autoimmun. Rev 2016, Apr; 15(4): 397- 404). Mouse studies demonstrated that depigmentation correlates with greater IL- 17 expression / secretion, which modulates vitiligo development (Eby J. et al., Pigment Cell & Melanoma Res. 2014, Nov;27(6): 1075-85).

[0396] For multiple sclerosis (MS): IL- 17 expression is increased in PBMCs, cerebrospinal fluid (CSF) as well as in brain lesions and cells from MS patients (Lock, C. et al., Nat. Med. 2002, 8: 500-508; Matusevicius, D. et al., Mult. Scler. 1999, 5: 101-104; Tzartos, J. et al., Am. J. Pathol. 2008, 172: 146-155). IL-17-producing T cells are enriched in active MS lesions (Tzartos, J. etal., Am. J. Pathol. 2008, 172: 146-155; Willing A. etal., J. Immunol. 2018, 200(3): 974-982). IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and correlated with the CSF / serum albumin quotient, a measure of blood-brain barrier (BBB) dysfunction, together with in vitro data that IL-17A in combination with IL-6 reduced the expression of tight junction - associated genes and disrupted monolayer integrity in a BBB cell line, highlighting the potential importance of targeting IL-17A in preserving BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol. 2019, 332:147-154). Secukinumab yielded promising first results in a proof-of- concept study in MS patients (Havrdova, E. et al., J. Neurol. 2016, 263: 1287-1295).

[0397] For Asthma: IL-17 expression is increased in the lung, sputum, bronchoalveolar lavage fluid, and sera in patients with asthma, and the severity of airway hyperresponsiveness is positively correlated with IL- 17 expression levels. (Chakir J. et al., J. Allergy Clin. Immunol. 2003,111(6): 1293-8). IL-17 was reported to be increased in asthmatic airways and induce human bronchial fibroblasts to produce cytokines (Molet S. et al., J. Allergy Clin. Immunol. 2001, 108(3):430-8). Anti-IL-17 antibody modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in chronic mouse asthma models (Camargo LdN. et al., Front Immunol. 2018; 8: 1835; dos Santos T. etal., Front. Physiol. 2018, 9: 1183).

[0398] For Chronic Obstructive Pulmonary Disease (COPD): An increase in Thl7 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects, and inverse correlations were found between Thl7 cells with lung function (Vargas-Rojas M. et al., Respir. Med. 2011 Nov; 105(11): 1648-54). In three recent human COPD studies, gene expression profile in bronchial epithelia showed that higher IL- 17 signature expression is associated with a lack of response to inhaled corticosteroid, suggesting that there is a COPD subgroup that may benefit from IL-17 inhibitor therapy (Christenson S. et al., J. Clin. Invest. 2019;129(l): 169-181).

[0399] For Uveitis: IL- 17 promotes the release of inflammatory mediators from retinal pigment epithelium cell line, disrupting the retinal pigment epithelium barrier function (Chen Y. et al., PLoS One. 2011 ;6:el 8139). IL-17 levels were elevated in the serum or aqueous humor of uveitis patients (El-Asrar A. etal., Clin. Immunol. 2011; 139(2): 177-84; Jawad S. et al., Ocul. Immunol. Inflamm. 2013; 21(6):434-9; Kuiper J. etal., Am. J. Ophthalmol. 2011 ; 152(2): 177-182.). Anti-IL- 17 antibody delayed the onset of ocular inflammation and markedly inhibited the development of experimental autoimmune uveitis in rats (Zhang R. et al., Curr. Eye Res. 2009 Apr;34(4):297- 303). The analysis of secondary efficacy data from subcutaneous (sc) secukinumab phase 3 trials in uveitis suggested a beneficial effect of secukinumab in reducing the use of concomitant immunosuppressive medication (Dick A. etal., Ophthalmology 2013; 120(4):777-87). Later study of intravenous secukinumab in uveitis demonstrated greater efficacy than sc dosing, suggesting requiring optimal exposure for efficacy and confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015, 122(5), 939-948). Ustekinumab that blocks IL- 23 / IL-17 pathway was also reported to successfully treat a noninfectious uveitis patient who had severe concomitant psoriasis and PsA and failed to respond to conventional immune suppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep;30(5);el2527.).

[0400] For multiple myeloma (MM): IL-17A serum levels were significantly higher in MM patients and also in patients with advanced stage compared with healthy subjects (Lemancewicz D. et al., Med. Sci. Monit. 2012; 18(1): BR54-BR59). Administration of secukinumab in the SCIDhu model of human myeloma weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice (Prabhala R. et al., Leukemia. 2016 February; 30(2): 379-389).

[0401] For systemic lupus erythematosus (SLE): Increased serum or plasma levels of IL-17, expansion ofIL-17-producing T cells in the peripheral blood, and infiltration of Thl7 cells in target organs like the kidneys was observed in SLE patients (Wong C. etal., Lupus. 2000;9(8): 589-593; Wong C. et al., Clinical Immunology. 2008;127(3):385-393; Zhao X-F. et al., Mol. Biol. Rep. 2010 Jan;37(l):81-5; Chen X. et al., J. Clin. Immunol. 2010 Mar;30(2):221-5; Xing Q. et al., Rheumatol. Int. 2012 Apr; 32(4): 949-58). Imbalance between Thl7 cells and regulatory T (Treg) cells has been observed in SLE patients including quiescent stage (Ma J. et al., Clin. Rheumatol. 2010;29(l 1): 1251—1258; Dolff S. et al., Clin. Immunol. 2011, 141(2): 197-204). Overexpression of IL-17A using adenovirus enhanced the severity of lupus nephritis, while blockade of IL-17A using neutralizing antibody resulted in decreased severity of lupus nephritis (Wen, Z. etal., PLoS One. 2013, 8: e58161 ). In a phase 2 study, ustekinumab, an anti-IL-12 / 23 p40 monoclonal antibody blocking IL-23 / IL-17 pathway, has demonstrated efficacy in SLE patients (van Vollenhoven R. et al., Lancet 2018; 392: 1330-39). Human expression studies, animal models, and clinical trials indicate that IL- 17 blockade may become a promising therapeutic strategy for SLE ( Koga T. el al., Expert Rev. Clin. Immunol. 2019, 15 (6) 629-637).

[0402] Accordingly, the present application is also directed to methods for treating and / or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.

[0403] In some embodiments, disclosed herein are methods for treating or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0404] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0405] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0406] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0407] In some embodiments, disclosed herein method for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0408] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0409] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0410] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0411] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0412] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0413] In some embodiments, disclosed herein are methods for treating or ameliorating and / an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[0414] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0415] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is asthma.

[0416] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is uveitis.

[0417] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0418] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0419] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of described herein, e.g., a compound Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0420] In some embodiments, disclosed herein is the use of a therapeutically effective amount of compound described herein, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0421] In some embodiments, disclosed herein is the use of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0422] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0423] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0424] In some embodiments, disclosed herein are methods of treating or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, and ankylosing spondylitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0425] In some embodiments, disclosed herein are methods of modulating IL- 17 activity in a mammal by administration of a therapeutically effective amount of at least one compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof.

[0426] Also disclosed herein are methods of inhibiting production of interleukin- 17, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof.

[0427] Combination Therapy

[0428] A compound described herein, e.g., a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.

[0429] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.

[0430] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as antiinflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, or hidradenitis suppurativa. In some embodiments, the IL- 17 mediated inflammatory syndrome, disorder or disease is psoriasis. In some embodiments, the IL- 17 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis. In some embodiments, the IL- 17 mediated inflammatory syndrome, disorder or disease is ankylosing spondylitis. In some embodiments, the IL- 17 mediated inflammatory syndrome, disorder or disease is hidradenitis suppurativa.

[0431] Dosage Regimen

[0432] The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.

[0433] It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present disclosure or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet, and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this disclosure.

[0434] Pharmaceutical Compositions

[0435] The compounds of the present disclosure, and pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic agents. Exemplary excipients that may also be components of the formulation include but not limited to fillers, binders, disintegrating agents, and lubricants.

[0436] The pharmaceutical compositions of the present disclosure may be administered by any means that accomplish their intended purpose. Examples include but not limited to administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular routes. Alternatively, or concurrently, administration may be by the oral route. Also disclosed herein are methods of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or pharmaceutically acceptable salt thereof. Additionally, the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present disclosure.

[0437] Although the present embodiments have been described in connection with certain specific embodiments for instructional purposes, the present embodiments are not limited thereto. Accordingly, various modifications, adaptations, and combinations of various features of the described embodiments can be practiced without departing from the scope of the invention as set forth in the claims. Furthermore, the following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. Any and all journal articles, patent applications, issued patents, or other cited references are incorporated by reference in their entirety.

[0438] In some embodiments, the following non-limiting embodiments are provided:

[0439] 1. A compound of F ormula I or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0440] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4)alkyl, or -OC(i-4)alkyl;

[0441] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0442] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0443] R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;

[0444] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0445] R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

[0446] 2. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: each R1is independently halo or -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0447] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4)alkyl, or -OC(i-4)alkyl;

[0448] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;

[0449] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0450] R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;

[0451] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0452] R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

[0453] 3. The compound of any one of embodiments 1-2, having a formula according to Formula (la): or a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;

[0454] X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4)alkyl, or -OC(i-4)alkyl;

[0455] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, oxo, -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0456] R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;

[0457] R3bis a H or -C(i-3)alkyl;

[0458] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;

[0459] R5is a 5- to 10-membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; and n is 0, 1, 2, 3, or 4.

[0460] 4. The compound of any one of embodiments 1-2, having a formula according to Formula (lb): or a pharmaceutically acceptable salt thereof, wherein:

[0461] R1is -C(i-3)alkyl, wherein the -C(i-3)alkyl is unsubstituted or substituted with one to six Rlagroups; each Rlais independently fluoro;

[0462] X is a -CH2- or absent;

[0463] R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, oxo, -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3- 4)cycloalkyl wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0464] R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms;

[0465] R5is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R5bgroups; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3.

[0466] 5. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein each R1is CF3.

[0467] 6. The compound of any one of embodiments 1, 2, 3, or 5, or a pharmaceutically acceptable salt thereof, wherein n is 1. 7. The compound of any one of embodiments 1, 2, 3, 5, or 6 or a pharmaceutically acceptable salt thereof, wherein X is a -CH2-, -CH2CH2-, r absent.

[0468] 8. The compound of any one of embodiments 1-7, having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0469] 9. The compound of any one of embodiments 1-6, having a formula according to Formula

[0470] (Ic): (Ic), or a pharmaceutically acceptable salt thereof.

[0471] 10. The compound of embodiment 9, having a formula selected from the group consisting of:

[0472] (Ic-1) and (Ic-2), or a pharmaceutically acceptable salt thereof.

[0473] 11. The compound of any one of embodiments 1-6, having a formula according to Formula (Id):

[0474] (Id), or a pharmaceutically acceptable salt thereof.

[0475] 12. The compound of embodiment 11, having a formula selected from the group consisting of:

[0476] (Id-1) and (Id- 2), or a pharmaceutically acceptable salt thereof.

[0477] 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein R2is 4- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups.

[0478] 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R2is 4- to 7-membered heterocyclyl that is unsubstituted or substituted with one to three oxo or -C(i-4)alkyl groups.

[0479] 15. The compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein R2is oxazolidinyl, imidazolidinyl, or morpholinyl, each of which is unsubstituted or substituted with one to three oxo or -C(i-4)alkyl groups.

[0480] 16. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R2is 5- to 6-membered heteroaryl that is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0481] 17. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein R2is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -C(i- 3)alkyl-O-C(i-4)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, and - C(3-4)cycloalkyl are unsubstituted or substituted with one to six fluorine atoms.

[0482] 18. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of: 20. The compound of any one of embodiments 1-15 or 18, or a pharmaceutically acceptable salt thereof, wherein

[0483] 21. The compound of any one of embodiments 1-15 or 18, or a pharmaceutically acceptable salt thereof, wherein

[0484] 22. The compound of any one of embodiments 1-3, 5-7, or 13-21, or a pharmaceutically acceptable salt thereof, wherein R3ais H.

[0485] 23. The compound of any one of embodiments 1-3, 5-7, or 13-22, or a pharmaceutically acceptable salt thereof, wherein R3bis H.

[0486] 24. The compound of any one of embodiments 1-3, 5-7, or 13-23, having a formula according to Formula (II):

[0487] (II), or a pharmaceutically acceptable salt thereof.

[0488] 25. The compound of any one of embodiments 1-3, 5-8, or 13-24, having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0489] 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-io)alkyl or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms.

[0490] I l l 27. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein

[0491] 28. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein

[0492] 29. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein

[0493] 30. The compound of any one of embodiments 1-2 or 5-29, or a pharmaceutically acceptable salt thereof, wherein R5is C(3-6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups.

[0494] 31. The compound of any one of embodiments 1-2 or 5-30, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently a halo, methyl, or cyclopropyl, wherein the methyl and cyclopropyl are unsubstituted or substituted with one to three halo atoms.

[0495] 32. The compound of any one of embodiments 1-2 or 5-31, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of:

[0496] 33. The compound of any one of embodiments 1-2 or 5-29, or a pharmaceutically acceptable salt thereof, wherein R5is -O-C(3-6)cycloalkyl.

[0497] 34. The compound of any one of embodiments 1-2, 5-29, or 33, or a pharmaceutically acceptable salt thereof, wherein R5is

[0498] 35. The compound of any one of embodiments 1-2 or 5-29, or a pharmaceutically acceptable salt thereof, wherein R5is 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to two R5bgroups. 36. The compound of any one of embodiments 1-29 or 35, or a pharmaceutically acceptable salt thereof, wherein R5is 5-membered heteroaryl that is substituted with one R5bgroup.

[0499] 37. The compound of any one of embodiments 1-29, 35, or 36, or a pharmaceutically acceptable salt thereof, wherein R5is pyrazolyl or oxadiazolyl, each of which is substituted with one R5bgroup.

[0500] 38. The compound of any one of embodiments 1-29 or 35-37, or a pharmaceutically

[0501] N'ox

[0502] JL / Nacceptable salt thereof, wherein R5is Fl-

[0503] 39. The compound of any one of embodiments 1-29 or 35-38, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently a -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3- 6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0504] 40. The compound of any one of embodiments 1-29 or 35-39, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently -CH3, -CHF2, -CF2CH3, -OCH3, or cyclopropyl.

[0505] 41. The compound of any one of embodiments 1-29 or 35-40, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting

[0506] 42. The compound of any one of embodiments 1-29 or 35-41, or a pharmaceutically acceptable salt thereof, wherein

[0507] 43. The compound of any one of embodiments 1-4, having a formula according to Formula (lo-l):

[0508]

[0509] (lo-l), or Formula (Io-2): (Io-2), or a pharmaceutically acceptable salt thereof, wherein:

[0510] X is a -CH2- or absent;

[0511] R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7- membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i- 4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms; and

[0512] R5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

[0513] 44. The compound of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0514] 45. The compound of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein X is absent. 46. A compound selected from the group consisting of the compounds in Table 1, Table 2, and Table 3 or a pharmaceutically acceptable salt thereof.

[0515] 47. The compound of any one of embodiments 1-2, having a formula selected from the group consisting of:

[0516] or a pharmaceutically acceptable salt thereof.

[0517] 48. The compound of any one of embodiments 1-2, having a formula selected from the group consisting of: 49. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0518] 50. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0519] 51. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof. 52. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0520] 53. The compound of embodiment 48, having the following formula:

[0521] or a pharmaceutically acceptable salt thereof.

[0522] 54. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0523] 55. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0524] 56. The compound of embodiment 48, having the following formula: 57. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0525] 58. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0526] 59. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0527] 60. The compound of embodiment 48, having the following formula:

[0528] or a pharmaceutically acceptable salt thereof.

[0529] 61. The compound of embodiment 48, having the following formula: or a pharmaceutically acceptable salt thereof.

[0530] 62. A pharmaceutical composition comprising a compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0531] 63. A method for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt thereof.

[0532] 64. The method of embodiment 63, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hi dradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0533] 65. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis. 66. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0534] 67. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0535] 68. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0536] 69. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0537] 70. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0538] 71. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0539] 72. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0540] 73. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[0541] 74. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0542] 75. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is asthma.

[0543] 76. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is uveitis.

[0544] 77. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0545] 78. The method of embodiment 64, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0546] 79. The method of any of embodiments 63-78, wherein the compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt thereof, is administered orally.

[0547] 80. The method of any of embodiments 63-78, wherein the compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt thereof, is administered as a tablet or a capsule. 81. A compound as described herein.

[0548] 82. A method as described herein.

[0549] EXAMPLES

[0550] ABBREVIATIONS

[0551] Herein and throughout the application, the following abbreviations may be used.

[0552] A angstrom

[0553] Ac acetyl

[0554] ACN acetonitrile atm atmosphere

[0555] Boc tert-butyloxycarbonyl br broad

[0556] Bu butyl

[0557] Burgess Reagent methyl A-(triethylammoniosulfonyl)carbamate

[0558] CDI 1 , 1’ -carbonyldiimidazole

[0559] 8 NMR chemical shift in parts per million downfield from a standard d doublet

[0560] DAST (diethylamino)sulfur trifluoride

[0561] DCM dichloromethane

[0562] DEA diethylamine

[0563] DIAD diisopropyl azodicarboxylate

[0564] DIEA / DIPEA / V, / V-di isopropyl ethylamine (Hiinig’s base)

[0565] DMA / V, / V-dimethylacetamide

[0566] DMAP 4-(dimethylamino)pyridine

[0567] DMF / V, / V-dimethylformamide

[0568] DMP Dess-Martin Periodinane

[0569] DMSO dimethyl sulfoxide dr diastereomeric ratio

[0570] EDCI l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride

[0571] ESI electrospray ionization

[0572] Et ethyl

[0573] EtOAc ethyl acetate

[0574] FA formic acid g gram(s) h hour(s)

[0575] HATU N- [(dimethylamino)- H- 1 ,2,3 -triazolo- [4, 5 - / >]pyridin- 1 - ylmethylene]-A-methylmethanaminium hexafluorophosphate N- oxide

[0576] HOBt 1 -hydroxybenzotriazole

[0577] HPLC high pressure liquid chromatography

[0578] Hz Hertz

[0579] IPA 2-propanol coupling constant (NMR spectroscopy)

[0580] L liter(s)

[0581] Lawesson reagent 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4- dithiadiphosphetane

[0582] LiHMDS lithium bis(trimethylsilyl)amide m milli or multiplet m / z mass-to-charge ratio

[0583] M+parent molecular ion

[0584] M molar (moles / liter)

[0585] M mega

[0586] Me methyl min minute(s) micro pM micromolar

[0587] Ms methanesulfonyl

[0588] MS mass spectrometry

[0589] N normal

[0590] NMM 4-methylmorpholine

[0591] NMR nuclear magnetic resonance

[0592] P para

[0593] Parkins' Catalyst Hydri do(dimethylphosphinous acid-kP) [hydrogen bis

[0594] (dimethylphosphinito-kP)]platinum(II)

[0595] Ph phenyl Rochelle salt potassium sodium tartrate tetrahydrate rt room temperature s singlet

[0596] SFC supercritical fluid chromatography t triplet or tert

[0597] TBAF tetrabutylammonium fluoride

[0598] TCFH chloro- / V, / V, / V',1-tetramethylformamidinium hexafluorophosphate

[0599] TEA triethylamine

[0600] TFA trifluoroacetic acid

[0601] THF tetrahydrofuran

[0602] TLC thin layer chromatography

[0603] TMS trimethylsilyl

[0604] TosMic / ?-toluenesulfonylmethyl isocyanide

[0605] Ts / ?-toluenesulfonyl wt% weight percent

[0606] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of the disclosure or pharmaceutically acceptable salts thereof. In the schemes below, the term PG is intended to mean “protecting group,” such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999. For example, a group PG attached to a nitrogen atom indicates a nitrogen protecting

[0607] group, such as / c / 7-butyloxycarbonyl (Boc), toluenesulfonyl (tosyl, Ts), or nitrobenzenesulfonyl (nosyl, Ns).

[0608] Scheme A

[0609] A-lll

[0610] PG1is a nitrogen protecting group, e.g., Boc

[0611] PG2is a nitrogen protecting group, e.g., Boc A-|V'

[0612] Compounds of Formula A-IV’ can be prepared according to Scheme 1. Compounds A-I can be converted to compounds A-II through a two-step sequence of i) reduction of the aldehyde with a reagent such as sodium borohydride in solvents such as DCM and MeOH to provide the corresponding alcohol (structure not shown), followed by ii) bromination of the alcohol with reagents such as CBu and PPl with additives such as imidazole in a solvent such as DCM. Alternatively, aldehyde A-I can be treated with an agent such as R3aM or R3bM, or both, for example, MeMgBr, in a solvent such as THF, followed by bromination with reagents such as CBr4 with additives such as imidazole and PPhy in a solvent such as DCM to provide compounds A-II. Compounds A-IV’ may be prepared by treating bromides A-II with lactams A-III in the presence of a base, such as LiHMDS, in a solvent such as THF. Scheme B

[0613] Compounds of Formula B-III, where R2is a substituted or unsubstituted heteroaryl group, can be prepared according to Scheme B. Treatment of compounds A-IV (i.e., compounds of formula A- IV’ where R3aand R3bare H) with a base such as LiHMDS in a solvent such as THF followed by treatment with a reagent such as CICO2R (where R is an alkyl group; e.g., ethyl chloroformate) gives ester compounds B-I. As shown in Route A, removal of the nitrogen protecting groups PG1and PG2can be achieved using reagents such as HC1 or TFA in a solvent such as DCM or 1,4- dioxane. Amide bond formation at the primary amine using carboxylic acids (R5CO2H) can be achieved through the use of a coupling agent (e.g., HATU, EDCI, TCFH, 2-chloro-l- methylpyridinium iodide, or any other suitable coupling agent) in the presence of a base, such as DIPEA or TEA, in a solvent, such as DMF, MeCN, or DCM, with or without an additive, such as HOBt, to yield compounds of Formula B-II. Alternatively, amide bond formation at the primary amine can be achieved by treatment with A-hydroxysuccinate esters in the presence of reagents such as DIPEA in a solvent such as acetonitrile to provide compounds of Formula B-II. The primary amine may, instead, be converted to a carbamate by reaction with an appropriate carbonochloridate (CICO2R5) in the presence of a coupling agent such as NMM in a solvent such as DCM to provide compounds of Formula B-II. Elaboration of the carboxylic ester within compounds B-II to various heteroaromatics can be achieved using common procedures known in the art to give compounds B-III. Alternatively, as shown in Route B, the order of the individual steps can be modified with ester conversion to the heteroaryl being performed first, followed by deprotection and amide bond formation as described in Route A to give compounds B-III.

[0614] Scheme C

[0615] The compounds of formula B-III may also be prepared as shown in Scheme C: treatment of compounds A-IV with a base such as potassium / c / 7-butoxide in a solvent such as THF and / or toluene followed by treatment with compound R2-X (where X is a halogen, such as bromide) provides compounds of the formula C-II. Following a similar sequence as described in Route B, protecting group removal and subsequent amide or carbamate bond formation then affords compounds B-III. Scheme D

[0616] 1

[0617] 2

[0618] D-II

[0619] PG1is a nitrogen protecting group, e.g., Boc

[0620] PG2is a nitrogen protecting group, e.g., Boc

[0621] Compounds of the formula B-III, where R2is a substituted or unsubstituted heteroaryl group, may also be prepared as shown in Scheme D. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with an electrophilic CN source, such as 3-oxo-ll3-benzo[<7][l,2]iodaoxole-l(3 / / )-carbonitrile, provides nitrile compounds D-I. Using a similar sequence as described in Scheme B, removal of the protecting groups followed by amide or carbamate bond formation then yields compounds D-II. Nitriles D-II can then be elaborated into heteroaryl-containing compounds B-III using common procedures known in the art.

[0622] Scheme E

[0623] Compounds of the formulas B-III (where R2is a 1,2,3 triazole) and B-III’ (where R2is a substituted or unsubstituted heterocyclyl group) may be prepared as shown in Scheme E. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with TMSN3 provides compounds E-I. Using a similar sequence as described in Scheme B, deprotection followed by amide or carbamate bond formation then generates azide E-II. Treatment of azide E-II with a reagent such as ethylene sulfonyl fluoride in a solvent such as ethyl acetate then generates a compound of the formula B-III, where R2is a 1,2,3 triazole. Alternatively, reduction of azide E-II using a reagent such as Pd / C in the presence of H2 generates primary amine E-III. Amine E-III may then be elaborated into heterocycle-containing compounds B-III’ using common procedures known in the art. Scheme F PG1is a nitrogen protecting group, e.g., Boc

[0624] PG2is a nitrogen protecting group, e.g., Boc

[0625] Compounds of the formula F-III, where R2is a substituted or unsubstituted heteroaryl group, may be prepared as shown in Scheme F. Treatment of compounds A-IV with a base such as potassium / / 7-butoxide or LiHMDS in a solvent such as THF and / or toluene followed by treatment with X- CH2R2(where X is a halide, such as chlorine or bromine) provides compounds of the formula F- II. Following a similar sequence described in Scheme B, deprotection and amide or carbamate bond formation then affords compounds F-III.

[0626] Scheme G

[0627] PG1is a nitrogen protecting group, e.g., Boc

[0628] PG2is a nitrogen protecting group, e.g., Boc

[0629] Compounds of the formula G-III, where R2is a substituted or unsubstituted heterocyclyl group, can be prepared as shown in scheme G. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with a suitable bromide electrophile affords intermediates G-I. Subsequent deprotection and amide or carbamate bond formation as described in scheme B gives the phthalimides G-II. Finally, deprotection of the phthalimide using a reagent such as hydrazine hydrate in a solvent such as MeOH affords the corresponding primary amine that may then be elaborated to the heterocycle-containing compounds of the formula G-III using common procedures known in the art.

[0630] Scheme H

[0631] Compounds of Formula F-III, where R2is a substituted or unsubstituted heteroaryl group, can also be prepared according to Scheme H. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with a suitable ester containing electrophile such as X-CH2CO2R (where R is an alkyl group and X is a halogen, such as bromine; e.g., ethyl 2- bromoacetate) gives intermediates H-I. As shown in Route A, deprotection and amide or carbamate bond formation as described in Scheme B affords compounds of the formula H-II. Elaboration of the carboxylic ester within compounds H-II to various heteroaromatics can be achieved using common procedures known in the art to give compounds F-III. Alternatively, as shown in Route B, the order of the individual steps can be switched with ester conversion to the heteroaryl being performed first, followed by deprotection and amide or carbamate bond formation to give compounds F-III.

[0632] Scheme I

[0633] PG1is a nitrogen protecting group, e.g., Boc

[0634] PG2is a nitrogen protecting group, e.g., Boc Compounds of Formula F-III, where R2is a triazole, can also be prepared according to Scheme I. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with (3 -bromoprop- l-yn-l-yl)trimethylsilane gives alkynes I-I. Deprotection of the TMS group within I-I using a reagent such as potassium fluoride dihydrate in a solvent such as DMF and subsequent treatment with trimethylsilyl azide in the presence of Cui in solvents such as DMF and MeOH generates compounds I-II, where R2is a triazole. Deprotection and amide or carbamate bond formation as described in Scheme B then provides compounds F-III.

[0635] Scheme J

[0636] Compounds of Formula B-III, where R2is a substituted or unsubstituted heteroaryl group, can also be prepared according to Scheme J. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with acetyl chloride provides the ketones J-I.

[0637] Subsequent deprotection and amide or carbamate bond formation as described in Scheme B affords compounds of the formula J-II. Treatment of ketones J-II with DMF and DMA in a solvent such as toluene provides compounds of the formula J-III. The compound of formula J-III can be elaborated to the heteroaryl- containing compounds of formula B-III using common procedures known in the art.

[0638] Scheme K

[0639] Compounds of formula F-III, where R2is a substituted or unsubstituted heteroaryl group (“hAr”), may also be prepared as shown in Scheme K. Treatment of intermediates A-IV with a base such as LiHMDS in a solvent such as THF followed by treatment with a reagent such as bromo acetonitrile provides nitrile compounds K-I. Using a similar procedure as described in Scheme B, removal of the protecting groups followed by amide or carbamate bond formation then yields compounds K-II. Elaboration of the nitrile-containing compounds of formula K-II to the heteroaryl-containing compounds of formula F-III can then be performed using conditions described in the literature.

[0640] EXAMPLES

[0641] INTERMEDIATES

[0642] Intermediate 1: tert-Butyl (S)-((7-(bromomethyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate

[0643] Step A: tert-Butyl (5)-((4,4-difluorocyclohexyl)(7-(hydroxymethyl)imidazo[l ,2- / ?]pyridazin-2-yl)methyl)carbamate. A solution of tert-butyl fS')-((4,4-difluorocyclohexyl)(7-formylimidazo[ l ,2- / ?]pyridazin- 2-yl)methyl)carbamate (2.17 g, 5.50 mmol) in DCM / MeOH (5: 1, 60 mL) was cooled to 0 °C. Then, sodium borohydride (265 mg, 6.90 mmol) was added, and the resulting mixture was stirred under an air atmosphere while warming to rt over 2.5 h. The mixture was cooled to 0 °C, quenched by dropwise addition of saturated aqueous NH4CI (0.2 mL) and stirred for 30 min while warming to rt. The reaction mixture was partitioned between DCM (100 mL) and water (200 mL), and the aqueous layer was further extracted with DCM (3 x 30 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered through diatomaceous earth, and concentrated to dryness. The residue was purified by silica gel chromatography (0-25% MeOH / DCM) to provide the title compound as a white solid (82% yield). MS (ESI) m / z: [M+H]+Found 397.2.

[0644] Step B: tert-Butyl (S)-((7-(bromomethyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate. To a solution of tert-butyl (5)-((4,4- difhiorocyclohexyl)(7-(hydroxymethyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)carbamate (132 mg, 0.330 mmol, Step A), PPhs (105 mg, 0.400 mmol) and imidazole (46 mg, 0.67 mmol) in dry DCM (10 mL) was added a mixture of CBn (221 mg, 0.670 mmol) in dry DCM (3.3 mL) drop wise at rt. The resulting mixture was stirred at rt for 1 h, then additional imidazole (11.5 mg, 0.168 mmol), PPhs (4.4 mg, 0.017 mmol) and CBn (5.5 mg, 0.017 mmol) were added, and the mixture was stirred at rt for 30 min. The reaction mixture was concentrated to dryness and the residue purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound as a white foam (79% yield). MS (ESI) m / z: [M+H]+Found 461.1.

[0645] Intermediate 2: tert-Butyl fS')-2-oxo-5-(trifluoromethyl)pyrrolidine- l -carboxylate 5-5-(Trifluoromethyl)pyrrolidin2-one (10.0 g, 65.3 mmol) and DMAP (107 mg, 0.877 mmol) were dissolved in DCM (218 mL). TEA (10.9 mL, 78.4 mmol) and di- / / 7-butyl dicarbonate (17.1 g, 78.4 mmol) were sequentially added and the reaction mixture was stirred at rt overnight. The reaction mixture was then washed sequentially with 10% aqueous citric acid, water, and brine, dried over anhydrous MgSCh, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-50% EtOAc / hexanes) to afford the title compound (70% yield). MS (ESI) m / z: [2M+Na]+Found 529.3.

[0646] Intermediate 3: tert-Butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluor omethyl)pyrrolidine- 1 -carboxylate

[0647] A solution of tert-butyl fS')-2-oxo-5-(trifluoromethyl)pyrrolidine- l -carboxylate (455 mg, 1.80 mmol, Intermediate 2) in THF (14 mL) was cooled to -78 °C. Then, a 1.5 M solution of LiHMDS in THF (1.4 mL, 2.1 mmol) was added dropwise and the resulting solution was stirred at -78 °C for 1 h. tert-Butyl (S)-((7-(bromomethyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate (642 mg, 1.40 mmol, Intermediate 1) was dissolved in THF (2 mL) and this solution was then added to the -78 °C mixture of Intermediate 2 in THF. The resulting mixture was stirred at -78 °C for 1 h. The reaction was then warmed to rt over 1 h, quenched with aqueous NH4CI and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound (68% yield). MS (ESI) m / z: [M+H]+Found 632.3.

[0648] Intermediate 4: A-((5)-(7-(((35,55)-3-(Aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide Step A: tert-Butyl (35,55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-((l,3-dioxoisoindolin-2- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. tert-Butyl (55)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (500 mg, 0.79 mmol, Intermediate 3) and THF (10 mb) were added to a flask which was subsequently evacuated and refilled with N2 three times. The solution was cooled to -78 °C and then LiHMDS (4.0 mL, 4.0 mmol, 1 M in THF) was added dropwise over 1 min. The resulting mixture was stirred at -78 °C for 30 min, then a solution of 2-(bromomethyl)isoindoline-l, 3-dione (950 mg, 3.96 mmol) in THF (2 mL) was added. The reaction mixture was stirred at -78 °C for 30 min, then saturated aqueous NH4CI (50 mL) was added drop wise over 10 min. The mixture was extracted with EtOAc (3 x 50 mL), then the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a colorless oil. The oil was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to provide a mixture of isomers as a white solid (70% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 791.3.

[0649] Step B: 2-(((3 ,55 -3-((2-((5)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)isoindoline-l, 3-dione hydrochloride. The title compound (97% yield), where the title compound was the major isomer, was prepared as described for the synthesis of Intermediate 5, Step B using tert-butyl (3S,5S)-3- ((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin- 7-yl)methyl)-3-((l,3-dioxoisoindolin-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l- carboxylate (Step A) in place of tert-butyl (37?,55)-3-azido-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. MS (ESI) m / z: [M+H]+Found 591.3.

[0650] Step C: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((l,3- dioxoisoindolin-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide. A mixture of 2-(((3 ,55)-3-((2-((5)- amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)isoindoline- 1,3-dione hydrochloride (283 mg, 0.450 mmol, Step B), lithium 4-cy cl opr opyl- 1,2, 5 -oxadiazole-3 -carboxy late (93 mg, 0.58 mmol), EDCI (277 mg, 1.44 mmol), HOBt (131 mg, 0.970 mmol) and NMM (0.26 mL, 2.4 mmol) in DCM (10 mL) was stirred at rt for 1 h. The reaction mixture was then diluted with water (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford yellow oil. The oil was purified by silica gel chromatography (60-70% EtOAc / petroleum ether) to provide a mixture of isomers as a brown solid (58% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Eound 727.2.

[0651] Step D: A-((5)-(7-(((35,55)-3-(Aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide. A mixture of 4-cyclopropyl-A-((6')-(4,4-difluorocyclohexyl)(7- (((35,5S)-3-((l,3-dioxoisoindolin-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide (270 mg, 0.37 mmol, Step C) and N2H H2O (93 mg, 1.86 mmol) in MeOH (5 mL) was stirred at rt for 2 h, then heated at 70 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a white solid. The solid was purified by silica gel chromatography (0-10% MeOH / DCM) to provide a mixture of isomers as a white solid (45% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Eound 597.2.

[0652] Intermediate 5: (37?,5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l ,2- / ?]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride

[0653] Step A: tert-Butyl (37?,55)-3-azido-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. A flask containing a solution of tert-butyl (5S)-3-((2- ((«S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2-Z>]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (250 mg, 0.4 mmol, Intermediate 3) in THF (8 mL) was evacuated and refilled with N2 three times. The mixture was cooled to -78 °C and then LiHMDS (2.0 mL, 2.0 mmol, 1 M in THF) was added dropwise over 2 min. The resulting mixture was stirred at -78 °C for 30 min. Then, a solution of TsNs (390 mg, 1.98 mmol) in THF (1 mL) was added followed by a solution of acetic acid (0.21 mL, 3.6 mmol) in THF (1 mL) that was added two min later. The resulting mixture was stirred at -78 °C for 30 min. The mixture was partitioned between saturated aqueous NH4Q (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous further extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow oil. The oil was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide a mixture of isomers as a yellow solid (17% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 673.1.

[0654] Step B: (3A,5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l ,2- / ?]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride. A mixture of tert-butyl (37?,55)-3-azido-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (90 mg, 0.13 mmol, Step A) in DCM (3 mL) was cooled to 0 °C in an ice water bath, then HC1 (3.0 mL, 12 mmol, 4 M in 1,4-di oxane) was added dropwise over 2 min. The resulting mixture was stirred at rt for 12 h, then concentrated to dryness to provide a mixture of isomers as a white solid (88% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 473.4.

[0655] Intermediate 6: A-f(5)-(7-(((37?,55)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide Step A: A-((S)-(7-(((3A,5S)-3-Azido-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide. A mixture of 4-cyclopropy 1-1, 2, 5 -oxadiazole-3 -carboxylic acid (50 mg, 0.32 mmol), EDCI (141 mg, 0.74 mmol), HOBt (65 mg, 0.48 mmol) and NMM (135 pL, 1.23 mmol) in DCM (3 mL) was stirred until homogeneous, then cooled to 0 °C in an ice water bath. Then, a solution of (37?,55)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride (125 mg, 0.25 mmol, Intermediate 5) in DCM (2 mL) was added and the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc / petroleum ether) to provide a mixture of isomers as a yellow solid (60% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Bound 609.2.

[0656] Step B: A-((S)-(7-(((37?,5S)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide. A flask containing a mixture of A-((5)-(7-(((37?,55)-3-azido-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide (90 mg, 0.15 mmol, Step A) and 10 wt% Pd / C (45 mg, 0.042 mmol) in EtOAc (5 mL) was evacuated and refilled with H2 three times. The resulting mixture was stirred under H2 (~3 atm) at rt for 1 h. The reaction mixture was then filtered by vacuum filtration and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (0-80% EtOAc / petroleum ether) to provide a mixture of isomers as a white solid (81% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 583.3.

[0657] Intermediate 7: Ethyl 2-((35,55)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate

[0658] Step A: tert-Butyl (35,55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(2-ethoxy-2-oxoethyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. A flask containing a solution of tert-butyl (55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine- l -carboxylate (500 mg, 0.79 mmol, Intermediate 3) in THF (19 mb) was evacuated and refilled with N2 three times. The mixture was cooled to -78 °C and then LiHMDS (4.8 mL, 4.8 mmol, 1 M in THF) was added dropwise over 2 min. The resulting mixture was stirred at -78 °C for 30 min, then a solution of ethyl 2-bromoacetate (0.70 mL, 6.31 mmol) in THF (1 mL) was added. The reaction was stirred at -78 °C for 3 h, then warmed to rt and treated with saturated aqueous NH4Q (30 mL) dropwise over 5 min. The mixture was extracted with EtOAc (3 x 30 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a yellow oil. The oil was purified by silica gel chromatography (0-60% EtOAc / petroleum ether) to provide a mixture of isomers as a yellow solid (84% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 718.2.

[0659] Step B: Ethyl 2-((35,55)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate. A mixture of tertbutyl (35,55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(2-ethoxy-2-oxoethyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (160 mg, 0.22 mmol, Step A) and HC1 (10 mL, 40 mmol, 4 M in 1,4-di oxane) in DCM (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated to dryness to provide a mixture of isomers as a yellow solid, where the title compound was the major isomer, which was used without further purification. MS (ESI) m / z: [M+H]+Found 518.2. Intermediate 8: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((Z)-3- (dimethylamino)acryloyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3-yl)methyl)imidazo[l,2- / ?]pyridazin-2-yl)methyl)- l ,2,5-oxadiazole-3-carboxamide

[0660] Step A: / c / 7-Butyl (35,55)-3-acetyl-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. The title compound was prepared as described for the synthesis of Intermediate 7 Step A using acetyl chloride in place of ethyl 2-bromoacetate. The residue was purified by preparative HPLC (Airs Science C18-M column, 20- 5 um, 100 A, 120 g, 5-95% ACN / HiO (with NH4HCO3 to provide a mixture of isomers as a colorless oil (35% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 674.4.

[0661] Step B: (35,55)-3-Acetyl-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l ,2- / ?]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidin-2-one. A mixture of tert-butyl (3S,5S)-3- acetyl-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine- l -carboxylate (80 mg, 0.12 mmol, Step A) in DCM (2 mL) was cooled to 0 °C in an ice- water bath. Then, HC1 (4.0 mL, 16 mmol, 4 M in 1,4-di oxane) was added dropwise over 5 min and the resulting mixture was stirred at 0 °C for 2 h. Then the mixture was placed in a warm water bath until it reached rt. The reaction was concentrated to dryness to provide a mixture of isomers as a light yellow solid (98% yield), where the title compound was the major isomer, which was used without further purification. MS (ESI) m / z: [M+H]+Found 474.2.

[0662] Step C: A-((S)-(7-(((35,5S)-3-Acetyl-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide. A mixture of (35,55)-3-acetyl-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidin- 2-one (56 mg, 0.12 mmol, Step B), 4-cyclopropyl-l,2,5-oxadiazole-3-carboxylic acid (28 mg, 0.18 mmol), EDCI (68 mg, 0.36 mmol), HOBt (32 mg, 0.24 mmol) and NMM (65 pL, 0.59 mmol) in DMF (2 mL) was stirred until homogeneous and then for an additional 2 h at rt. The reaction mixture was poured over water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a light yellow solid. The solid was purified by reverse flash chromatography (Airs Science C18-M column, 20-35 pm, 100 A, 80 g, 5-95% ACN / H2O (with 0.05% TEA)) to provide a mixture of isomers as a white solid (83% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 610.3.

[0663] Step D: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((Z)-3- (dimethylamino)acryloyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide. A mixture of A-((5)-(7-(((3 ,55)-3- acetyl-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide (410 mg, 0.67 mmol, Step C) and DMF-DMA (450 pL, 3.39 mmol) in toluene (6 mL) was heated at 110 °C for 2 h. The reaction mixture was cooled to rt and concentrated to dryness to afford a light-yellow oil. The oil was purified by reverse flash chromatography (Airs Science C18-M column, 20-35 pm, 100 A, 90 g; 0-95% ACN / H2O (with 0.05% TFA)) to provide a mixture of isomers as a light-yellow solid (49% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 665.8.

[0664] Intermediate 9: Mixture of cA-Ethyl 2-((35,55)-3-((2-((5)-(4,4-difluorocyclohexyl)((17?*,25*)-2- (trifl uoromethyl (cyclopropane- ! -carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2- oxo-5-(trifhroromethyl)pyrrolidin-3-yl)acetate and cA-ethyl 2-((3 ,55)-3-((2-((5)-(4,4- difluorocyclohexyl)((LS'*,2 / ?*)-2-(trifluoromethyl)cyclopropane- l - carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-

[0665] 3-yl)acetate

[0666]

[0667] Intermediate 10: Mixture of / raw.s-Ethyl 2-((35,5S)-3-((2-((S)-(4,4- difluorocyclohexyl)((lA*,2A*)-2-(trifluoromethyl)cyclopropane-l- carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-

[0668] 3-yl)acetate and / raw.s-ethyl 2-((35,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)((15*,25*)-2-

[0669] (trifluoromethyl)cyclopropane- 1 -carboxamido)methyl)imidazo[ 1 ,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate

[0670] The title compounds for Intermediates 9 and 10 were prepared as described for the synthesis of Example 10 and Example 11 Step A using 2-(trifluoromethyl)cyclopropane-l -carboxylic acid in place of [l,l'-bi(cyclopropane)]-2-carboxylic acid, and the reaction was stirred at rt for 15 h instead of 2 h. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to provide Intermediate 9 (the cis cyclopropyl isomers) as the first eluting peak (63% yield) and Intermediate 10 (the trans cyclopropyl isomers) as the second eluting peak (24% yield). Intermediate 9: MS (ESI) m / z: [M+H]+Found 654.2. Intermediate 10: MS (ESI) m / z: [M+H]+Found 654.2.

[0671] Intermediate 11: (35,55)-3-((2 / 7-l,2,3-Triazol-2-yl)methyl)-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidin- 2-one

[0672]

[0673] Step A: / r / -Butyl (35,55)-3-((27 / -l,2,3-triazol-2-yl)methyl)-3-((2-((5)-((terL butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. A solution of tert-butyl (55)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (300 mg, 0.47 mmol, Intermediate 3) and 2- (chloromethyl)-277-l,2,3-triazole (129 mg, 1.04 mmol) in anhydrous toluene (1.58 mL) was cooled to 0 °C in an ice- water bath. Then, KOtBu (1.09 mL, 1 mmol, 1 M in THF) was added dropwise over 2 min. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of a solution of AcOH (30 pL) in THF (0.47 mL). The mixture was partitioned between water (10 mL), saturated aqueous NaHCCh (5 mL) and EtOAc (10 mL). The aqueous layer was further extracted with EtOAc (2 x 10 mL). Then the organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated to provide the title compound as an orange oil (100% yield), which was used without further purification. MS (ESI) m / z: [M+H]+Found 613.3.

[0674] Step B: (35,55)-3-((27 / -l,2,3-Triazol-2-yl)methyl)-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidin- 2-one. To a solution of tert-butyl (35,55)-3-((27 / -l,2,3-triazol-2-yl)methyl)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifhroromethyl)pyrrolidine-l -carboxylate (292 mg, 0.48 mmol, Step A) in anhydrous DCM (4.76 mL) was added TFA (1.59 mL, 0.48 mmol) in one portion. The resulting mixture was stirred at rt for 2 h then concentrated. The residue was dissolved in MeOH and DMSO and purified directly by preparative HPLC (XBridge OBD Cl 8, 5 pm, 100 x 50 mm, 10-100% ACN / H2O (with 10 mM NH4OH)) to provide a mixture of diastereomers in 52% yield. The diastereomers were separated by chiral SFC (Chiralpak IH, 5 pm, 250 x 30 mm, 20% methanol with 0.2% NH4OH, 80% CO2). The first eluting peak (49% yield) was the title compound. MS (ESI) m / z: [M+H]+Found 513.3. Intermediate 12: 4,4-Difluorospiro[2.2]pentane-l-carboxylic acid

[0675] Step A: 2,2,2-Triphenyl-3-oxa-2X5-phosphabicyclo[3.1.0]hexane. A flask containing a mixture of methyltriphenylphosphonium iodide (87.30 g, 215.4 mmol) and / BuOK (24.30 g, 216.6 mmol) in toluene (364 mL) was evacuated and backfilled with N2 three times, then heated to 120 °C and stirred for 5 min. Then, a solution of 2-(chloromethyl)oxirane (10.00 g, 108.1 mmol) in toluene (22 mL) was added dropwise over 10 min. The resulting mixture was stirred at 120 °C for 30 min, then it was removed from the heat and placed in an ice- water bath until the mixture reached rt. The reaction mixture was filtered and the filtrate concentrated to dryness to afford a light-yellow oil. The oil was purified by recrystallization with ACN (50 mL) to provide the title compound as a white solid (70% yield). MS (ESI) m / z: [M+H]+Found 333.1.

[0676] Step B: (2-Methylenecyclopropyl)methanol. A flask containing 2,2,2-triphenyl-3-oxa- 2X5-phosphabicyclo[3.1.0]hexane (25.30 g, 76.10 mmol, Step A), paraformaldehyde (4.57 g, 152 mmol) and tetrahydrothiophene 1,1 -dioxide (12.6 mL) was evacuated and backfilled with N2 three times, then heated to 100 °C for 45 min. The reaction mixture was removed from the heat and placed in an ice-water bath until the mixture reached rt. The reaction mixture was then distilled in vacuo. The fraction with bp 65-67 °C / 2 mmHg was collected to provide the title compound as a colorless oil (42% yield). 'H NMR (300 MHz, CDCh) 8 5.50 - 5.47 (m, 1H), 5.45 - 5.42 (m, 1H), 3.65 - 3.60 (m, 1H), 3.53 - 3.47 (m, 1H), 1.85 - 1.75 (m, 1H), 1.36 - 1.29 (m, 1H), 1.00 - 1.94 (m, 1H).

[0677] Step C: ((4,4-Difluorospiro[2.2]pentan-l-yl)methoxy)trimethylsilane. A mixture of (2- methylenecyclopropyl)methanol (3.40 g, 40.4 mmol, Step B), Nal (6.00 g, 40.0 mmol) and TMSCF3 (90.00 g, 633.0 mmol) in THF (150 mL) in a high-pressure autoclave was heated to 60 °C and stirred at that temperature for 16 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated to dryness to afford a light-yellow oil. The oil was dissolved in DCM (150 mL), the remaining solid was filtered off, and the filtrate was concentrated to dryness in vacuo to provide the title compound as a light-yellow oil (67% yield). 'H NMR (300 MHz, CDCh) 8 3.70 - 3.50 (m, 2H), 1.79 - 1.55 (m, 3H), 1.40 - 1.28 (m, 1H), 1.02 - 0.94 (m, 1H), 0.14 (s, 9H).

[0678] Step D: (4,4-Difluorospiro[2.2]pentan-l-yl)methanol. A solution of ((4,4- difluorospiro[2.2]pentan-l-yl)methoxy)trimethylsilane (5.60 g, 27.1 mmol, Step C) in THF (54 mL) was cooled to 0 °C in an ice- water bath. Then, HC1 (7.0 mL, 3.5 mmol, 0.5 M in water) was added dropwise over 10 min. The resulting mixture was stirred at 0 °C for 3 h, then the reaction was placed in a warm-water bath until it reached rt. The mixture was diluted with water (27 mL) and extracted with diethyl ether (2 x 27 mL). The combined organic layers were washed with brine (27 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford yellow oil. The oil was distilled in vacuo. The fraction with bp 32-34 °C / 1 mmHg was collected to provide the title compound as a light-yellow oil (98% yield).1H NMR (300 MHz, CDCh) 8 3.71 - 3.59 (m, 2H), 1.81 - 1.66 (m, 2H), 1.62 - 1.56 (m, 1H), 1.38 - 1.31 (m, 1H), 1.02 - 0.94 (m, 1H).

[0679] Step E: 4,4-Difluorospiro[2.2]pentane-l -carboxylic acid. A mixture of (4,4- difluorospiro[2.2]pentan -l-yl)methanol (3.28 g, 24.5 mmol, Step D), RuCh*H2O (56.0 mg, 0.0370 mmol) and NalCh (13.21 g, 61.18 mmol) in MeCN (33.0 mL) and H2O (33.0 mL) was stirred at rt for 3 h. After that time, the reaction mixture was filtered and the filter cake rinsed with EtOAc (24 mL). The filtrate was separated and the aqueous layer further extracted with EtOAc (2 x 24 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford the title compound (77% yield) as an off-white solid which was used without further purification. 'H NMR (300 MHz, CDCh) 8 11.56 (br s, 1H), 2.33 - 2.29 (m, 1H), 191 - 1.83 (m, 1H), 1.81 - 1.76 (m, 1H),1.75 - 1.72 (m, 2H).

[0680] Intermediate 13: (3R,5S)-3-((2-((S)-(4-Cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylic acid

[0681]

[0682] To a solution of ethyl (37?,55)-3-((2-((5)-(4-cyclopropyl-l,2,5-oxadiazole-3- carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate (325 mg, 0.508 mmol, Intermediate 15) dissolved in 4.5 mL of THF:H2O (8: 1) was added LiOH (48.7 mg, 2.03 mmol) and the resulting mixture was stirred at rt for 30 min. Then, the reaction was concentrated under reduced pressure and was azeotroped with ACN (3x). The residue was purified by preparative HPLC (XBridge Prep Cl 8, 5 pm, 50 x 100 mm, 10-100% acetonitrile / water (with 20 mM NH4OH)) to provide the title compound as a white solid (84% yield). MS (ESI) m / z: [M+H]+Pound 611.9.

[0683] Intermediate 14: 4-(l,l-Difluoroethyl)-l,2,5-oxadiazole-3-carboxylic acid

[0684] Step A: Ethyl 4,4-difluoro-2-(hydroxyimino)-3-oxopentanoate. A mixture of sodium nitrite (3.84 g, 55.7 mmol) and water (36.5 mL) was cooled to 0 °C in an ice- water bath, then a solution of ethyl 4,4-difluoro-3-oxopentanoate (5.02 g, 27.9 mmol) in acetic acid (18.3 mL) was added dropwise over 10 min. The reaction mixture was warmed to rt and then stirred at rt for 5 h. The mixture was diluted with water (100 mL) and extracted with Et2O (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCCh (3 x 100 mL) followed by brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to provide the title compound (86% yield) as a yellow oil, which was used without further purification. MS (ESI) m / z: [M+H]+Eound 209.9.

[0685] Step B: Ethyl 4,4-difluoro-2,3-bis(hydroxyimino)pentanoate. A mixture of ethyl 4,4- difluoro-2-(hydroxyimino)-3-oxopentanoate (3.00 g, 14.3 mmol, Step A) and hydroxylamine hydrochloride (3.00 g, 43.2 mmol) in EtOH (50 mL) was cooled to 0 °C in an ice- water bath. Then, NaOAc (2.36 g, 28.8 mmol) was added, and the mixture was warmed to rt over 10 min. The reaction was then heated to 50 °C for 5 h. The mixture was filtered and the filtrate extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a pink oil. The oil was purified by silica gel chromatography (20-40% EtOAc / petroleum ether) to provide the title compound as a yellow-pink oil (8% yield). MS (ESI) m / z: [M+H]+Found 225.1.

[0686] Step C: Ethyl 4-(l,l-difluoroethyl)-l,2,5-oxadiazole-3-carboxylate. A flask containing a solution of ethyl 4,4-difluoro-2,3-bis(hydroxyimino)pentanoate (500 mg, 2.23 mmol, Step B) in THF (10 mL) was evacuated and backfilled with N2. Then, the mixture was cooled to 0 °C in an ice- water bath, and CDI (542 mg, 3.34 mmol) was added. The ice- water bath was removed, and the reaction was heated at 35 °C for 15 h. The mixture was cooled to rt and concentrated to dryness to afford brown oil. The oil was purified by silica gel chromatography (0-5% THF / petroleum ether) to provide the title compound as a yellow oil (8% yield). 'H NMR (400 MHz, CDCh) 5 4.54 - 4.49 (m, 2H), 2.25 - 2.14 (m, 3H), 1.46 - 1.43 (m, 3H).

[0687] Step D: 4-(l,l-Difluoroethyl)-l,2,5-oxadiazole-3-carboxylic acid. A mixture of ethyl 4- (l,l-difluoroethyl)-l,2,5-oxadiazole-3-carboxylate (100 mg, 0.49 mmol, Step C), LiOH (61.1 mg, 2.55 mmol), EtOH (1 mL) and water (0.5 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to remove the EtOH, then the pH of the aqueous layer was adjusted to -pH 2 by the addition of 2 N aqueous HC1 (~2 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to provide the title compound as a yellow oil (57% yield), which was used without further purification. MS (ESI) m / z: [2M-H]+Found 355.0.

[0688] Intermediate 15: Ethyl (3A,55)-3-((2-((5)-(4-cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate

[0689]

[0690] Step A: l -( / c / 7-Butyl) 3-ethyl (3A,5S)-3-((2-((S)-((terLbutoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l,3-dicarboxylate. A flask containing a solution of tert-butyl (55)-3- ((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin- 7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate (2.00 g, 3.17 mmol, Intermediate 3) in THF (30 mL) was evacuated and refilled with N2 three times and then cooled to -78 °C in a dry-ice / EtOH bath. Then, LiHMDS (5.0 mL, 6.5 mmol, 1.3 M in THF) was added dropwise over 25 min, and the resulting mixture was stirred at -78 °C for 30 min. A solution of ethyl carbonocyanidate (345 mg, 3.48 mmol) in THF (2 mL) was added dropwise over 15 min, and the mixture was stirred at -78 °C for 1 h. A saturated aqueous NH4Q solution (30 mL) was then added dropwise over 10 min, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford yellow oil. The oil was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound (63% yield) as a yellow solid. MS (ESI) m / z: [M+H]+Found 704.0.

[0691] Step B: Ethyl (37?,55)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate hydrochloride. The title compound (97% yield) was prepared as described for the synthesis of Examples 182 and 183 Step B using 1 -(tert- butyl) 3-ethyl (3A,55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine- 1,3 -di carboxylate (Step A) in place of ethyl 2-((3S,5S)-3-((2-((S)- (( / / 7-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7- yl)methyl)-2-oxo-5-(trifhioromethyl)pyrrolidin-3-yl)-2-methylpropanoate. MS (ESI) m / z: [M+H]+Found 504.2. Step C: Ethyl (37?,55)-3-((2-((5)-(4-cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3 -carboxylate. The title compound (66% yield) was prepared as described for the synthesis of Example 8 Step A using ethyl (37?,5S)-3-((2-((S)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate hydrochloride (Step B) in place of ethyl 2- (3S,5S)-3- ((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate. MS (ESI) m / z: [M+H]+Found 640.3.

[0692] Intermediate 16: tert-Butyl (S)-(l-(7-(bromomethyl)imidazo[l,2- / >]pyridazin-2-yl)-5,5,5- trifluoro-4,4-dimethylpentyl)carbamate

[0693] The title compound (30% yield) was prepared as described for the synthesis of Intermediate 1 using tert-butyl (5)-(5,5,5-trifluoro-l-(7-formylimidazo[l,2- / >]pyridazin-2-yl)-4,4- dimethylpentyl)carbamate in place of tert-butyl (5)-((4,4-difluorocyclohexyl)(7- formylimidazof l ,2- / ?]pyridazin-2-yl)methyl)carbamate. MS (ESI) m / z: [M+H]+Found 479.2 (Br splitting).

[0694] Intermediate 17: tert-Butyl (5S)-3-((2-((S)-l-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4- dimethylpentyl)imidazo[l,2-Z>]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l- The title compound (42% yield) was prepared as described for the synthesis of Intermediate 3 using tert-butyl (S)-(l-(7-(bromomethyl)imidazo[l,2- / >]pyridazin-2-yl)-5,5,5-trifluoro-4,4- dimethylpentyl)carbamate (Intermediate 16) in place of tert-butyl (5)-((7- (bromomethyl)imidazo[ l ,2- / ?]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. MS (ESI) m / z: [M+H]+Found 652.3.

[0695] Intermediate 18: Ethyl 2-((35,55)-3-((2-((5)-l-amino-5,5,5-trifluoro-4,4- dimethylpentyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)acetate

[0696] The title compound (90% yield) was prepared as described for the synthesis of Intermediate 7 using tert-butyl (5S)-3-((2-((S)-l-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4- dimethylpentyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l- carboxylate (Intermediate 17) in place of tert-butyl (55)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifhioromethyl)pyrrolidine-l -carboxylate in Step A and in Step B, trifluoracetic acid in place of 4 M HC1 in 1,4-dioxane. MS (ESI) m / z: [M+H]+Found 538.2.

[0697] EXAMPLES

[0698] Example 1 : 4-Cyclopropyl-7V-((5)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-3-(pyrimidin-2- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide

[0699]

[0700] Step A: / / 7-Butyl ((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-3-(pyrimidin-2-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)carbamate.To a suspension of tert-butyl (55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (31.6 mg, 0.05 mmol, Intermediate 3) in toluene (0.5 mb) was added 2-bromopyrimidine (11.9 mg, 0.075 mmol), followed by potassium tert-butoxide (16.8 mg, 0.15 mmol). The resulting mixture was heated to 100 °C and stirred at this temperature for 2 h. The reaction was then cooled to rt and concentrated to dryness to provide a mixture of isomers where the title compound was the major isomer. This mixture of isomers was used without further purification. MS (ESI) m / z: [M+H]+Found 610.3.

[0701] Step B: (3 ,5S -3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-3-(pyrimidin-2-yl)-5-(trifluoromethyl)pyrrolidin-2-one. A solution of tert-butyl ((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrimidin-2-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)carbamate (30 mg, 0.05 mmol, Step A) in dichloromethane (0.5 m ) was cooled to 0 °C, then trifluoroacetic acid (0.25 mL, 0.22 M) was added dropwise and the resulting mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated and azeotroped with toluene (2 x 5 mL). To the resulting residue was added EtOAc (2 mL) and saturated aqueous NaHCCh (2 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was dried under a high vacuum and used without further purification. This residue was a mixture of isomers where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 510.2.

[0702] Step C: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrimidin- 2-yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)- l ,2,5- oxadiazole-3-carboxamide. To a solution of (35,55)-3-((2-((8)-amino(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(pyrimidin-2-yl)-5- (trifluoromethyl)pyrrolidin-2-one (25 mg, 0.05 mmol, Step B) in DMF (0.5 mL) was added 1- methylimidazole (40 pL, 0.50 mmol) dropwise at rt. To the resulting mixture, 4-cyclopropyl- l,2,5-oxadiazole-3-carboxylic acid (13 mg, 0.09 mmol) and TCFH (19 mg, 0.07 mmol) were added, and the reaction was allowed to stir at rt for 16 h. The reaction was diluted with H2O (5 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous MgSO-i, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% EtOAc / hexanes, then 0-5% MeOH / EtOAc) to provide a mixture of diastereomers (90: 10 dr) in 65% yield. The diastereomers were separated by chiral SFC (Stationary phase: Chiralpak Whelk 01 SS, 5 pm, 250 x 21 mm, Mobile phase: 30% methanol with 0.2% diethylamine, 70% CO2). The second eluting peak (32% yield) was the title compound.JH NMR (500 MHz, MeOH-<L) 8 8.82 (d, J= 4.9 Hz, 1H), 8.38 (d, J= 2.1 Hz, 1H), 8.09 (s, 1H), 7.82 (d, J= 2.0 Hz, 1H), 7.40 (t, J = 4.9 Hz, 1H), 5.25 (d, J= 8.6 Hz, 1H), 4.54 - 4.46 (m, 1H), 3.69 (s, 2H), 2.98 (dd, J= 13.6, 8.0 Hz, 1H), 2.42 - 2.32 (m, 2H), 2.27 - 2.18 (m, 1H), 2.17 - 1.96 (m, 3H), 1.89 - 1.65 (m, 2H), 1.62 - 1.59 (m, 1H), 1.52 - 1.46 (m, 1H), 1.44 - 1.36 (m, 1H), 1.19 - 1.15 (m, 3H), 1.14 - 1.07 (m, 2H), 1.06 - 0.96 (m, 2H). MS (ESI) m / z: [M+H]+Found 646.2.

[0703] Example 2: 4-Cyclopropyl-A-((8)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrazin-2-yl)- 5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imi dazo[l,2- / >]pyridazin-2-yl)methyl)- 1,2,5- oxadiazole-3 -carboxamide

[0704] Step A: tert-Butyl ((8)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrazin-2-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)carbamate. To a suspension of tert-butyl (58)-3-((2-((8)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (94.7 mg, 0.15 mmol, Intermediate 3) in toluene (1.5 mL) was added 2-bromopyrazine (20 pL, 0.225 mmol), followed by potassium terZ-butoxide (50.4 mg, 0.45 mmol). The resulting mixture was heated to 100 °C and stirred at this temperature for 2 h. The reaction was then cooled to rt and concentrated to dryness to provide a mixture of isomers where the title compound was the major isomer. This mixture of isomers was used without further purification. MS (ESI) m / z: [M+H]+Found 610.3.

[0705] Step B: (35,55)-3-((2-((5)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-3-(pyrazin-2-yl)-5-(trifluoromethyl)pyrrolidin-2-one. A solution of tert-butyl ((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrazin-2-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)carbamate (55 mg, 0.09 mmol, Step A) in dichloromethane (0.9 mL) was cooled to 0 °C, then trifluoroacetic acid (0.4 mL, 0.22 M) was added dropwise and the resulting mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated and azeotroped with toluene (2 x 5 mL). To the resulting residue were added EtOAc (2 mL) and saturated aqueous NaHCCh (2 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was dried under high vacuum and used without further purification. This residue was a mixture of isomers where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 510.2.

[0706] Step C: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyrazin-2- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3-carboxamide. To a solution of (55)-3-((2-((5)-amino(4,4- difhjorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(pyrazin-2-yl)-5- (trifluor omethyl)pyrrolidin-2-one (46 mg, 0.09 mmol, Step B) in DMF (0.9 mL) was added 1- methylimidazole (72 pL, 0.90 mmol) dropwise at rt. To the resulting mixture, 4-cyclopropyl- l,2,5-oxadiazole-3-carboxylic acid (24 mg, 0.156 mmol) and TCFH (34 mg, 0.125 mmol) were added, and the reaction was allowed to stir at rt for 16 h. The reaction was diluted with FEO (5 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% EtOAc / hexanes, then 0-5% MeOH / EtOAc) to provide a mixture of diastereomers (90: 10 dr) in 94% yield. The diastereomers were separated by chiral SFC (Stationary phase: Chiralpak IC, 5 pm, 250 x 21 mm, Mobile phase: 30% methanol with 0.2% diethylamine, 70% CO2). The second eluting peak (24% yield over three steps) was the title compound.JH NMR (500 MHz, MeOH- d4) 8 8.96 (s, 1H), 8.64 (t, J= 2.0 Hz, 1H), 8.56 (d, J= 2.6 Hz, 1H), 8.25 (d, J= 2.0 Hz, 1H), 8.10 (s, 1H), 7.73 (d, J= 2.0 Hz, 1H), 5.26 (d, J= 8.5 Hz, 1H), 4.33 - 4.26 (m, 1H), 3.66 (d, J = 14.1 Hz, 1H), 3.48 (d, J= 14.2 Hz, 1H), 3.25 (dd, J= 13.8, 7.9 Hz, 1H), 2.43 - 2.30 (m, 2H), 2.26 - 2.18 (m, 1H), 2.15 - 1.95 (m, 4H), 1.89 - 1.68 (m, 2H), 1.63 (d, J= 13.4 Hz, 1H), 1.53 - 1.37 (m, 2H), 1.15 - 1.10 (m, 3H), 1.03 - 0.99 (m, 2H). MS (ESI) m / z: [M+H]+Found 646.2.

[0707] Example 3: 4-Cyclopropyl-A-((8)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(6-methylpyrimidin-4- yl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l, 2- / ?]pyridazin-2-yl)methyl)- 1,2,5- oxadiazole-3 -carboxamide

[0708] Step A: / cr / -Butyl ((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-(6-methylpyrimidin-4-yl)- 2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)methyl)carbamate. To a suspension of tert-butyl (58)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifhroromethyl)pyrrolidine-l -carboxylate (158 mg, 0.25 mmol, Intermediate 3) in toluene (1.25 mL) was added 4-bromo-6-methylpyrimidine (74 mg, 0.425 mmol), followed by potassium tert-butoxide (84 mg, 0.75 mmol). The resulting mixture was heated to 100 °C and stirred at this temperature for 2 h. The reaction was then cooled to rt and concentrated to dryness to provide a mixture of isomers where the title compound was the major isomer. This mixture of isomers was used without further purification. MS (ESI) m / z: [M+H]+Found 624.0.

[0709] Step B: (35,58)-3-((2-((5)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-3-(6-methylpyrimidin-4-yl)-5-(trifluoromethyl)pyrrolidin-2-one. A solution of tert-butyl ((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-(6-methylpyrimidin-4-yl)-2- oxo-5-(trifhioromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)carbamate (102 mg, 0.16 mmol, Step A) in dichloromethane (1.6 mL) was cooled to 0 °C, then trifluoroacetic acid (0.74 mL, 0.22 M) was added drop wise and the resulting mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated and azeotroped with toluene (2 x 5 mL). To the resulting residue was added EtOAc (2 mL) and saturated aqueous NaHCCh (2 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was dried under a high vacuum and used without further purification. This residue was a mixture of isomers where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 524.3.

[0710] Step C: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(6- methylpyrimidin-4-yl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide. To a solution of (3 ,55)-3-((2-((5)- amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(6- methylpyrimidin-4-yl)-5-(trifluoromethyl)pyrrolidin-2-one (26 mg, 0.05 mmol, Step B) in DMF (0.5 mL) was added 1 -methylimidazole (40 pL, 0.50 mmol) dropwise at rt. To the resulting mixture, 4-cyclopropyl-l,2,5-oxadiazole-3-carboxylic acid (13 mg, 0.09 mmol) and TCFH (19 mg, 0.07 mmol) were added, and the reaction was allowed to stir at rt for 2 h. The reaction was diluted with FEO (5 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% EtOAc / hexanes, then 0-5% MeOH / EtOAc) to provide a mixture of diastereomers (90:10 dr) in 84% yield. The diastereomers were separated by chiral SFC (Stationary phase: Chiralcel OD-H, 5 pm, 250 x 21 mm, Mobile phase: 20% methanol with 0.2% diethylamine, 80% CO2). The first eluting peak (55% yield over three steps) was the title compound. 'H NMR (500 MHz, MeOH-A) 8 9.00 (d, J= 1.3 Hz, 1H), 8.27 (d, J= 2.1 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J= 1.9 Hz, 1H), 7.71 (d, J= 1.3 Hz, 1H), 5.26 (d, J= 8.5 Hz, 1H), 4.35 - 4.29 (m, 1H), 3.60 (dd, J= 14.1, 0.8 Hz, 1H), 3.41 (d, J= 14.1 Hz, 1H), 3.19 (dd, J= 13.8, 8.0 Hz, 1H), 2.56 (s, 3H), 2.43 - 2.36 (m, 1H), 2.29 (dd, J= 13.8, 7.6 Hz, 1H), 2.24 - 2.19 (m, 1H), 2.14 - 1.97 (m, 4H), 1.87 - 1.69 (m, 2H), 1.65 - 1.61 (m, 1H), 1.54 - 1.33 (m, 3H), 1.17 - 1.09 (m, 2H), 1.05 - 0.99 (m, 2H). MS (ESI) m / z: [M+H]+Found 660.3.

[0711] Example 4: 4-Cyclopropyl-7V-((5)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-3-((2- oxoimidazolidin-l-yl)methyl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-

[0712] / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0713] A mixture of A-((5)-(7-(((35,55)-3-(aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3-carboxamide (130 mg, 0.218 mmol, Intermediate 4), TEA (91 pL, 0.66 mmol) and 2-chloroethyl isocyanate (19 pL, 0.22 mmol) in THF (7 mL) was stirred at rt for 1 h. The mixture was then cooled to 0 °C in an ice- water bath and treated with NaH (24 mg, 0.60 mmol, 60% in mineral oil) portion-wise over 3 min. The resulting mixture was stirred at 0 °C for 1 h, then warmed to rt. The reaction was partitioned between saturated aqueous NH4Q (20 mL) and EtOAc (20 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a mixture of isomers as a white solid. The solid was purified by HPLC (Xselect CSH Fluoro-Phenyl, 5 pm, 250 x 19 mm, 25-55% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound as the major isomer which was a white solid (46% yield). 'H NMR (300 MHz, DMSO-t / e) 8 9.51 (br s, 1H), 8.81 (br s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.22 (s, 1H), 7.91 (d, J= 1.5 Hz, 1H), 6.55 (br s, 1H), 5.21 - 5.19 (m, 1H), 4.18 - 4.09 (m, 1H), 3.52 - 3.48 (m, 1H), 3.44 - 3.38 (m, 1H), 3.25 - 3.24 (m, 3H), 3.05 - 2.78 (m, 3H), 2.48 - 2.40 (m, 1H), 2.29 - 2.26 (m, 1H), 2.25 - 2.22 (m, 1H), 2.02 - 2.00 (m, 2H), 1.94 - 1.87 (m, 4H), 1.45 - 1.24 (m, 3H), 1.13 - 1.07 (m, 2H), 0.97 - 0.94 (m, 2H). MS (ESI) m / z: [M+H]+Found 666.2. Example 5: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-((2- oxooxazolidin-3-yl)methyl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-

[0714] 2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0715] Step A: 2-Chloroethyl (((35,55)-3-((2-((5)-(4-cyclopropyl-l,2,5-oxadiazole-3- carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)carbamate. A flask containing A-((5)-(7-(((3 , 55)-3- (aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l ,2, 5 -oxadiazole-3 -carboxamide (40 mg, 0.067 mmol, Intermediate 4) and TEA (28 pL, 0.2 mmol) in THF (4 mL) was evacuated and refilled with N2 three times. Then, a solution of 2-chloroethyl carbonochloridate (9.6 mg, 0.067 mmol) in THF (1 mL) was added and the resulting mixture was stirred at rt for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide a mixture of isomers as a yellow oil (50% yield), where the title compound was the major isomer. MS (ESI) m / z: [M+H]+Found 703.2.

[0716] Step B: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-((2- oxooxazolidin-3-yl)methyl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin- 2-yl)methyl)-l, 2, 5-oxadiazole-3 -carboxamide. A mixture of 2-chloroethyl (((3 ,55)-3-((2-((5)- (4-cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)carbamate (47 mg, 0.067 mmol, Step A) and NaH (8.0 mg, 0.20 mmol, 60% in mineral oil) in THF (2 mL) was heated at 50 °C for 2 h. The mixture was cooled to rt, poured into water (5 mL), and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford yellow oil. The oil was purified by preparative HPLC (XBridge OBD Cl 8, 5 pm, 150 x 30 mm, 27-57% ACN / H2O (with 10 mM NH4HCO3 and 0.05% NH3*H2O)) to provide the title compound as the major isomer which was a white solid (55% yield). 'H NMR (300 MHz, DMSO-t / e) 5 9.49 (br s, 1H), 8.86 (br s, 1H), 8.33 (d, J= 1.5 Hz, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 5.23 - 5.20 (m, 1H), 4.28 - 4.24 (m, 3H), 3.54 - 3.51 (m, 3H), 3.28 - 3.23 (m, 1H), 3.01 - 2.97 (m, 1H), 2.86 - 2.81 (m, 1H), 2.41 - 2.33 (m, 1H), 2.28 - 2.18 (m, 2H), 2.07 - 1.73 (m, 6H), 1.62 - 1.58 (m, 1H), 1.41 - 1.25 (m, 2H), 1.11 - 1.08 (m, 2H), 0.95 - 0.94 (m, 2H). MS (ESI) m / z: [M+H]+Found 667.2.

[0717] Example 6: 4-Cyclopropyl- V-((S)-(4,4-difluorocyclohexyl)(7-(((37?,5S)-2-oxo-3-(2- oxoimidazolidin-l-yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0718] Step A: A-((5)-(7-(((37?,55)-3-(3-(2-Chloroethyl)ureido)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide. To a mixture ofN- ((S -(7-(((37?,5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3- carboxamide (30.0 mg, 0.052 mmol, Intermediate 6) and TEA (22.5 L, 0.162 mmol) in THF (2 mL) was added 2-chloroethyl isocyanate (5.4 mg, 0.051 mmol). The resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (10 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound as the major isomer, which was a white solid (56% yield) that was used without further purification. MS (ESI) m / z: [M+H]+Found 688.2.

[0719] Step B: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((3A,55)-2-oxo-3-(2- oxoimidazolidin-l-yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide. A mixture of A-((S)-(7-(((37?,5S)-3-(3-(2- chloroethyl)ureido)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l ,2, 5 -oxadiazole-3 -carboxamide (20 mg, 0.029 mmol, Step A) and NaH (4.0 mg, 0.10 mmol, 60% in mineral oil) in THF (2 mL) was heated at 50 °C for 1 h. The reaction mixture was quenched by the addition of ice water (10 mL), then extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO-i, filtered, and concentrated to dryness to afford a white solid. The solid was purified by preparative HPLC (XSelect CSH Prep Fluoro-Phenyl, 5 pm, 250 x 19 mm, 27-47% ACN / H2O (with 0.1% FA)) to provide the title compound as the major isomer which was a white solid (64% yield). NMR (300 MHz, DMSO-t / e) 5 9.51 (br s, 1H), 8.94 (br s, 1H), 8.34 (d, J= 1.8 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J= 1.2 Hz, 1H), 6.73 (br s, 1H) 5.23- 5.17 (m, 1H), 4.39 - 4.13 (m, 1H), 3.54 - 3.44 (m, 2H), 3.33 - 3.22 (m, 3H), 2.84 - 2.75 (m, 1H), 2.32- 2.21 (m, 1H), 2.20 - 2.07 (m, 2H), 2.06 - 1.93 (m, 2H), 1.92 - 1.82 (m, 2H), 1.81 - 1.67 (m, 1H), 1.65 - 1.53 (m, 1H), 1.51 - 1.38 (m, 3H), 1.12 - 1.07 (m, 2H), 0.98- 0.94 (m, 2H). MS (ESI) m / z: [M+H]+Found 652.3.

[0720] Example 7: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((3A,55)-2-oxo-3-(2- oxooxazolidin-3-yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0721] Step A: 2-Chloroethyl ((3A,55)-3-((2-((5)-(4-cyclopropyl-l,2,5-oxadiazole-3- carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)carbamate. The title compound (66% yield), where the title compound was the major isomer, was prepared as described for the synthesis of Example 5 Step A using A-((S)-(7-(((3A, 5S)-3 -amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide (Intermediate 6) in place ofA-((5)-(7-(((35,55)-3-(aminomethyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide. MS (ESI) m / z: [M+H]+Found 689.2. Step B: 4-Cyclopropyl- / V-(CS')-(4,4-difluorocyclohexyl)(7-(((3 / ?,56')-2-oxo-3-(2- oxooxazolidin-3-yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide. The title compound was prepared as described for the synthesis of Example 6 Step B using 2-chloroethyl ((3A,55)-3-((2-((5)-(4-cyclopropyl-l,2,5- oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7- yl)methyl)-2-oxo-5-(trifhjoromethyl)pyrrolidin-3-yl)carbamate (Step A) in place of 7V-((S)-(7- (((37?,55)-3-(3-(2-chloroethyl)ureido)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3 -carboxamide. The residue was purified by preparative HPLC (XSelect CSH Phenyl-Hexyl, 5 pm, 250 x 19 mm, 40-65% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (49% yield). (400 MHz, DMSO-t / e) 5 9.52 (br s, 1H), 9.18 (br s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 5.23 - 5.18 (m, 1H), 4.32 - 4.30 (m, 3H), 3.77 - 3.68 (m, 2H), 3.28 (br s, 2H), 2.92 - 2.86 (m, 1H), 2.28 - 2.17 (m, 3H), 2.08 - 2.01 (m, 2H), 1.87 - 1.75 (m, 3H), 1.62 - 1.59 (m, 1H), 1.43 - 1.23 (m, 2H), 1.11 - 1.09 (m, 2H), 0.96 - 0.95 (m, 2H). MS (ESI) m / z: [M+H]+Found 653.2.

[0722] Example 8: A-((5)-(7-(((35,55)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide

[0723] Step A: Ethyl 2-((35,5S)-3-((2-((S)-(4-cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate. To a mixture of ethyl 2-((35,55)-3-((2-((5)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (408 mg, 0.79 mmol, Intermediate 7), 4-cyclopropyl- l,2,5-oxadiazole-3-carboxylic acid (146 mg, 0.95 mmol), HOBt (213 mg, 1.58 mmol) and EDCI (453 mg, 2.37 mmol) in DCM (5 mL) was added NMM (0.44 mL, 3.94 mmol) dropwise over 2 min. The resulting mixture was stirred at rt for 3 h. Then, water (20 mL) was added, and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a yellow solid. The solid was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound, which was the major isomer, as a yellow solid (18% yield). MS (ESI) m / z: [M+H]+Found 654.2.

[0724] Step B: 4-Cyclopropyl- / V-(fS')-(4,4-difluorocyclohexyl)(7-(((35',55')-3-(2-hydrazineyl-2- oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide. A mixture of ethyl 2-((35,55)-3-((2-((5)-(4- cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate (82 mg, 0.13 mmol, Step A) and hydrazine hydrate (300 mg, 5.09 mmol, 85%) in EtOH (5 mL) was heated at 70 °C for 20 h. The mixture was cooled to rt and purified directly by preparative HPLC (5-95% ACN / water (with 0.05% TFA)) to provide the title compound, which was the major isomer, as a white solid (97% yield). MS (ESI) m / z: [M+H]+Found 640.3.

[0725] Step C: A-((S)-(7-(((35,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide. A mixture of 4- cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole- 3-carboxamide (96 mg, 0.15 mmol, Step B) and >-TsOH (11 mg, 0.058 mmol) in trimethoxymethane (98 pL, 0.89 mmol) was heated at 120 °C for 2 h. The reaction was cooled to rt, water (10 mL) was added, and the mixture extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a white solid. The solid was purified by preparative HPLC (XBridge BEH Shield RP18, 5 pm, 250 x 19 mm, 46-76% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (12% yield). 'H NMR (300 MHz, DMSO- e) 8 9.51 (br s, 1H), 9.22 (br s, 1H), 8.87 (s, 1H), 8.35 (d, J= 2.1 Hz, 1H), 8.23 (s, 1H), 7.94 (d, J= 1.5 Hz, 1H), 5.21 - 5.18 (m, 1H), 4.23 - 4.16 (m, 1H), 3.29 - 3.22 (m, 2H), 3.10 - 2.92 (m, 2H), 2.47 - 2.42 (m, 1H), 2.29 - 2.24 (m, 2H), 2.08 - 1.85 (m, 7H), 1.24 - 1.14 (m, 2H), 1.12 - 1.07 (m, 2H), 0.98 - 0.95 (m, 2H). MS (ESI) m / z: [M+H]+Found 650.2.

[0726] Example 9: Cyclopropyl ((5)-(7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate

[0727] Step A: Ethyl 2-((35,55)-3-((2-((5)-((cyclopropoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate. To a mixture of ethyl 2-((35,55)-3-((2-((5)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (130 mg, 0.25 mmol, Intermediate 7) in DCM (5 mL) were added cyclopropyl carbonochloridate (45.3 mg, 0.375 mmol) and NMM (83 pL, 0.75 mmol). The resulting mixture was stirred at rt for 2 h. The reaction was poured over water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a colorless oil. The oil was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to provide the title compound, which was the major isomer, as a white solid (53% yield). MS (ESI) m / z: [M+H]+Found 602.2.

[0728] Step B: Cyclopropyl ((S)-(4,4-difhrorocyclohexyl)(7-(((35,5S)-3-(2-hydrazineyl-2- oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-exyl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)methyl)carbamate. The title compound was prepared as described for the synthesis of Example 8 Step B using ethyl 2-((35,55)-3-((2-((5)-((cyclopropoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (Step A) in place of ethyl 2-((35,55)-3-((2-((5)-(4- cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate. The reaction was purified by preparative HPLC (XBridge Prep OBD Cl 8, 5 pm, 150 x 30 mm, 20-40% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (77% yield). MS (ESI) m / z: [M+H]+Found 588.2.

[0729] Step C: Cyclopropyl ((5)-(7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate. A mixture of cyclopropyl ((5')-(4,4-difluorocyclohexyl)(7- (((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)carbamate (50 mg, 0.085 mmol, Step B) and p- TsOH (2.0 mg, 0.011 mmol) in trimethoxymethane (14 pL, 0.13 mmol) was heated at 70 °C for 16 h. The reaction mixture was concentrated to dryness and the residue was purified by preparative HPLC (XBridge BEH Shield RP18, 5 pm, 250 x 19 mm, 25-55% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (21% yield). 'H NMR (400 MHz, DMSO ) 5 9.21 (br s, 1H), 8.86 (s, 1H), 8.32 (d, J= 2.0 Hz, 1H), 8.06 (s, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.64 (br s, 1H), 4.72 - 4.69 (m, 1H), 4.20 - 4.18 (m, 1H), 3.96 - 3.93 (m, 1H), 3.24 - 3.22 (m, 2H), 3.08 - 3.05 (m, 1H), 2.95 - 2.91 (m, 1H), 2.45- 2.40 (m, 1H), 2.06 - 1.97 (m, 4H), 1.83 - 1.76 (m, 3H), 1.70 - 1.67 (m, 1H), 1.58 - 1.55 (m, 1H), 1.34 - 1.30 (m, 1H), 0.62 - 0.54 (m, 4H). MS (ESI) m / z: [M+H]+Found 598.2.

[0730] Example 10: cA-(lA*,2A*)-A-((5)-(7-(((35,55)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-[l,l'-bi(cyclopropane)]-2-carboxamide and cA-(1 *,2 *)-A-((5)-(7- (((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-[l,r- bi(cyclopropane)]-2-carboxamide Example 11 : tra«s-(15*,2A*)-A-((S)-(7-(((35,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-[l,l'-bi(cyclopropane)]-2-carboxamide and trans-(lR* ,2S*)-N-((S)- (7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-[l,l'- bi(cyclopropane)]-2-carboxamide

[0731] Step A: Ethyl 2-((35,55)-3-((2-((15)-([l,l'-bi(cyclopropane)]-2-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate. A mixture of ethyl 2-((35,55)-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (300 mg, 0.58 mmol, Intermediate 7), [1,1'- bi(cyclopropane)]-2-carboxylic acid (110 mg, 0.87 mmol), HATU (265 mg, 0.7 mmol) and DIPEA (0.3 mL, 1.74 mmol) in DCM (10 mL) was stirred at rt for 2 h. The reaction mixture was poured over water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a colorless oil. The oil was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to provide the title compound, which was the major isomer, as a white solid (78% yield). MS (ESI) m / z: [M+H]+Found 626.3.

[0732] Step B: A-((S)-(4,4-Difluorocyclohexyl)(7-(((35,5S)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo- 5-(trifhioromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-[l,l'- bi(cyclopropane)]-2-carboxamide. The title compound was prepared as described for the synthesis of Example 8 Step B using ethyl 2-((35,5S)-3-((2-((lS)-([l,l'-bi(cyclopropane)]-2- carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (Step A) in place of ethyl 2-((35,55)-3-((2-((5)-(4- cyclopropyl-l,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate. The reaction was purified by preparative HPLC (XBridge Prep OBD Cl 8, 5 pm, 150 x 30 mm, 20-40% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (79% yield). MS (ESI) m / z: [M+H]+Found 612.3.

[0733] Step C: cA-(17?*,27?*)-A-((5)-(7-(((35,55)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-Z>]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-[l,r-bi(cyclopropane)]-2-carboxamide and cis-(lS* ,25*)-7V-((5)-(7- (((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-[l,r- bi(cyclopropane)]-2-carboxamide and / rart.s-(LS'*,2 / ?*)-A-((5)-(7-(((3 ,55)-3-(( l ,3,4-oxadiazol-2- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-[l,l'-bi(cyclopropane)]-2-carboxamide and trans-(lR* ,2S*)-N-((S)- (7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-[l,r- bi(cyclopropane)]-2-carboxamide. The four title compounds were prepared as described for the synthesis of Example 9 Step C using A-((5)-(4, 4-difhiorocyclohexyl)(7-(((35, 55)-3-(2- hydrazineyl-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / ?]pyridazin-2-yl)methyl)-[ l , l '-bi(cyclopropane)]-2-carboxamide (Step B) in place of cyclopropyl ((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)carbamate. The reaction was purified and the two cA-bi(cyclopropane) diastereomers were separated from the two / raw.s-bi(cyclopropane) diastereomers by preparative HPLC (CHIRALPAK IA, 5 pm, 25 x 2 cm, 30% isocratic EtOH / hexanes (with 0.5% 2 M NH3 in MeOH)).

[0734] The first-eluting peak (12% yield) provided the two c / .s-bi (cyclopropane) diastereomers: a mixture of the cis-(lR* ,27?*) and cis-(lS* ,25*) isomers (Example 10). Example 10: 'H NMR (400 MHz, DMSO-t / e) 5 9.21 (s, 1H), 8.87 (s, 1H), 8.39 (br s, 1H), 8.32 (d, J= 2.0 Hz, 1H), 8.06 (s, 1H), 7.88 (d, J= 1.2 Hz, 1H), 4.96 - 4.92 (m, 1H), 4.17 - 4.08 (m, 1H), 3.22 - 3.17 (m, 2H), 3.05 - 2.95 (m, 1H), 2.88 - 2.85 (m, 1H), 2.39 - 2.33 (m, 1H), 2.06 - 1.94 (m, 4H), 1.67 - 1.64 (m, 2H), 1.58 - 1.53 (m, 2H), 1.34 - 1.21 (m, 2H), 1.15 - 1.10 (m, 2H), 0.87 - 0.74 (m, 2H), 0.73 - 0.72 (m, 1H), 0.38 - 0.34 (m, 2H), 0.09 - 0.07 (m, 2H). MS (ESI) m / z: [M+H]+Found 622.3. The second-eluting peak (10% yield) provided the two / raw .s-bi (cyclopropane) diastereomers: a mixture of the trans-(lS* ,2R*) and trans-(lR* ,2S*) isomers (Example 11). Example 11:

[0735] NMR (400 MHz, DMSO-t / e) 5 9.20 (s, 1H), 8.85 (s, 1H), 8.39 (br s, 1H), 8.30 (d, J= 2.0 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J= 1.6 Hz, 1H), 5.02 - 4.98 (m, 1H), 4.21 - 4.14 (m, 1H), 3.22 - 3.20 (m, 2H), 3.07 - 3.03 (m, 1H), 2.93 - 2.90 (m, 1H), 2.43 - 2.37 (m, 1H), 2.04 - 1.96 (m, 4H), 1.69 - 1.66 (m, 2H), 1.56 - 1.53 (m, 2H), 1.26 - 1.21 (m, 2H), 1.17 - 1.13 (m, 2H), 0.83 - 0.75 (m, 3H), 0.32 - 0.28 (m, 2H), 0.02 - 0.01 (m, 2H). MS (ESI) m / z: [M+H]+Found 622.2.

[0736] Example 12: 4-Cyclopropyl- V-((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-3-(pyrimidin-4- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide

[0737] A mixture of 4-cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((Z)-3- (dimethylamino)acryloyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / ?]pyridazin-2-yl)methyl)- l ,2,5-oxadiazole-3-carboxamide (110 mg, 0.166 mmol, Intermediate 8), formamidine hydrochloride (135 mg, 1.68 mmol) and TEA (350 pL, 2.52 mmol) in MeOH (3 mL) was heated at 80 °C for 16 h. The reaction mixture was cooled to rt, concentrated to dryness, and purified by preparative TLC (33% (75% EtOAc / EtOH) / petroleum ether) to provide a yellow solid. The solid was repurified by preparative achiral SFC (GreenSep Naphthyl, 5 pm, 250 x 30 mm, isocratic 25% MeOH (with 20 mM NH3) / CO2) to provide the title compound, which was the major isomer, as a white solid (27% yield). 'H NMR (300 MHz, DMSO-t / e) 5 9.50 (br s, 1H), 9.18 (d, J= 1.2 Hz, 1H), 9.09 (br s, 1H), 8.86 (d, J= 5.4 Hz, 1H), 8.25 (d, J= 1.8 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.85 (m, 1H), 7.81 (d, J= 1.5 Hz, 1H), 5.21 - 5.15 (m, 1H), 4.39 - 4.37 (m, 1H), 3.44 - 3.42 (m, 2H), 3.14 - 3.07 (m, 1H), 2.29 - 2.22 (m, 3H), 2.20 - 1.99 (m, 2H), 1.88 - 1.85 (m, 2H), 1.78 - 1.69 (m, 1H), 1.62 - 1.57 (m, 1H), 1.44 - 1.21 (m, 2H), 1.23 - 1.08 (m, 2H), 0.97 - 0.92 (m, 2H). MS (ESI) m / z: [M+H]+Found 646.3. Example 13: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(l-methyl-17 / - pyrazol-3-yl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0738] A mixture of 4-cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-((Z)-3- (dimethylamino)acryloyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide (100.0 mg, 0.151 mmol, Intermediate 8), NaOAc (310 mg, 3.78 mmol) and methylhydrazine (232 mg, 3.02 mmol, 60% in water) in EtOH (5 mL) was heated at 70 °C for 16 h. The reaction mixture was cooled to rt and concentrated to dryness to afford yellow oil. The oil was purified by preparative HPLC (XSelect CSH Cl 8 OBD, 5 pm, 150 x 30 mm, 30-60% ACN / water (with 0.1% FA)) to provide the title compound, which was the major isomer, as a white solid (17% yield).JH NMR (300 MHz, DMSO-t / e) 5 9.49 (br s, 1H), 8.75 (br s, 1H), 8.18 (s, 1H), 8.17 (d, J= 1.8 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.69 (d, J= 2.1 Hz, 1H), 6.38 (d, J= 2.1 Hz, 1H), 5.20 - 5.15 (m, 1H), 4.33 - 4.31 (m, 1H), 3.78 (s, 3H), 3.28 - 3.28 (m, 2H), 2.85 - 2.81 (m, 1H), 2.29 - 2.24 (m, 1H), 2.18 - 2.14 (m, 2H), 2.11 - 1.92 (m, 2H), 1.90 - 1.81 (m, 2H), 1.78 - 1.69 (m, 1H), 1.62 - 1.58 (m, 1H), 1.44 - 1.32 (m, 2H), 1.14 - 1.07 (m, 2H), 0.97 - 0.92 (m, 2H). MS (ESI) m / z: [M+H]+Found 648.3.

[0739] Example 14: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(17 / -tetrazol-5- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide

[0740]

[0741] Step A: tert-Butyl (35,55)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-cyano-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. A flask with a mixture of tert-butyl (5S)-3-((2-((S)- ((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (600 mg, 0.95 mmol, Intermediate 3) in THF (25 mL) was evacuated and refilled with N2 three times and then cooled to -78 °C. Then, LiHMDS (3.8 mL, 3.8 mmol, 1 M in THF) was added dropwise over 5 min. The resulting mixture was stirred at -78 °C for 50 min, then a solution of 3-oxo-lX3- benzo[<7][l,2]iodaoxole-l(37y)-carbonitrile (780 mg, 2.86 mmol) in THF (10 mL) was added dropwise over 5 min. The reaction mixture was stirred at -78 °C for 50 min, then warmed to -20 °C and treated with AcOH (0.1 M in EtOAc) to adjust the pH to -pH 4-5. The mixture was diluted with EtOAc (150 mL), washed with saturated aqueous NH4Q (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a yellow oil. The oil was purified by silica gel chromatography (50-60% EtOAc / petroleum ether) to provide the title compound, which was the major isomer, as a yellow solid (40% yield). MS (ESI) m / z: [M+H]+Found 657.3.

[0742] Step B: (3 ,5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carbonitrile hydrochloride. The title compound, where the title compound was the major isomer, (96% yield) was prepared as described for the synthesis of Intermediate 5 Step B using tert-butyl (35,55)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3- cyano-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (Step A) in place of tert-butyl (37?,55)-3-azido-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. MS (ESI) m / z: [M+H]+Found 457.2. Step C: A-((5)-(7-(((35,55)-3-Cyano-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5- oxadiazole-3-carboxamide. The title compound was prepared as described for the synthesis of Intermediate 6, Step A using (35,55)-3-((2-((5)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carbonitrile hydrochloride (Step B) in place of (3A,55)-3-((2-((5)- amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-azido-5- (trifluoromethyl)pyrrolidin-2-one hydrochloride and DMF in place of DCM. The residue was purified by silica gel chromatography (40-60% EtOAc / petroleum ether) to provide the title compound, which was the major isomer, as a white solid (54% yield). MS (ESI) m / z: [M+H]+Found 593.4.

[0743] Step D: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(17 / -tetrazol- 5-yl)-5-(trifhjoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide. A mixture ofA-((5)-(7-(((35,55)-3-cyano-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide (70 mg, 0.12 mmol, Step C), Fe(OAc)2 (50 mg, 0.29 mmol) and TMSN3 (80 mg, 0.69 mmol) in DMF (3.6 mL) and MeOH (0.4 mL) was heated at 80 °C for 48 h. The reaction was cooled to rt and diluted with EtOAc (10 mL) and saturated aqueous NH4CI (10 mL). The mixture was extracted with EtOAc (3 x 50 mL), then the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a yellow oil. The oil was purified by preparative HPLC (XBridge Prep OBD Cl 8 ExRS, 5 pm, 150 x 30 mm, 23-53% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (20% yield). 'H NMR (400 MHz, DMSO-t / e) 5 9.49 (d, J= 9.2 Hz, 1H), 8.96 (s, 1H), 8.26 (br s, 1H), 8.19 (s, 1H), 7.78 (br s, 1H), 7.30 - 6.91 (m, 1H), 5.20 - 5.15 (m, 1H), 4.53 - 4.51 (m, 1H), 3.57 - 3.53 (m, 1H), 3.41 - 3.33 (m, 1H), 2.87 - 2.86 (m, 1H), 2.31 - 2.24 (m, 2H), 2.23 - 2.16 (m, 1H), 2.03 - 1.99 (m, 2H), 1.88 - 1.73 (m, 3H), 1.58 - 1.51 (m, 1H), 1.39 - 1.11 (m, 2H), 1.10 - 1.08 (m, 2H), 0.96 - 0.92 (m, 2H). MS (ESI) m / z: [M+H]+Found 636.2. Example 15: cA-(17?*,25*)-A-((S)-(7-(((35,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5-

[0744] (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide

[0745] Example 16: cA-(15*,27?*)-A-((5)-(7-(((35,55)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5-

[0746] (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide

[0747] Step A: cis-(l 7?*,25*)-A-((5)-(4,4-Difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2- oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide and cA-(1 *,27?*)-A-((5)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide. A mixture of c / .s-ethyl 2-((35,55)-3-((2-((5)-(4,4- difluorocyclohexyl)(( l / *,25'*)-2-(trifluoromethyl)cyclopropane- l - carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin- 3-yl)acetate and c / .s-ethyl 2-((35,55)-3-((2-((5)-(4,4-difluorocyclohexyl)((15*,2A*)-2- (trifl uoromethyl (cyclopropane- ! -carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate (340 mg, 0.52 mmol, Intermediate 9) and hydrazine hydrate (3.12 g, 62.4 mmol) in EtOH (4 mL) was heated at 100 °C for 12 h. The reaction mixture was filtered and concentrated to dryness to provide the mixture of title compounds as a yellow solid (66% yield) that was used without further purification. MS (ESI) m / z: [M+H]+Found 640.2.

[0748] Step B: cA-(17?*,25*)-A-((5)-(7-(((35,55)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-Z>]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide and cis-(lS*,2R*)- A-((5)-(7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[l,2-Z>]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide. A mixture of cA-(17?*,25*)-A-((5)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-Z>]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide and cA-(1 *,27?*)-A-((5)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-Z>]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide (220 mg, 0.34 mmol, Step A) and -TsOH’FFO (0.98 mg, 5.16 pmol) in trimethoxymethane (1 mL) was heated at 120 °C for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to afford a yellow solid. The solid was purified by preparative HPLC (XBridge Prep OBD Cl 8, 5 pm, 250 x 19 mm, 38-63% ACN / H2O (with 10 mM NH4HCO3)) to provide a mixture of diastereomers as a white solid. The diastereomers were separated by preparative chiral HPLC (CHIRALPAK IA, 5 pm, 250 x 20 mm, isocratic 30% EtOH / (25% DCM / hexanes (with 0.5% 2 M NH3 in MeOH)). The first-eluting peak (5% yield) was designated as the cis-(lR* ,25*) isomer (Example 15) and the second-eluting peak (5% yield) was designated as the cis-(lS* ,27?*) isomer (Example 16). Example 15:XH NMR (400 MHz, MeOH- d4) 5 8.93 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 5.13 - 5.04 (m, 1H), 4.18 - 4.08 (m, 1H), 3.67 - 3.60 (m, 1H), 3.35 - 3.30 (m, 2H), 3.07 - 2.99 (m, 1H), 2.65 - 2.54 (m, 1H), 2.24 - 2.12 (m, 3H), 2.10 - 1.95 (m, 4H), 1.90 - 1.81 (m, 2H), 1.75 - 1.66 (m, 2H), 1.62 - 1.52 (m, 2H), 1.45 - 1.41 (m, 1H). MS (ESI) m / z: [M+H]+Found 650.3. Example 16: 'H NMR (400 MHz, MeOH-<A) 5 8.94 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 5.12 - 5.05 (m, 1H), 4.20 - 4.10 (m, 1H), 3.65 - 3.62 (m, 1H), 3.38 - 3.33 (m, 2H), 3.06 - 2.98 (m, 1H), 2.67 - 2.55 (m, 1H), 2.22 - 2.06 (m, 5H), 2.05 - 1.95 (m, 2H), 1.90 - 1.81 (m, 2H), 1.75 - 1.66 (m, 3H), 1.63 - 1.55 (m, 2H). MS (ESI) m / z: [M+H]+Found 650.3.

[0749] Example 17: trans-(1R *,2A*)-A-((S)-(7-(((3S,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5-

[0750] (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-b>]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide

[0751] Example 18: trans-(1S*,2S*)-A-((S)-(7-(((3S,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5-

[0752] (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-b>]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide

[0753] Step A: trans -(1 R*,2R *)-A-((S)-(4,4-Difluorocyclohexyl)(7-(((3S,5S)-3-(2-hydrazineyl-

[0754] 2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide and trans -(1S*,2S*)-A-((S)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide. The title compounds (87% yield) were prepared as described for the synthesis of Example 15 and Example 16 Step A using tran s -ethyl 2- ((3S,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)((lA*,2A*)-2-(trifluoromethyl)cyclopropane-l- carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-

[0755] 3-yl)acetate and trans-ethyl 2-((35,55)-3-((2-((5)-(4,4-difluorocyclohexyl)((15*,25*)-2- (trifl uoromethyl (cyclopropane- ! -carboxamido)methyl)imidazo[ l ,2- / ?]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate (Intermediate 10) in place of c / .s-ethyl 2-((3S,5S)- 3-((2-((S)-(4,4-difluorocyclohexyl)((lA*,25*)-2-(trifluoromethyl)cyclopropane-l- carboxamido)methyl)imidazo[l ,2- / ?]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin- 3-yl)acetate and c / .s-ethyl 2-((3S,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)((15*,2A*)-2- (trifl uoromethyl (cyclopropane- ! -carboxamido)methyl)imidazo[l ,2- b]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate. MS (ESI) m / z: [M+H]+Found 640.2.

[0756] Step B: trans-(17?*,2A*)-A-((S)-(7-(((3S,5S)-3-((l,3,4-Oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane- 1 -carboxamide and trans- (1S*,2S*)-A-((S)-(7-(((35,55)-3-((l,3,4-oxadiazol-2-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-2-(trifluoromethyl)cyclopropane- 1 -carboxamide. The title compounds were prepared as described for the synthesis of Example 15 and Example 16 Step B using tra«s-(1 R*,2R*)-A-((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-(2-hydrazineyl-2- oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)methyl)-2-(trifluoromethyl)cyclopropane-l -carboxamide and trans -(1S*,2S*)-A-((S)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide (Step A) in place of cA-(1S *,2S*)-A-((S)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide and cA-(1S*,2R *)-A-((S)-(4,4- difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2-oxoethyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-2- (trifluoromethyl)cyclopropane-l -carboxamide. The yellow solid obtained was subjected to preparative chiral HPLC (CHIRALPAK IA, 5 pm, 250 x 20 mm, isocratic 30% EtOH / (25% DCM / hexanes (with 0.5% 2 M NH3 in MeOH)). The first-eluting peak (6% yield) was designated as the trans-(1R* ,2R*) isomer (Example 17) and the second-eluting peak (7% yield) was designated as the lrans-( 1S* .2S*) isomer (Example 18). Example 17: NMR (400 MHz, MeOH-d4) 5 8.95 (s, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 5.09 - 5.07 (m, 1H), 4.15 - 4.14 (m, 1H), 3.37 - 3.33 (m, 1H), 3.30 - 3.27 (m, 2H), 3.05 - 3.02 (m, 1H), 2.64 - 2.61 (m, 1H), 2.19 - 1.98 (m, 6H), 1.88 - 1.72 (m, 5H), 1.63 - 1.60 (m, 2H), 1.55 - 1.37 (m, 1H). MS (ESI) m / z: [M+H]+Found 650.3. Example 18: 'H NMR (400 MHz, MeOH-A) 5 8.93 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 5.14 - 5.07 (m, 1H), 4.18 - 4.06 (m, 1H), 3.51 - 3.45 (m, 3H), 3.07 - 2.99 (m, 1H), 2.66 - 2.53 (m, 1H), 2.20 - 1.95 (m, 7H), 1.90 - 1.64 (m, 5H), 1.61 - 1.50 (m, 2H). MS (ESI) m / z: [M+H]+Found 650.3.

[0757] Example 19: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-((5-methyl-l,3,4- oxadiazol-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0758] A mixture of 4-cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-3-(2-hydrazineyl-2- oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide (100 mg, 0.16 mmol, Example 8 Step B) and 1,1,1- trimethoxy ethane (28.2 mg, 0.23 mmol) in DMF (2 mL) was stirred at rt until it was homogeneous, then heated at 65 °C for 3.5 h. The reaction mixture was concentrated to dryness, then -TsOH’FFO (0.45 mg, 0.0023 mmol) and toluene (2 mL) were added, and the resulting mixture was heated at 110 °C for 2 h. The reaction was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (XSelect CSH Cl 8 OBD, 5 pm, 150 x 30 mm, 33-63% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound, which was the major isomer, as a white solid (28% yield). 'H NMR (400 MHz, DMSO-t / e) 5 9.52 (br s, 1H), 8.86 (br s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 5.22 - 5.18 (m, 1H), 4.21 - 4.19 (m, 1H), 3.20 - 3.09 (m, 3H), 3.04 - 2.91 (m, 1H), 2.50 - 2.47 (m, 3H), 2.45 - 2.42 (m, 1H), 2.29 - 1.26 (m, 1H), 2.26 - 2.19 (m, 1H), 2.17 - 1.99 (m, 3H), 1.90 - 1.75 (m, 3H), 1.74 - 1.58 (m, 1H), 1.51 - 1.32 (m, 1H),1.32 - 1.26 (m, 1H), 1.13 - 1.09 (m, 2H), 0.97 - 0.93 (m, 2H). MS (ESI) m / z: [M+H]+Found 664.3.

[0759] Example 20: 4-Methyl-At-((5)-5,5,5-trifluoro-4,4-dimethyl-l-(7-(((35,55)-2-oxo-3-(pyrimidin-2- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)pentyl)-l,2,5- oxadiazole-3 -carboxamide

[0760] The title compound (23% yield) was prepared as described for the synthesis of Example 1 using tert-butyl (55)-3-((2-((5)-l-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4- dimethylpentyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l- carboxylate (Intermediate 17) in place of tert-butyl (55)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2- oxo-5-(trifhioromethyl)pyrrolidine-l -carboxylate.JH NMR (600 MHz, CD3OD) 5 8.83 (d, J = 5.0 Hz, 2H), 8.39 (d, 7 = 1.9 Hz, 1H), 8.07 (s, 1H), 7.83 (d, J= 1.5 Hz, 1H), 7.41 (t, 7 = 4.8 Hz, 1H), 5.33 (dd, 7= 5.9, 8.6 Hz, 1H), 4.54 - 4.49 (m, 1H), 3.75 - 3.67 (m, 2H), 3.01 - 2.97 (m, 1H),

[0761] 2.74 - 2.70 (m, 1H), 2.56 (s, 3H), 2.39 - 2.35 (m, 1H), 2.25 - 2.18 (m, 1H), 2.11 - 2.04 (m, 1H),

[0762] 1.75 - 1.69 (m, 1H), 1.62 - 1.56 (m, 1H), 1.19 - 1.15 (m, 1H), 1.15 (s, 6H). MS (ESI) m / z: [M+H]+Found 640.2.

[0763] Example 21 : 4-Cyclopropyl- V-((S)-(4,4-difluorocyclohexyl)(7-(((37?,5S')-2-oxo-3-(3- oxomorpholino)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide

[0764]

[0765] Step A: A-((S)-(7-(((3A,5S)-3-(2-(2-Chloroethoxy)acetamido)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3-carboxamide. A mixture of N- f(S)-(7-(((37?,5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3- carboxamide (100 mg, 0.17 mmol, Intermediate 6), 2-(2-chloroethoxy)acetic acid (28 mg, 0.20 mmol), EDCI (99 mg, 0.52 mmol), HOBt (46 mg, 0.34 mmol) and NMM (90 pL, 0.82 mmol) in DCM (2 mL) was stirred at rt for 16 h. The reaction mixture was filtered and the filtrate concentrated to dryness to afford a colorless oil. The oil was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound as a white solid (29% yield). MS (ESI) m / z: [M+H]+Found 703.2, 705.2.

[0766] Step B: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((3A,58)-2-oxo-3-(3- oxomorpholino)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2- yl)methyl)-l,2,5-oxadiazole-3-carboxamide. A mixture of A-((8)-(7-(((37?,55)-3-(2-(2- chloroethoxy)acetamido)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l,2,5-oxadiazole-3- carboxamide (30 mg, 0.043 mmol, Step A) and NaH (3.4 mg, 0.085 mmol, 60% in mineral oil) in THF (2 mL) was stirred for 1 h at rt. Then, the reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a white solid. The solid was purified by preparative HPLC (XBridge OBD Cl 8, 5 pm, 150 x 30 mm, 33-63% ACN / water (with 10 mM NH4HCO3)) to provide the title compound as a white solid (35% yield). 'H NMR (300 MHz, DMSO-t / e) 8 9.51 (br s, 1H), 8.88 (br s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 5.23 - 5.19 (m, 1H), 4.25 - 4.22 (m, 1H), 4.18 - 4.02 (m, 2H), 3.93 - 3.89 (m, 1H), 3.81 - 3.79 (m, 1H), 3.52 - 3.50 (m, 2H), 2.66 - 2.58 (m, 2H), 2.28 - 2.21 (m, 3H), 2.02 - 2.00 (m, 2H), 1.89 - 1.86 (m, 2H), 1.78 - 1.69 (m, 1H), 1.63 - 1.58 (m, 1H), 1.46 - 1.20 (m, 3H), 1.12 - 1.06 (m, 2H), 1.00 - 0.92 (m, 2H). MS (ESI) m / z: [M+H]+Found 667.3.

[0767] Example 22: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((3 ,55)-2-oxo-3-(pyridazin-3- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide

[0768] Step A: tert-Butyl ((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-3-(pyridazin-3-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)carbamate. To a suspension of tert-butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (63.2 mg, 0.100 mmol, Intermediate 3) in toluene (0.5 mL) were added 2-bromopyridazine (47.7 mg, 0.300 mmol) followed by potassium tert-butoxide (45 mg, 0.40 mmol). The resulting mixture was heated to 100 °C and stirred at this temperature for 2 h. The reaction was then cooled to rt and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound as a mixture of diastereomers, with the title compound as the major diastereomer, in 75% yield.

[0769] Step B: (3 ,5S -3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- / ?]pyridazin-7-yl)methyl)-3-(pyridazin-3-yl)-5-(trifluoromethyl)pyrrolidin-2-one. A solution of tert-butyl ((5)-(4,4-difluorocyclohexyl)(7-(((35,55)-2-oxo-3-(pyridazin-3-yl)-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[ l ,2- / ?]pyridazin-2-yl)methyl)carbamate (46 mg, 0.075 mmol, Step A) in di chloromethane (0.75 mL) was cooled to 0 °C, then trifluoroacetic acid (0.34 mL, 0.22 M) was added drop wise and the resulting mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated and azeotroped with toluene (2 x 5 mL). To the resulting residue was added EtOAc (2 mL) and saturated aqueous NaHCOs (2 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO-i, filtered, and concentrated to dryness. The resulting residue was dried under a high vacuum and used without further purification.

[0770] Step C: 4-Cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7-(((3 ,5S)-2-oxo-3-(pyridazin-3- yl)-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- / >]pyridazin-2-yl)methyl)-l,2,5- oxadiazole-3-carboxamide. To a solution of (3 ,55)-3-((2-((5)-amino(4,4- difhjorocyclohexyl)methyl)imidazo[l,2- / >]pyridazin-7-yl)methyl)-3-(pyridazin-3-yl)-5- (trifluor omethyl)pyrrolidin-2-one (37 mg, 0.072 mmol, Step B) in DMF (0.7 mL) was add...

Claims

CLAIMSWe Claim:

1. A compound of F ormula Ior a pharmaceutically acceptable salt thereof, wherein: each R1is independently -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4)alkyl, or -OC(i-4)alkyl;R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, - C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

2. A compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein: each R1is independently halo or -C(i-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently halo;X is a -C(i-3)alkylene or absent, wherein the -C(i-3)alkylene is optionally substituted with one to four groups selected from halo, -OH, -C(i-4)alkyl, or -OC(i-4)alkyl;R2is a 4- to 10-membered heterocyclyl, -C(6-io)aryl, or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to six R2agroups; each R2ais independently a halo, CN, oxo, -C(i-6)alkyl, -O-C(i-4)alkyl, -C(i-3)alkyl-O-C(i- 4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -C(i-3)alkyl-O-C(i-4)alkyl, -O-C(i-4)alkyl, -C(=O)NH-C(i-4)alkyl, -C(=O)N(C(i-4)alkyl)2, -O-C(3-6)cycloalkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms, one to six D atoms, one to six OH, or one to six -C(i-6)alkyl;R3ais a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl;R3bis a H, -OH, -C(i-3)alkyl, or -C(i-3)alkyl-O-C(i-3)alkyl; provided that R3aand R3bare not both -OH;R4is a -C(i-io)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, -C(i-6)alkyl-O-C(3-5)cycloalkyl, -C(i-6)alkyl- O-C(3-5)cycloalkyl-C(i-3)alkyl, -C(3-8)cycloalkyl, or -C(i-3)alkyl-(C(3-5)cycloalkyl)i-2, each of which is unsubstituted or substituted with one to six halo atoms;R5is a -C(3-6)cycloalkyl, -O-C(3-6)cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein the -C(3-6)cycloalkyl is unsubstituted or substituted with one to two R5agroups, and wherein the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one to two R5bgroups; each R5ais independently a halo, -C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl and -C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; each R5bis independently a halo, -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, or - C(o-2)alkyl-C(3-6)cycloalkyl, wherein the -C(i-6)alkyl, -O-C(i-6)alkyl, -C(i-6)alkyl-O-C(i-6)alkyl, and - C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3; n is 0, 1, 2, 3, or 4; and m is 1, 2, or 3.

3. The compound of any one of claims 1-2, having a formula selected from the group consisting of:(Ib-1) and (Ib-2), or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, having a formula according to Formula (Ic):or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, having a formula selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-3, having a formula according to Formula (Id):or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, having a formula selected from the group consisting of:(Id-1) and (Id-2), or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of:

9. The compound of any one of claims 1-3, having a formula according to Formula (II):or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-3, having a formula selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R4is a -C(i-io)alkyl or -C(3-8)cycloalkyl, each of which is unsubstituted or substituted with one to six halo atoms.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R5is C(3-6)cycloalkyl that is unsubstituted or substituted with one to two R5agroups.

13. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R5is 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is unsubstituted or substituted with one to two R5bgroups.

14. The compound of any one of claims 1-3 and 13, having a formula according to Formula (lo-l):(lo-l), or Formula (Io-2):(Io-2), or a pharmaceutically acceptable salt thereof, wherein: X is a -CH2- or absent;R2is 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 4- to 7- membered heterocyclyl is unsubstituted or substituted with one oxo group and / or one or two -C(i- 4)alkyl groups, and wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one to three groups selected from fluorine, -C(i-4)alkyl, -CH2-O-C(i-4)alkyl, and -C(3-4)cycloalkyl, wherein the -C(i-4)alkyl is unsubstituted or substituted with one to six fluorine atoms; andR5bis -C(i-6)alkyl, -O-C(i-6)alkyl, or -C(3-6)cycloalkyl, wherein the -C(i-6)alkyl is unsubstituted or substituted with one to six fluorine atoms.

15. The compound of any one of claims 1 3, 8-11 and 13 having a formula selected from theor a pharmaceutically acceptable salt thereof.5 16. The compound of any one of claims 1-3, 8-11, 13, and 15 having a formula selected from the group consisting of:

17. The compound of claim 16, having the following formula:or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

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