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, R3, R4, and m are 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] IMIDAZOPYRIDAZINE IL-17 INHIBITOR COMPOUNDS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefits of U.S. Provisional Application No. 63 / 570,318, filed on March 27, 2024, the entire disclosure 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-oc, and IL- 10 that recruit and activate lymphocytes to the site of injury or inflammation and maintain a pro inflammatory state.

[0006] Preclinical and clinical data have demonstrated the significant pathological role of IL- 17A in multiple autoimmune and inflammatory diseases. Animal and human studies have shown that IL-17A plays a crucial role in pathogenesis of the multiple diseases and / or conditions discussed herein. The significance of targeting IL-17A has been demonstrated by the transformational efficacy of injectable IL-17A neutralizing antibodies in patients.

[0007] 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.

[0008] 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.

[0009] SUMMARY

[0010] The present application discloses a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and m are as defined herein.

[0011] The present application also discloses a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] The present application also discloses 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 Formula (I), 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.

[0013] 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 in 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. To 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.

[0021] 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.

[0022] 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.

[0023] 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 Set., 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.

[0024] As used herein, “IL- 17” or “IL-17A” refers to interleukin 17A. It is also named IL17, 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.

[0025] The term “modulator” as used herein refers to any agents or molecules that can bind to IL- 17, including small molecule compounds.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] As used herein, the term “QD” means once daily.

[0030] As used herein, the term “BID” means twice daily.

[0031] 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., (C1- C6)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (z-Pr, z-propyl, -CH(CH3)2), 1- butyl (zz-bu, zz-butyl, -CH2CH2CH2CH3), 2-butyl (.s-bu, .s-butyl, -CH(CH3)CH2CH3), / c / V-butyl ( / - bu, / -butyl, -CH(CH3)3), 1 -pentyl (n -pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (- CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (- CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2)10CH3), and dodecyl (-(CH2)IICH3). Any alkyl group may be unsubstituted or substituted.

[0032] The term (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. 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., (C1-C6)alkylene), 1 to 4 carbon atoms (i.e., (Ci-C4)alkylene), or 1 to 3 carbon atoms (i.e., (C1-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 another embodiment, alkylene refers to C(1-2)alkylene.

[0033] The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon ring system having 3 to 8 carbon atoms (i.e., C(3-8)cycloalkyl), such as, but not limited to 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 is for example and without limitation, examples of spirohexyl groups include ; ffor example and without limitation examples of cycloheptyl groups siprocycloalkyl group may be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include 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. The terms “heterocyclyl” and “heterocycloalkyl” include but not limited to cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). 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.

[0034] The term “heteroaryl” refers to a single aromatic ring 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. Exemplary heteroaryl ring systems include but are not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0035] The term “halogen” or “halo” refers to bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1). 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.

[0036] “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0037] “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.

[0038] 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 rotamers of compounds may exist which are observable by NMR leading to complex multiplets and peak integration in the NMR spectrum.

[0039] 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).

[0040] 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.

[0041] 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 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. Radiolabelled 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. In some embodiments, the radioactive isotope is selected from the group of3H,nC and18F.

[0042] Compounds

[0043] The present application discloses a compound having a formula of Formula (I), Formula (I- 1 ), or Formula (1-2): or a pharmaceutically acceptable salt thereof, wherein: each R1is independently a -C(1-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently a halo;

[0044] R2is

[0045] R3is -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms;

[0046] R4is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3- 6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0047] R5is H, -C(1-3)alkyl, or -C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R5agroups; each R5ais independently a halo;

[0048] R6is H or -C(1-3)alkyl;

[0049] R7is H or -C(1-3)alkyl;

[0050] R8is NH2, -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R8agroups; each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl; each m is independently 0, 1 , or 2; and each n is independently 0 or 1.

[0051] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (1-1) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (1-2) or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R1is independently -Ccpalkyl that is unsubstituted or substituted with one to three Rlagroups. In some embodiments, each R1is independently - Ccpalkyl that is unsubstituted. In some embodiments, each R1is independently -Ccpalkyl that is substituted with one to six Rlagroups. In some embodiments, each R1is independently -Ccpalkyl that is substituted with one Rlagroup. In some embodiments, each R1is independently -Ccpalkyl that is substituted with two Rlagroups. In some embodiments, each R1is independently - Ccpalkyl that is substituted with three Rlagroups.

[0054] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R1is independently -Ccpalkyl that is substituted with one to three Rlagroups and each Rlais independently a halo. In some embodiments, the halo is bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1). In some embodiments, the halo is bromo (-Br). In some embodiments, the halo is chloro (-C1). In some embodiments, the halo is fluoro (-F). In some embodiments, the halo is iodo (-1).

[0055] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0056] R2is

[0057] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0058] R2is

[0059] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0060] R2is and n is 0 . In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0061] R2is and n is i.

[0062] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0063] R2is and R5is H, -C(1-, or -C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R5agroups; each R5ais independently a halo.

[0064] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0065] R2is and R5is H.

[0066] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0067] R2is and R5is -C(1-3)alkyl that is unsubstituted or substituted with one to six R5agroups.

[0068] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0069] R2is and R5is -Ccpalkyl that is unsubstituted or substituted with one to three R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein that is unsubstituted or substituted with one to five R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein that is unsubstituted or substituted with one to six R5agroups.

[0070] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein that is unsubstituted or substituted with one to six R5agroups.

[0071] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein cycloalkyl that is unsubstituted or substituted with one to four R5agroups.

[0072] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein cycloalkyl that is unsubstituted or substituted with one to six R5agroups.

[0073] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein cycloalkyl that is unsubstituted or substituted with one to six R5agroups.

[0074] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is unsubstituted. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with one R5agroup. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with two R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with three R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with four R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with five R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is substituted with six R5agroups.

[0075] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently a halo. In some embodiments, the halo is bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1). In some embodiments, the halo is bromo (-Br). In some embodiments, the halo is chloro (-C1). In some embodiments, the halo is fluoro (-F). In some embodiments, the halo is iodo (-1).

[0076] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and R6is H or -C(1-.

[0077] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0078] R2is and R6is H. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0079] R2is and R6is -C(1-.

[0080] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and R6is -C(1)alkyl.

[0081] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0082] R2is and R6is -C(2)alkyl.

[0083] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0084] R2is and R6is -C(3)alkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0085] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0086] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein .

[0087] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0088] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein . In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0089] R2is and R7is -C(1)alkyl.

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

[0091] R2is and R7is -C(2)alkyl.

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

[0093] R2is and R7is -C(3)alkyl.

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

[0095] R2is and R8is NH2, -C(1-, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R8agroups; each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

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

[0097] R2is and R8is NH2.

[0098] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and R8is -C(1-.

[0099] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0100] R2is and R8is -C(1)alkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0101] R2is and R8is -C(2)alkyl.

[0102] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and R8is -C(3)alkyl.

[0103] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein and R8is -C(3-.

[0104] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0105] R2is and R8is -C(3)cycloalkyl.

[0106] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and -C(4)cycloalkyl.

[0107] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0108] R2is and R8is -C(5)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0109] R2is and R8is -O-C(1-.

[0110] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0111] R2is and R8is -O -C(1)alkyl.

[0112] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0113] R2is and R8is -O-C(2)alkyl.

[0114] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0115] R2is and R8is -O-C(3)alkyl.

[0116] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and R8is -O-C(3-5)cycloalkyl.

[0117] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0118] R2is and R8is -O-C(3)cycloalkyl.

[0119] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0120] R2is and R8is -O-C(4)cycloalkyl.

[0121] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0122] R2is and R8is -O-C(5)cycloalkyl.

[0123] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0124] R2is and R8is -C(1-3)alkyl or -C(3-5)cycloalkyl which are unsubstituted or substituted with one to six R8agroups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0125] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0126] R2is and R8is -C(1-3)alkyl or -C(3-5)cycloalkyl which are unsubstituted. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0127] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with one to six R8agroups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0128] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0129] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with one R8a group and R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0130] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0131] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with two R8agroups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0132] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0133] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with three R 8agroups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0134] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0135] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with four R8a groups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0136] R2is and R8is -C(1-3)alkyl or -C(3-which are substituted with five R8agroups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0137] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0138] R2is and R8is -C(1-3)alkyl or -C(3-5)cycloalkyl which are substituted with six R8a groups and each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl.

[0139] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3- 5)cycloalkyl. In some embodiments R8ais independently a halo. In some embodiments, the halo is bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1). In some embodiments, the halo is bromo (- Br). In some embodiments, the halo is chloro (-C1). In some embodiments, the halo is fluoro (-F). In some embodiments, the halo is iodo (-1). In some embodiments R8ais independently a -O-C(i- 3)alkyl. In some embodiments R8ais independently a -O-C(3-5)cycloalkyl.

[0140] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(3-5)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is - C(3)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(4)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(5)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(3-5)cycloalkyl that is unsubstituted or substituted with one to six halo atoms. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with one halo atom. In some embodiments, R3is substituted with two halo atoms. In some embodiments, R3is substituted with three halo atoms. In some embodiments, R3is substituted with four halo atoms. In some embodiments, R3is substituted with five halo atoms. In some embodiments, R3is substituted with six halo atoms.

[0141] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is unsubstituted or substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3- 6)cycloalkyl are unsubstituted or substituted with one to six halo atoms. In some embodiments, the halo is bromo (-Br), chloro (-C1), fluoro (-F) or iodo (-1). In some embodiments, the halo is bromo (-Br). In some embodiments, the halo is chloro (-C1). In some embodiments, the halo is fluoro (-F). In some embodiments, the halo is iodo (-1).

[0142] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is unsubstituted.

[0143] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0144] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is substituted with one R4agroup; R4ais a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0145] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is substituted with two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0146] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is substituted with one to two R4agroups; each R4ais independently a -C(i-6)alkyl 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 5-membered heteroaryl that is substituted with one to two R4agroups; each R4ais independently a -O-C(i-6)alkyl which is unsubstituted or substituted with one to six halo atoms.

[0147] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl that is substituted with one to two R4agroups; each R4ais independently a -C(o-2)alkyl-C(3-6)cycloalkyl which is unsubstituted or substituted with one to six halo atoms.

[0148] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is unsubstituted or substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0149] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is unsubstituted.

[0150] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0151] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with one R4agroup; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0152] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with one R4agroup; each R4ais independently a -C(i-6)alkyl that is are unsubstituted or substituted with one to six halo atoms.

[0153] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with one R4agroup; each R4ais independently a -O-C(i-6)alkyl that is are unsubstituted or substituted with one to six halo atoms.

[0154] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with one R4agroup; each R4ais independently a -C(o-2)alkyl-C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms.

[0155] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3-6)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0156] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with two R4agroups; each R4ais independently a -C(i-6)alkyl that is are unsubstituted or substituted with one to six halo atoms.

[0157] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with two R4agroups; each R4ais independently a -O-C(i-6)alkyl that is are unsubstituted or substituted with one to six halo atoms.

[0158] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is an oxadiazole that is substituted with two R4agroups; each R4ais independently a -C(o-2)alkyl-C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms.

[0159] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein m is zero.

[0160] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein m is one.

[0161] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein m is two.

[0162] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is zero. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is one.

[0163] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0164] R1is independently for each occurrence -C(1-2)alkyl that is unsubstituted or substituted with one to four Rlagroups;

[0165] R3is -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms;

[0166] R4is a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S that is unsubstituted or substituted with one R4agroup; and each R4ais independently -C(1-3)alkyl, -O-C(1-3)alkyl, or -C(3-6)cycloalkyl, wherein the -C(1-3)alkyl, -O-C(1-3)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to four halo atoms.

[0167] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R1is independently -C(1)alkyl that unsubstituted or substituted with one to three Rlagroups;

[0168] R3is -C(5-6)cycloalkyl that is unsubstituted or substituted with one to four halo atoms;

[0169] R4is a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N and O that is substituted with one R4agroup; and each R4ais independently a -C(1-2)alkyl, -O-C(1-2)alkyl, or -C(3-4)cycloalkyl, wherein the -C(i- 2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (la), Formula (la-a), or Formula (la-b):

[0170]

[0171] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la)

[0172] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-a)

[0173] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-b)

[0174] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (lb), Formula (lb- 1), or Formula (Ib-2)

[0175] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (lb)

[0176] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (lb-1)

[0177] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (lb-2)

[0178] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (Ic), Formula (Ic- 1 ), or Formula (Ic-2): lc-2

[0179] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (Ic)

[0180] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (lc-1)

[0181] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (Ic-2) lc-2

[0182] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is -CH3that is unsubstituted or substituted with one to three Rlagroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is -C(Rla)3.

[0183] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-1)

[0184] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-2)

[0185] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-3)

[0186] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-4)

[0187] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

[0188] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0189] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0190] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(1-3)alkyl unsubstituted or substituted with one to six R5agroups and R6is H or -C(1-2)alkyl.

[0191] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(1-2)alkyl unsubstituted or substituted with one to four R5agroups and R6is H or -C(1-2)alkyl.

[0192] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is H or -C(1-2)alkyl.

[0193] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is -CH2CH3.

[0194] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is H.

[0195] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is -CH3.

[0196] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2.

[0197] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2 and R6is -C(1-3)alkyl.

[0198] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2 and R6is H.

[0199] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(3-5)cycloalkyl that is unsubstituted or substituted with one to four R5agroups. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(3-4)cycloalkyl that is unsubstituted or substituted with one to four R5agroups.

[0200] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups.

[0201] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups and R6is H.

[0202] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is H.

[0203] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is

[0204] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2is and n is 0.

[0205] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R7is -C(1-3)alkyl.

[0206] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R7is -CH3.

[0207] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R7is H.

[0208] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is NH2, -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0209] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0210] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl or -C(3-5)cycloalkyl wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0211] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to six halo atoms.

[0212] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to four halo atoms.

[0213] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to four fluorine atoms.

[0214] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -CH3, -CHF2 or -C(CH3)F2.

[0215] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(3-5)cycloalkyl that is unsubstituted or substituted with one to four halo atoms.

[0216] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -C(3-4)cycloalkyl that is unsubstituted or substituted with one to four halo atoms.

[0217] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is - cyclopropyl that is unsubstituted or substituted with one to two halo atoms.

[0218] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is - cyclopropyl that is substituted with one halo atom.

[0219] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R8is -O-C(1-3)alkyl or -O-C(3-5)cycloalkyl. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms.

[0220] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(4-6)cycloalkyl that is unsubstituted or substituted with one to four halo atoms.

[0221] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -C(5-6)cycloalkyl that is unsubstituted or substituted with one to two halo atoms.

[0222] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -cyclohexyl that is unsubstituted or substituted with one to two halo atoms.

[0223] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is -cyclohexyl that is unsubstituted or substituted with two F atoms.

[0224] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is

[0225] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N and O, which is substituted with one to two R4agroups; each R4ais independently -C(1-2)alkyl, -O-C(1-2)alkyl, or -C(3-4)cycloalkyl, wherein the -C(1-2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0226] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl having 3 heteroatoms selected from N and O, which is substituted with one R4agroup; each R4ais independently -C(1-2)alkyl, -O-C(1-2)alkyl, or - C-(3-4)cycloalkyl, wherein the -C(1-2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0227] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl having 3 heteroatoms selected from N and O, that is substituted with one R4agroup; each R4ais independently -C(1-2)alkyl, -O-C(i)alkyl, or - C(3)cycloalkyl, wherein the -C(1-2)alkyl and -C(3)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0228] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is a 5-membered heteroaryl having 3 heteroatoms selected from N and O, that is substituted with one R4agroup; each R4ais independently -CH3, -C(CH3)F2, -OCH3, or -cyclopropyl.

[0229] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is oxadiazolyl substituted with one R4agroup.

[0230] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is

[0231] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(1-2)alkyl .

[0232] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4ais - CH3.

[0233] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -CF3, -CHF2 or- CF2(CH3)

[0234] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -O-C(1-2)alkyl.

[0235] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4ais -O-CH3. In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(3-5)cycloalkyl, unsubstituted or substituted with one to three halo atoms.

[0236] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(3-4)cycloalkyl, unsubstituted or substituted with one to three halo atoms.

[0237] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4ais

[0238] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is

[0239] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is

[0240] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is

[0241] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4is

[0242] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of

[0243]

[0244]  In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0245] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0246] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0247]

[0248] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0249] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0250] In some embodiments, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is

[0251] In some embodiments, disclosed herein is a pharmaceutical composition comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, disclosed herein is a pharmaceutical composition comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof and an excipient.

[0253] In some embodiments, disclosed herein is a pharmaceutical composition, comprising a compound of Formula I, 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).

[0254] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0255] In some embodiments, disclosed herein is a process for making a pharmaceutical composition comprising mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0256] Therapeutic Use Preclinical and clinical data have demonstrated the significant pathological role of IL- 17A in multiple autoimmune and inflammatory diseases.

[0257] 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 selfamplifying 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 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).

[0258] 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. etal., J. Comp. Eff. Res. 2019, 8(7):497-510; Nash P. etal., Rheumatol. Ther. 2018, 5(1 ):99-l 22). 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.

[0259] 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. et al., 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).

[0260] 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. et al., Joint Bone Spine. 2007;74:304-305; Shen H. etal., Arthritis Rheum. 2009;60(6): 1647-56; Zhang L. et al., PLoS One. 2012;7(4):e31000; Jansen D. et al., 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 pl9 biologies failed to demonstrate beneficial effect (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. etal., 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.

[0261] 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. etal., British J. Dermatol. 2015 Dec;173(6): 1431-9; Moran B. et al., J. Invest. Dermatol. 2017; 137(11):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.

[0262] Dermatol. 2019 Sep;181(3):609-611), and more clinical trials with anti-IL-17 mAbs in HS are on-going.

[0263] 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).

[0264] 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).

[0265] 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. et al., 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).

[0266] 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. etal., Nat. Med. 2002, 8: 500-508; Matusevicius, D. etal., 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. et al., 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).

[0267] 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).

[0268] 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. etal., 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).

[0269] 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:el8139). 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. et al., 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. et al., 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. etal., Dermatol. Ther. 2017 Sep;30(5);el2527.).

[0270] 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. etal., 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).

[0271] For systemic lupus erythematosus (SLE): Increased serum or plasma levels of IL- 17, expansion of IL-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. et al., Lupus.

[0272] 2000;9(8): 589-593; Wong C. etal., 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. etal., 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. etal., Expert Rev. Clin. Immunol. 2019, 15 (6) 629-637).

[0273] Accordingly, the present application is also directed to a method 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 of Formula (I), or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. In some embodiments, disclosed herein is a method 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 of Formula (I), or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, disclosed herein is 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 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.

[0275] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0276] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0277] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0278] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0279] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0280] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0281] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0282] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0283] In some embodiments, disclosed herein is a method 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 of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[0284] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0285] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is asthma.

[0286] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is uveitis.

[0287] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0288] In some embodiments, disclosed herein is 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 Formula (I), or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0289] In some embodiments, disclosed herein is 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 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). In some embodiments, disclosed herein is the use of a therapeutically effective amount of 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.

[0290] In some embodiments, disclosed herein is the use of 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.

[0291] In some embodiments, disclosed herein is a method 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 of Formula (I), or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0292] In some embodiments, disclosed herein is a method 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 of Formula (I), or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0293] In some embodiments, disclosed herein is a method 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 of Formula (I), or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0294] 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 of Formula (I), or pharmaceutically acceptable salt thereof.

[0295] Also disclosed herein is a method of inhibiting production of interleukin- 17, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof.

[0296] Combination Therapy

[0297] 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.

[0298] 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.

[0299] In some embodiments, disclosed herein is a method 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 anti-inflammatory 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.

[0300] Dosage Regimen

[0301] 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. 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, appropriate 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.

[0302] Pharmaceutical Compositions

[0303] The compounds of Formula (I), or 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.

[0304] 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.

[0305] 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 but not limited to pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present disclosure.

[0306] 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.

[0307] In some embodiments, the following non-limiting embodiments are provided:

[0308] 1. A compound having a formula of Formula (I), Formula (1-1), or Formula (1-2): wherein: each R1is independently a -C(1-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently a halo;

[0309] R2is

[0310] R3is -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms;

[0311] R4is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3- 6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;

[0312] R5is H, -C(1-3)alkyl, or -C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R5agroups; each R5ais independently a halo;

[0313] R6is H or -C(1-3)alkyl;

[0314] R7is H or -C(1-3)alkyl;

[0315] R8is NH2, -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R8agroups; each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl; each m is independently 0, 1 , or 2; and each n is independently 0 or 1.

[0316] 2. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein

[0317] R1is independently for each occurrence -C(1-2)alkyl that is unsubstituted or substituted with one to four Rlagroups;

[0318] R3is -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms;

[0319] R4is a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S that is unsubstituted or substituted with one R4agroup; and each R4ais independently -C(1-3)alkyl, -O-C(1-3)alkyl, or -C(3-6)cycloalkyl, wherein the -C(1-3)alkyl, -O-C(1-3)alkyl, and -C(3-6)cycloalkyl are unsubstituted or substituted with one to four halo atoms.

[0320] 3. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein each R1is independently -C(1)alkyl that unsubstituted or substituted with one to three Rlagroups;

[0321] R3is -C(5-6)cycloalkyl that is unsubstituted or substituted with one to four halo atoms;

[0322] R4is a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N and O that is substituted with one R4agroup; and each R4ais independently a -C(1-2)alkyl, -O-C(1-2)alkyl, or -C(3-4)cycloalkyl, wherein the - C(1-2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0323] 4. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (la), Formula (la-a), or Formula (la-b):

[0324]

[0325] 5. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (lb), Formula (Ib-1 ), or Formula (Ib-2)

[0326] 6. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of having a formula of Formula (Ic), Formula (Ic- 1 ), or Formula (Ic-2):

[0327] lc-2

[0328] 7. The compound of any one of embodiments 1 -6 or a pharmaceutically acceptable salt thereof, wherein R1is -CH3that is unsubstituted or substituted with one to three Rlagroups. 8. The compound of any one of embodiments 1-7 or a pharmaceutically acceptable salt thereof, wherein R1is -C(Rla)3.

[0329] 9. The compound of any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-1) 10. The compound of any one of embodiments 1-9 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-2)

[0330] 11. The compound of any one of embodiments 1-10 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la- 3)

[0331] 12. The compound of any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, wherein

[0332] 13. The compound of any one of embodiments 1-12 or a pharmaceutically acceptable salt thereof, wherein

[0333] 14. The compound of any one of embodiments 1-13 or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0334] 15. The compound of any one of embodiments 1-12 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0335] 16. The compound of any one of embodiments 1-15 or a pharmaceutically acceptable salt thereof, wherein R5is -C(1-3)alkyl unsubstituted or substituted with one to six R5agroups and R6is H or -C(1-2)alkyl.

[0336] 17. The compound of any one of embodiments 1-16 or a pharmaceutically acceptable salt thereof, wherein R5is -C(1-2)alkyl unsubstituted or substituted with one to four R5agroups and R6is H or -C(1-2)alkyl.

[0337] 18. The compound of any one of embodiments 1-17 or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is H or -C(1-2)alkyl.

[0338] 19. The compound of any one of embodiments 1-18 or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is -CH2CH3.

[0339] 20. The compound of any one of embodiments 1-18 or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is H.

[0340] 21. The compound of any one of embodiments 1-18 or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is -CH3. 22. The compound of any one of embodiments 1-18 or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2.

[0341] 23. The compound of any one of embodiments 1-17 and 22 or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2 and R6is -C(1-3)alkyl.

[0342] 24. The compound of any one of embodiments 1-17 and 22 or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CHF2 and R6is H.

[0343] 25. The compound of any one of embodiments 1-15 or a pharmaceutically acceptable salt thereof, wherein R5is -C(3-5)cycloalkyl that is unsubstituted or substituted with one to four R5agroups.

[0344] 26. The compound of any one of embodiments 1-15 and 25 or a pharmaceutically acceptable salt thereof, wherein R5is -C(3-4)cycloalkyl that is unsubstituted or substituted with one to four R5agroups.

[0345] 27. The compound of any one of embodiments 1-15, 25 and 26 or a pharmaceutically acceptable salt thereof, wherein R5is -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups.

[0346] 28. The compound of any one of embodiments 1-15, and 25- 27 or a pharmaceutically acceptable salt thereof, wherein R5is -C(3)cycloalkyl that is unsubstituted or substituted with one to two R5agroups and R6is H.

[0347] 29. The compound of any one of embodiments 1-15 or a pharmaceutically acceptable salt thereof, wherein R5is H.

[0348] 30. The compound of any one of embodiments 1-11, 14 and 15 or a pharmaceutically acceptable salt thereof, wherein

[0349] 31. The compound of any one of embodiments 1-11, 14 and 30 or a pharmaceutically acceptable salt thereof, wherein

[0350] 32. The compound of any one of 1-11, 14, 15, 30 and 31 or a pharmaceutically acceptable salt thereof, wherein R7is -C(1-3)alkyl. 33. The compound of any one of embodiments 1-11, 14, 15, and 30-32 or a pharmaceutically acceptable salt thereof, wherein R7is -CH3.

[0351] 34. The compound of any one of embodiments 1-11, 14, 15 or a pharmaceutically acceptable salt thereof, wherein R7is H.

[0352] 35. The compound of any one of embodiments 1-11, 14, 15, and 30-34 or a pharmaceutically acceptable salt thereof, wherein R8is NH2, -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0353] 36. The compound of any one of embodiments 1-11, 14, 15, and 30-35 or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0354] 37. The compound of any one of embodiments 1-11, 14, 15, and 30-36 or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl or -C(3-5)cycloalkyl wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six halo atoms.

[0355] 38. The compound of any one of embodiments 1-11, 14, 15, and 30-37 or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to six halo atoms.

[0356] 39. The compound of any one of embodiments 1-11, 14, 15, and 30-38 or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to four halo atoms.

[0357] 40. The compound of any one of embodiments 1-1-11, 14, 15, and 30-39 or a pharmaceutically acceptable salt thereof, wherein R8is -C(1-3)alkyl that is unsubstituted or substituted with one to four fluorine atoms.

[0358] 41. The compound of any one of embodiments 1-11, 14, 15, and 30-40 or a pharmaceutically acceptable salt thereof, wherein R8is -CH3, -CHF2 or -C(CH3)F2.

[0359] 42. The compound of any one of embodiments 1-11, 14, 15 and 30-37 or a pharmaceutically acceptable salt thereof, wherein R8is -C(3-5)cycloalkyl that is unsubstituted or substituted with one to four halo atoms. 43. The compound of any one of embodiments 1-11, 14, 15, 30-37 and 42 or a pharmaceutically acceptable salt thereof, wherein R8is -C(3-4)cycloalkyl that is unsubstituted or substituted with one to four halo atoms.

[0360] 44. The compound of any one of embodiments 1-11, 14, 15, 30-37, 42 and 43 or a pharmaceutically acceptable salt thereof, wherein R8is - cyclopropyl that is unsubstituted or substituted with one to two halo atoms.

[0361] 45. The compound of any one of embodiments 1-11, 14, 15, 30-37, and 42-44 or a pharmaceutically acceptable salt thereof, wherein R8is - cyclopropyl that is substituted with one halo atom.

[0362] 46. The compound of any one of embodiments 1-11, 14, 15 and 30-36 or a pharmaceutically acceptable salt thereof, wherein R8is -O-C(1-3)alkyl or -O-C(3-5)cycloalkyl.

[0363] 47. The compound of any one of embodiments 1-46 or a pharmaceutically acceptable salt thereof, wherein R3is -C(3-6)cycloalkyl that is unsubstituted or substituted with one to six halo atoms.

[0364] 48. The compound of any one of embodiments 1-47 or a pharmaceutically acceptable salt thereof, wherein R3is -C(4-6)cycloalkyl that is unsubstituted or substituted with one to four halo atoms.

[0365] 49. The compound of any one of embodiments 1-48 or a pharmaceutically acceptable salt thereof, wherein R3is -C(5-6)cycloalkyl that is unsubstituted or substituted with one to two halo atoms.

[0366] 50. The compound of any one of embodiments 1-49 or a pharmaceutically acceptable salt thereof, wherein R3is -cyclohexyl that is unsubstituted or substituted with one to two halo atoms.

[0367] 51. The compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, wherein R3is -cyclohexyl that is unsubstituted or substituted with two F atoms.

[0368] 52. The compound of any one of embodiments 1-51 or a pharmaceutically acceptable salt thereof, wherein R3is 53. The compound of any one of embodiments 1-52 or a pharmaceutically acceptable salt thereof, wherein R4is a 5 -membered heteroaryl having 1 to 3 heteroatoms selected from N and O, which is substituted with one to two R4agroups; each R4ais independently -C(1-2)alkyl, -O-C(1-2)alkyl, or -C(3-4)cycloalkyl, wherein the -C(1-2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0369] 54. The compound of any one of embodiments 1-53 or a pharmaceutically acceptable salt thereof, wherein R4is a 5 -membered heteroaryl having 3 heteroatoms selected from N and O, which is substituted with one R4agroup; each R4ais independently -C(1-2)alkyl, -O-C(1-2)alkyl, or - C-(3-4)cycloalkyl, wherein the -C(1-2)alkyl, -O-C(1-2)alkyl, and -C(3-4)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0370] 55. The compound of any one of embodiments 1-54 or a pharmaceutically acceptable salt thereof, wherein R4is a 5 -membered heteroaryl having 3 heteroatoms selected from N and O, that is substituted with one R4agroup; each R4ais independently -C(1-2)alkyl, -O-C(i)alkyl, or - C(3)cycloalkyl, wherein the -C(1-2)alkyl and -C(3)cycloalkyl are unsubstituted or substituted with one to three halo atoms.

[0371] 56. The compound of any one of embodiments 1-55 or a pharmaceutically acceptable salt thereof, wherein R4is a 5 -membered heteroaryl having 3 heteroatoms selected from N and O, that is substituted with one R4agroup; each R4ais independently -CH3, -C(CH3)F2, -OCH3, or -cyclopropyl.

[0372] 57. The compound of any one of embodiments 1-56 or a pharmaceutically acceptable salt thereof, wherein R4is oxadiazolyl substituted with one R4agroup.

[0373] 58. The compound of any one of embodiments 1-57 or a pharmaceutically acceptable salt thereof, wherein R4is

[0374] 59. The compound of any one of embodiments 1-58 or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(1-2)alkyl . 60. The compound of any one of embodiments 1-59 or a pharmaceutically acceptable salt thereof, wherein R4ais - CH3.

[0375] 61. The compound of any one of embodiments 1-55, 57 or 58 or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -CF3, -CHF2 or- CF2(CH3)

[0376] 62. The compound of any one of embodiments 1-55, 57 or 58 or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -O-C(1-2)alkyl.

[0377] 63. The compound of any one of embodiments 1-55, 57, 58 or 62 or a pharmaceutically acceptable salt thereof, wherein R4ais -O-CH3.

[0378] 64. The compound of any one of embodiments 1-55, 57 or 58 or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(3-5)cycloalkyl, unsubstituted or substituted with one to three halo atoms.

[0379] 65. The compound of any one of embodiments 1-55, 57, 58 or 64 or a pharmaceutically acceptable salt thereof, wherein each R4ais independently a -C(3-4)cycloalkyl, unsubstituted or substituted with one to three halo atoms.

[0380] 66. The compound of any one of embodiments 1-1-55, 57, 58, 64 or 65 or a pharmaceutically acceptable salt thereof, wherein R4ais

[0381] 67. The compound of any one of embodiments 1-55, 57 or 58 or a pharmaceutically acceptable salt thereof, wherein R4is

[0382] 68. The compound of any one of embodiments 1-58 or 64-67, or a pharmaceutically acceptable salt thereof, wherein R4is

[0383] 69. The compound of any one of embodiments 1-58, or 61-63 or a pharmaceutically acceptable salt thereof, wherein R4is

[0384] 70. The compound of any one of embodiments 1-55, 57, 58, 61 or 67 or a pharmaceutically acceptable salt thereof, wherein R4is 71. The compound of any one of embodiments 1-58, 61 or 67 or a pharmaceutically acceptable salt thereof, wherein R4is

[0385] 72. A compound selected from the group consisting of

[0386] or a pharmaceutically acceptable salt thereof. 73. A compound as claimed in embodiment 72, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof. 74. A compound as claimed in embodiment 73, wherein the compound is selected from the group consisting of

[0387] or a pharmaceutically acceptable salt thereof.

[0388] 5 75. A compound as claimed in embodiment 72, wherein the compound is selected from the group consisting of

[0389] or a pharmaceutically acceptable salt thereof. 76. A compound as claimed in embodiment 72, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof. 77. A compound selected from the group consisting or a pharmaceutically acceptable salt thereof. 78. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0390] 79. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof. 80. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0391] 81. The compound of embodiment 77, having the following formula

[0392] or a pharmaceutically acceptable salt thereof.

[0393] 82. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0394] 83. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0395] 84. The compound of embodiment 77, having the following formula

[0396] or a pharmaceutically acceptable salt thereof.

[0397] 85. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0398] 86. The compound of embodiment 77, having the following formula or a pharmaceutically acceptable salt thereof.

[0399] 87. A pharmaceutical composition comprising at least one compound, or a pharmaceutically acceptable salt thereof, of embodiments 1-86.

[0400] 88. A pharmaceutical composition comprising at least one compound, or a pharmaceutically acceptable salt thereof, of embodiments 1-86 and an excipient. 89. 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 1-86, or a pharmaceutically acceptable salt thereof.

[0401] 90. The method of embodiment 89, 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.

[0402] 91. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0403] 92. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0404] 93. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0405] 94. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0406] 95. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0407] 96. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0408] 97. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0409] 98. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0410] 99. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[0411] 100. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0412] 101. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is asthma. 102. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is uveitis.

[0413] 103. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0414] 104. The method of embodiment 90, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0415] 105. The method of any of embodiments 90, wherein the compound of any one of embodiments 1-58, or a pharmaceutically acceptable salt thereof, is administered orally.

[0416] 106. The method of embodiments 90, wherein the compound of any one of embodiments 1-58, or a pharmaceutically acceptable salt thereof, is administered as a tablet or a capsule.

[0417] EXAMPLES

[0418] EXAMPLES

[0419] ABBREVIATIONS

[0420] Herein and throughout the application, the following abbreviations may be used.

[0421] Ac acetyl

[0422] ACN acetonitrile atm atmosphere

[0423] Boc tert-butyloxycarbonyl br broad

[0424] 8 NMR chemical shift in parts per million downfield from a standard d doublet

[0425] DCM dichloromethane

[0426] DIPEA N,N-di isopropyl ethylamine (Hϋ nig’s base)

[0427] DMF N,N-dimethylformamide

[0428] DMSO dimethyl sulfoxide

[0429] EDCI l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride

[0430] ESI electrospray ionization

[0431] Et ethyl

[0432] EtOAc ethyl acetate

[0433] FA formic acid g gram(s) h hour(s)

[0434] HATU N- [(dimethylamino)- 1H- 1 ,2,3 -triazolo- [4, 5 - b]pyridin- 1 - ylmethylene]-A-methylmethanaminium hexafluorophosphate N- oxide

[0435] HOBt 1 -hydroxybenzotriazole

[0436] HPLC high pressure liquid chromatography

[0437] Hz Hertz

[0438] IPA isopropanol coupling constant (NMR spectroscopy)

[0439] L liter(s)

[0440] LC liquid chromatography

[0441] LiHMDS lithium bis(trimethylsilyl)amide m milli or multiplet

[0442] M molar (moles / liter)

[0443] M mega

[0444] Me methyl min minute(s) g micro

[0445] MS mass spectrometry

[0446] N normal (equivalent concentration)

[0447] NMM 4-methylmorpholine

[0448] NMR nuclear magnetic resonance

[0449] Parkin’s Catalyst hydrido(dimethylphosphinous acid-kP) [hydrogen bis(dimethylphosphinito-kP)]platinum (II) Ghaffar-Parkins Catalyst

[0450] Ph phenyl q quartet rt room temperature s singlet

[0451] SFC supercritical fluid chromatography t triplet or tert

[0452] T3P 1-propanephosphonic anhydride

[0453] TCFH chloro- N, N,N, N'-tetramethylformamidinium hexafluorophosphate

[0454] TEA triethylamine TFA trifluoroacetic acid

[0455] THF tetrahydrofuran

[0456] Ts p-toluenesulfonyl

[0457] NMR spectra were recorded on a Bruker 600 MHz instrument equipped with a 5 mm BBO probe or a 500 MHz instrument with a 5 mm BBFO probe at 300K in DMSO- d6. For1H NMR signal assignments and relative stereochemistry determination, spectra of ID 1H, ID 13C, 2D correlation spectroscopy (COSY),1H-13C heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), nuclear Overhauser effect spectroscopy (NOESY) and 1H-19F heteronuclear Overhauser effect spectroscopy (HOESY) were acquired using the standard pulse sequences available in TopSpin 4.1 (Bruker Inc.).

[0458] Intermediate 1: tert-Butyl (S)-((7-(bromomethyl)imidazo[l,2-b ]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate

[0459] Step A: tert-Butyl (S)-((4,4-difluorocyclohexyl)(7-(hydroxymethyl)imidazo[l ,2- b ]pyridazin-2-yl)methyl)carbamate. A solution of tert-butyl (S)-((4,4-difluorocyclohexyl)(7- formylimidazo[l,2- b]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 the dropwise addition of saturated aqueous NH4Q (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.

[0460] Step B: tert-Butyl (S -((7-(bromomethyl)imidazo[l,2-b ]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate. To a solution of tert-butyl (5)-((4,4- difhiorocyclohexyl)(7-(hydroxymethyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)carbamate (132 mg, 0.330 mmol, Step A), PPh3(105 mg, 0.400 mmol) and imidazole (46 mg, 0.67 mmol) in dry DCM (10 mL) was added a mixture of CBr4(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), PPh3(4.4 mg, 0.017 mmol) and CBr4(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.

[0461] Intermediate 2: / ef / -Butyl fS')-2-oxo-5-(trifluoromethyl)pyrrolidine- 1 -carboxylate

[0462] 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-tert-butyl dicarbonate (17.1 g, 78.4 mmol) were sequentially added and the reaction was stirred at rt overnight. The reaction was then washed sequentially with 10% aqueous citric acid, water, and brine, dried over anhydrous MgSO-i, 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.

[0463] Intermediate 3: tert-Butyl (5S)-3-((2-((5')-(( / c / 7-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluor omethyl)pyrrolidine- 1 -carboxylate

[0464] A solution of tert-butyl (S)-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, 2.0 mmol) was added dropwise and the resulting solution was stirred at -78 °C for 1 h. tert-Butyl (S)-((7-(bromomethyl)imidazo[1,2-b ]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 into the -78 °C mixture of Intermediate 2 in THF. The resulting mixture was stirred at -78 °C for 1 h. The reaction mixture was then warmed to rt over 1 h, quenched with aqueous NH4Q 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. Intermediate 4: 1 -(tert-Butyl) 3-ethyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine- 1,3 -di carboxylate

[0465] A solution of tert-butyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (500 mg, 0.792 mmol, Intermediate 3) in dry THF (7 mb) was cooled to -78 °C in a dry ice / acetone bath under N2. After 3 min of stirring at -78 °C, LiHMDS (1.8 mL, 1.80 mmol, 1 M in THF) was added dropwise and the resulting mixture was stirred at -78 °C for 1.5 h. A solution of ethyl chloroformate (98.4 μL, 1.03 mmol) in THF (2 mb) was then added dropwise into the reaction at -78 °C and the reaction mixture was stirred at - 78 °C for 1 h. The reaction was then warmed to 0 °C using an ice / water bath and stirred at 0 °C for 30 min. The mixture was then quenched with 7.9 mb of 9: 1 EtOAc: AcOH solution at 0 °C. To the opaque solution was added water (4 mb) and the mixture was extracted with EtOAc (3 x 10 mb). The organic layers were combined, dried over anhydrous Mg2SO4, filtered, and concentrated to dryness to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 704.3.

[0466] Intermediate 5: Ethyl (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate

[0467] To a solution of 1 -(tert-butyl) 3-ethyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluor omethyl)pyrrolidine- 1,3 -di carboxy late (1.1 g, 1.56 mmol, Intermediate 4) in DCM (1 mL) was added TFA (1.08 mL, 14.1 mmol) dropwise and the resulting mixture was stirred at rt for 3 h. The reaction was concentrated to dryness and purified by basic preparative HPLC (XBridge C 18, 5 pm, 50 x 100 mm, 10-100% MeCN / H2O (20 mM NH4OH)) to afford the title compound (31% yield over two steps). MS (ESI) m / z: [M+H]+Found 504.1.

[0468] Intermediate 6: (5S)-3-((2-((5)-(4-Cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylic acid

[0469] Step A: Ethyl (5S)-3-((2-((5)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate.

[0470] To a solution of ethyl (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (245 mg, 0.487 mmol, Intermediate 5) in DCM (1 mL) were added 2,5-dioxopyrrolidin-l-yl 4-cyclopropyl- 1,2,5 - oxadiazole-3 -carboxylate (159 mg, 0.633 mmol, Intermediate 9) and DIPEA (0.335 mL, 1.95 mmol). The reaction was stirred at rt for 2.5 h. The reaction mixture was purified directly by silica gel chromatography (0-100% EtOAc / hexanes) to give the title compound (92% yield). MS (ESI) m / z: [M+H]+Found 640.9.

[0471] Step B: (5S)-3-((2-((5)-(4-Cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylic acid. To a solution of ethyl (5S)-3-((2-((5)-(4- cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (325 mg, 0.508 mmol, Step A) in 4.5 mL of THFH2O (8: 1) was added LiOH (48.7 mg, 2.03 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated and then azeotroped using ACN (3x) to provide a residue which was purified by basic preparative HPLC (XB ridge Cl 8, 5 pm, 50 x 100 mm, 10-100% MeCN / H2O (20 mM NH4OH)) to afford the title compound (84% yield). MS (ESI) m / z: [M+H]+Found 612.3.

[0472] Intermediate 7: tert-Butyl (5S)-2-oxo-3-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl)-5- (trifluoromethyl)pyrrolidine- 1 -carboxylate

[0473] A solution of tert-butyl (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (1.0 g, 3.95 mmol, Intermediate 2) in THF (15 mL) was added dropwise via addition funnel to a solution of LiHMDS in THF (7.9 mL, 1.0 M, 7.9 mmol) at -78 °C and the resulting mixture was stirred at - 78 °C for 30 min. Then a solution of (bromomethyl)boronic acid pinacol ester (2.6 g, 11.85 mmol) in THF (8 mL) was added, and the resulting mixture was allowed to warm to rt over 1 h. The reaction mixture was then quenched by the dropwise addition of water (20 mL) at 0 °C. The organic layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO-i, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0-50% EtOAc / hexanes (with 0.1% NEts)) to provide the title compound (82% yield).

[0474] Intermediate 8: 4-(l,l-Difluoroethyl)-1,2,5-oxadiazole-3-carboxylic acid

[0475] A mixture of ethyl 4-(l,l-difluoroethyl)-1,2,5-oxadiazole-3-carboxylate (10.0 g, 48.5 mmol) and LiOH»H2O (6.11 g, 146 mmol) in EtOH / water (120 mL, 2: 1) was stirred at rt for 3 h. The mixture was concentrated to remove EtOH. Then, water (50 mL) was added and the mixture was extracted with EtOAc (2 x 100 mL). The pH of the aqueous layer was adjusted to pH <3 by the addition of 1 N aqueous HC1, and then the aqueous layer was extracted EtOAc (3 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a yellow oil. The oil was diluted with ACN and water, frozen and lyophilized to provide the title compound as a yellow solid (6.8% yield). MS (ESI) m / z: [M-H]+Found 177.0.

[0476] Intermediate 9: 2,5-Dioxopyrrolidin-l-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate

[0477] Step A: 4-Cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride. A solution of 4- cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (200 mg, 1.30 mmol) in DCM (2.6 mL) was cooled to 0 °C, then oxalyl chloride (0.224 mL, 2.60 mmol) was added dropwise followed by 1 drop of DMF. The mixture was stirred for 3 h as it warmed to rt. The reaction mixture was concentrated under reduced pressure into a yellow oil and dissolved in DCM to result in a 2 M solution of 4-cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride that was used without further purification.

[0478] Step B: 2,5-Dioxopyrrolidin-l-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate. A flask was charged with A-hydroxysuccinimide (231 mg, 1.95 mmol), DCM (3.25 mL) and DIPEA (0.336 mL, 1.95 mmol). The reaction mixture was cooled to 0 °C and 4-cyclopropyl-1,2,5- oxadiazole-3 -carbonyl chloride (2 M in DCM, 0.649 mL, 1.30 mmol, Step A) was then added dropwise. The reaction mixture was stirred for 1 h as it warmed to rt. The reaction mixture was then washed with water and brine sequentially, dried over anhydrous MgSO-i, filtered and concentrated to dryness. The material was purified by silica gel chromatography (0-100% (EtOAc with 10% MeOH) / hexanes) to afford the title compound as a clear oil (39% yield). MS (ESI) m / z: [M+H]+Found 252.2.

[0479] Intermediate 10: (5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin- 7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride

[0480] Step A: tert-Butyl (5S)-3-azido-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]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[1,2-b ]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 1 M LiHMDS in THF (2.0 mL, 2.0 mmol) 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) 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 the title compound as a yellow solid (17% yield). MS (ESI) m / z: [M+H]+Found 673.1.

[0481] Step B: (5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin- 7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride. A mixture of tert-butyl (5S)-3-azido-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]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 the title compound as a white solid (88% yield). MS (ESI) m / z: [M+H]+Found 473.4. Intermediate 11 : A-((15)-(7-(((5S)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide

[0482] Step A: A-((15)-(7-(((5S)-3-Azido-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- 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 (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride (125 mg, 0.25 mmol, Intermediate 10) 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 to dryness. The residue was purified by silica gel chromatography (0- 80% EtOAc / petroleum ether) to provide the title compound as a yellow solid (60% yield). MS (ESI) m / z: [M+H]+Bound 609.2.

[0483] Step B: A-((15)-(7-(((5S)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide. A flask containing a mixture of A-((15)-(7-(((5S)-3-azido-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-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 concentrated to dryness. The residue was purified by silica gel chromatography (0-80% EtOAc / petroleum ether) to provide the title compound as a white solid (81% yield). MS (ESI) m / z: [M+H]+Found 583.3.

[0484] Intermediate 12: A-((15)-(7-(((5S)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- oxadiazole-3 -carboxamide

[0485] The title compound was prepared as described for the synthesis of Intermediate 11 using 4- methoxy-1,2,5-oxadiazole-3-carboxylic acid in place of 4-cyclopropyl-1,2,5-oxadiazole-3- carboxylic acid in Step A. MS (ESI) m / z: [M+H]+Found 573.1.

[0486] Intermediate 13: N-((1S)-(7-(((5S)-3-Amino-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[l, 2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide

[0487] The title compound was prepared as described for the synthesis of Intermediate 11 using 4- methyl- 1,2,5-oxadiazole-3-carboxylic acid in place of 4-cyclopropyl-1,2,5-oxadiazole-3- carboxylic acid in Step A. MS (ESI) m / z: [M+H]+Found 557.1.

[0488] Intermediate 14: N-((5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)-2-methoxyacetamide

[0489]

[0490] Step A: tert-Butyl (5S)-3-amino-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. The title compound (96% yield) was prepared as described for the synthesis of Intermediate 11 Step B using tert-butyl (5S)-3-azido-3-((2-((5)- ((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate (Intermediate 10, Step A) in place of A-((S)-(7-(((5S)-3-azido-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5-oxadiazole-3- carboxamide. MS (ESI) m / z: [M+H]+Found 647.3.

[0491] Step B: tert-Butyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-(2-methoxyacetamido)-2- oxo-5-(trifhioromethyl)pyrrolidine-l -carboxylate. The title compound was prepared as described for the synthesis of Example 6 using tert-butyl (5S)-3-amino-3-((2-((S)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (Step A) in place of A-((S)-(7-(((5S)-3-amino- 2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4- difhiorocyclohexyl)methyl)-4-methoxy-1,2,5-oxadiazole-3-carboxamide and 2-methoxyacetyl chloride in place of 1 -fluorocyclopropane- 1 -carbonyl chloride. The residue was purified by silica gel chromatography (0-40% EtOAc / petroleum ether) to provide the title compound as a white solid (74% yield). MS (ESI) m / z: [M+H]+Found 719.2.

[0492] Step C: A-((5S)-3-((2-((5)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)-2-methoxyacetamide. The title compound was prepared as described for the synthesis of Intermediate 1002 Step B using tert-butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-(2-methoxyacetamido)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (Step B) in place of tert-butyl (5S)-3-azido-3- ((2-((5)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l ,2-b ]pyridazin- 7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. The residue was purified by preparative HPLC (XBridge OBD Cl 8, 5 pm, 150 x 30 mm, 14-41% ACN / H2O (with 10 mM NH4HCO3 + 0.05% NH3)) to provide the title compound as a single diastereomer, which was designated as the (35) diastereomer which was a white solid (59% yield). MS (ESI) m / z: [M+H]+Found 519.2.

[0493] Intermediate 15: Methyl (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate

[0494] Step A: 1 -(tert-Butyl) 3-methyl (5S)-3-((2-((5)-(( / er / -butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluor omethyl)pyrrolidine- 1,3 -di carboxy late. The title compound was prepared as described for the synthesis of Intermediate 5 using methyl carbonochloridate in place of ethyl chloroformate. The residue was purified by silica gel chromatography (50-60% EtOAc / petroleum ether) to provide the title compound as a brown solid (74% yield). MS (ESI) m / z: [M+H]+Found 690.4.

[0495] Step B: Methyl (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. The title compound (94% yield) was prepared as described for the synthesis of Intermediate 10 Step B using 1 -(tert-butyl) 3-methyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l,3-dicarboxylate (Step A) in place of tert-butyl (5S)-3-azido-3-((2- ((5)-(( / er / -butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate. MS (ESI) m / z: [M+H]+Found 490.2. Intermediate 16: 2-Cyclopropoxyacetyl chloride

[0496] A mixture of 2-cyclopropoxyacetic acid (50 mg, 0.43 mmol) in DCM (2 mL) was stirred until it became homogeneous, and was then cooled to 0 °C in an ice-water bath. Then, a solution of DMF (0.0033 mL, 0.043 mmol) in DCM (1 mL) was added followed by a solution of (COC1)2 (0.036 mL, 0.43 mmol) in DCM (1 mL). The resulting mixture was stirred at rt for 1 h and was used as a solution in DCM in the next reaction.

[0497] Intermediate 17: A-((S)-(7-(((5S)-3-(Aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrohdin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide

[0498] Step A: tert-Butyl (5S)-3-((2-((S)-((tertbutoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-((l,3-dioxoisoindolin-2- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate. A solution of tert-butyl (5«S)-3- ((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin- 7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate (500 mg, 0.79 mmol, Intermediate 3) in THF (10 mL) was cooled to -78 °C, 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 NH4Q (50 mL) was added dropwise 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 the title compound as a white solid (70% yield). MS (ESI) m / z: [M+H]+Found 791.3.

[0499] Step B: 2-(((5S)-3-((2-((5)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)isoindoline- l , 3-dione hydrochloride. The title compound (97% yield) was prepared as described for the synthesis of Intermediate 10, Step B using tert-butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]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 (3R ,5S)-3-azido-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. MS (ESI) m / z: [M+H]+Found 591.3.

[0500] Step C: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((5S)-3-((l,3-dioxoisoindolin- 2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)methyl)-1,2,5-oxadiazole-3-carboxamide. A mixture of 2-(((5S)-3-((2-((5)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]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 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 a yellow oil. The oil was purified by silica gel chromatography (60-70% EtOAc / petroleum ether) to provide the title compound as a brown solid (58% yield). MS (ESI) m / z: [M+H]+Found 727.2.

[0501] Step D: A-((S)-(7-(((5S)-3-(Aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide. A mixture of 4-cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7- (((5S)-3-((l,3-dioxoisoindolin-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (550 mg, 0.76 mmol, Step C) and N2H4.H2O (187 mg, 3.66 mmol) in MeOH (15 mL) was stirred at rt for 30 min, 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 the title compound as a white solid (49% yield). MS (ESI) m / z: [M+H]+Found 597.2.

[0502] Intermediate 18: 2-((5S)-3-((2-((5)-(4-Cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetic acid

[0503] Step A: tert-Butyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-(2-methoxy-2-oxoethyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate. The title compound was prepared as described for the synthesis of Intermediate 4 using methyl bromoacetate in place of ethyl chloroformate. The residue was purified by silica gel chromatography (0-100% EtOAc (with 10% MeOH) / hexanes) followed by basic preparative HPLC (loaded with minimal DMF, XBridge Cl 8, 5 pm, 50 x 250 mm, 10-100% MeCN / H2O (20 mM NH4OH)) to provide the title compound as a brown solid (34% yield). MS (ESI) m / z: [M+H]+Found 718.2.

[0504] Step B: Methyl 2-((5S)-3-((2-((S)-amino(4,4-difhiorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate. A solution of tertbutyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[ 1 ,2- b ]pyridazin-7-yl)methyl)-3-(2-methoxy-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine- l - carboxylate (434 mg, 0.62 mmol, Step A) in DCM (3 mL) was cooled to 0 °C in an ice-water bath, and then TFA (0.94 mL, 12.3 mmol) was added dropwise. The resulting solution was stirred at 0 °C for 2 min, then the ice-water bath was removed and the solution was stirred at rt for 1 h. The reaction was concentrated to dryness, then diluted with 4: 1 DCMTPA and saturated aqueous NaHCO3The pH of the mixture was adjusted to -pH 11 by the addition of 1 M aqueous NaOH, then the layers were separated and the aqueous layer was further extracted with 4: 1 DCM:IPA (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and anhydrous MgSO-i, filtered and concentrated to dryness to provide the title compound as an oil that was used without further purification. MS (ESI) m / z: [M+H]+Found 518.2.

[0505] Step C: Methyl 2-((5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate. To a solution of methyl 2-((5S)-3-((2-((5)-amino(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetate (310 mg, 0.62 mmol, Step B) in ACN (1.7 mL) were added 2,5-dioxopyrrolidin-l-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate (201 mg, 0.8 mmol, Intermediate 9) and DIPEA (320 μL, 1.85 mmol). The reaction mixture was stirred at rt for 30 min and then concentrated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc (with 10% MeOH) / hexanes) to provide the title compound as a light-yellow oil (100% yield). MS (ESI) m / z: [M+H]+Found 654.2.

[0506] Step D: 2-((5S)-3-((2-((5)-(4-Cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetic acid. To a solution of methyl 2-((5S)-3-((2-((S)-(4- cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)acetate (330 mg, 0.52 mmol, Step C) in 2.5 mL of THF:H2O (4:1) was added LiOH (31 mg, 1.3 mmol). The reaction was heated at 45 °C for 1 h, then additional LiOH (25 mg, 1.03 mmol) was added and the mixture was heated at 45 °C for 21 h. 4 M HC1 in water (0.62 mL) was then added and the mixture was concentrated and then azeotroped using THF to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 626.3.

[0507] Intermediate 19: 1 -(tert-Butyl) 3-ethyl (5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-l,3- dicarboxylate A solution of tert-butyl (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate (2.0 g, 7.9 mmol, Intermediate 2) in THF (30 mL) was added dropwise to a solution of LiHMDS (15.8 mL, 1 M in THF, 15.8 mmol) at -78 °C and the resulting mixture was stirred at -78 °C for 1 h. A solution of ethyl chloroformate (0.83 mL, 8.7 mmol) in THF (15 mL) was then added dropwise to the reaction mixture at -78 °C. The temperature of the mixture was increased to rt, and held at rt for 1 h. Then, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc / hexane) to afford the title compound (98% yield). MS (ESI) m / z: [(M-100)+H]+Found 226.1.

[0508] EXAMPLES

[0509] Example 1 : 4-Cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-((2,2- difhroroethyl)carbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- b ]pyridazin-2-yl)methyl)- l ,2,5-oxadiazole-3-carboxamide

[0510] To a solution of (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylic acid (75 mg, 0.123 mmol, Intermediate 6) in DMF (1.2 mL) were added 2,2-difhioroethylamine (17.8 pL, 0.245 mmol), HATU (65.3 mg, 0.172 mmol) and DIPEA (84.5 pL, 0.491 mmol). After 2 h of stirring at rt, additional 2,2-difluoroethylamine (14.3 pL, 0.196 mmol), HATU (60.6 mg, 0.159 mmol) and DIPEA (63.4 pL, 0.368 mmol) were added and the reaction mixture was stirred for an additional 30 min at rt. The reaction was filtered and directly purified by basic preparative HPLC (XBridge Cl 8, 5 pm, 50 x 100 mm, 10- 100% MeCN / H2O (20 mM NH4OH)) to provide a mixture of diastereomers. The diastereomers were separated by chiral SFC (Stationary phase: Whelk 01 SS, 5 pm, 250 x 21 mm, Mobile phase: 20% methanol, 80% CO2). The first eluting isomer was the (3R) isomer, 4-cyclopropyl-A- ((5)-(4,4-difluorocyclohexyl)(7-(((3A,5S)-3-((2,2-difluoroethyl)carbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5-oxadiazole- 3 -carboxamide. The second eluting isomer which was the major isomer, the (35) isomer, 4- cyclopropyl- / V-((5)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-((2,2-difluoroethyl)carbamoyl)-2- oxo-5-(trifhioromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5- oxadiazole-3 -carboxamide, was obtained in 36% yield. NMR (500 MHz, DMSO- d6) 5 8.14 - 8.12 (m, 1H), 7.92 - 7.89 (m, 1H), 7.77 - 7.72 (m, 1H), 7.71 - 7.69 (m, 1H), 7.52 (t, J= 6.0 Hz, 1H), 6.10 - 6.02 (m, 1H), 6.01 - 5.96 (m, 1H), 5.90 - 5.85 (m, 1H), 5.79 - 5.74 (m, 1H), 5.31 (dd, .7= 8.0, 8.6 Hz, 1H), 4.18 - 4.09 (m, 1H), 3.86 - 3.72 (m, 1H), 3.65 - 3.50 (m, 1H), 3.33 - 3.21 (m, 3H), 2.61 - 2.56 (m, 1H), 2.25 - 2.13 (m, 3H), 2.14 - 2.06 (m, 1H), 2.05 - 1.98 (m, 1H), 1.77 - 1.67 (m, 2H), 1.49 - 1.35 (m, 1H), 1.25 - 1.13 (m, 3H), 1.13 - 1.07 (m, 1H). MS (ESI) m / z: [M+H]+Found 675.2.

[0511] Example 2: A-((5)-(4,4-Difluorocyclohexyl)(7-(((3 / ?,5S)-3-(2-methoxyacetamido)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4-(l,l- difluoroethyl)-!, 2, 5-oxadiazole-3-carboxamide

[0512] To a solution of A-((5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)-2-methoxyacetamide (18 mg, 0.035 mmol, Intermediate 14) in DCM (1 mL) was added a solution of 4-(l,l-difluoroethyl)- 1,2,5-oxadiazole-3-carboxylic acid (9.89 mg, 0.055 mmol, Intermediate 8) in EtOAc (0.5 mL).

[0513] To the resulting mixture were added 1-propanephosphonic anhydride (0.062 mL, 0.104 mmol, 50 wt. % in EtOAc) and DIPEA (0.036 mL, 0.208 mmol) and the mixture was stirred at rt for 45 min. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (0-100% EtOAc / hexanes) to give the major isomer as the title compound (19% yield).1H NMR (500 MHz, DMSO- d6) 8 8.23 - 8.18 (m, 1H), 7.91 (s, 1H), 7.82 (d, J= 8.6 Hz, 1H), 7.76 - 7.72 (m, 1H), 6.98 - 6.94 (m, 1H), 6.40 (s, 1H), 5.35 - 5.28 (m, 1H), 4.40 - 4.32 (m, 1H), 3.92 - 3.88 (m, 2H), 3.42 - 3.36 (m, 4H), 3.14 (d, J= 14.3 Hz, 1H), 2.84 (dd, J= 9.7, 14.9 Hz, 1H), 2.50 (dd, J= 4.6, 14.9 Hz, 1H), 2.28 - 2.13 (m, 5H), 2.12 - 2.04 (m, 1H), 1.99 (d, J = 12.3 Hz, 1H), 1.85 - 1.66 (m, 3H), 1.60 - 1.49 (m, 1H), 1.44 - 1.33 (m, 1H). MS (ESI) m / z: [M+H]+Found 679.5.

[0514] Example 3: A-((5)-(4,4-Difluorocyclohexyl)(7-(((35,5S)-3-(methylcarbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4- (difluoromethyl)-1,2,5-oxadiazole-3-carboxamide

[0515] Step A: (S)-N-((7-Chloroimidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)- 4-(difluoromethyl)- 1,2, 5 -oxadiazole-3 -carboxamide. To a solution of (5)-(7-chloroimidazo[l,2- b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanamine (1.40 g, 4.66 mmol) in THF (30 mL) was added a solution of trimethylaluminum in THF (4.70 mL, 9.31 mmol, 2.0 M) drop wise at 0 °C over 10 min. The resulting solution was stirred at rt for 1 h, then the reaction mixture was cooled to 0 °C and a solution of ethyl 4-(difluoromethyl)-1,2,5-oxadiazole-3-carboxylate (1.30 g, 6.98 mmol) in THF (15 mL) was added dropwise via addition funnel. The resulting mixture was heated to 70 °C and stirred at this temperature for 16 h. The reaction was cooled to rt and quenched with IPA (10 mL) followed by MeOH (10 mL) and saturated aqueous Na2SO4 solution (20 mL) and stirred for 30 min at rt. The reaction mixture was filtered through diatomaceous earth, and the filtrate extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous MgSO-i, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound (73% yield). MS (ESI) m / z: [M+H]+Found 447.1. Step B: (45)-4-((tert-Butoxycarbonyl)amino)-2-((2-((5)-(4,4-difluorocyclohexyl)(4- (difluoromethyl)-1,2,5-oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)- 5,5,5-trifluoropentanoic acid. To a vial (1), (5)-A-((7-chloroimidazo[1,2-b ]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-4-(difluoromethyl)-1,2,5-oxadiazole-3-carboxamide (500 mg, 1.12 mmol, Step A) and mesylate[(di(l-adamantyl)-«-butylphosphine)-2-(2'-amino-l,l'- biphenyl)]palladium(II) (81.5 mg, 0.11 mmol) were added. In a separate vial (2), tert-butyl (5S)-

[0516] 2-oxo-3-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl)-5-(trifluoromethyl)pyrrolidine-l- carboxylate (660 mg, 1.68 mmol, Intermediate 7) was added and both vials were taken inside the glovebox. 1,4-Dioxane (5.6 mL) was added to vial (2) and the resulting solution was added to vial (1). A solution of K2CO3 (464 mg, 3.36 mmol) in water (1.12 mL) was then added. The vial was sealed and taken out of the glovebox. The reaction was heated to 100 °C for 16 h. Upon cooling to rt, the reaction mixture was filtered through diatomaceous earth, and the filtrate extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous MgSO-i, filtered, and concentrated to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 696.2.

[0517] Step C: tert-Butyl (5S)-3-((2-((5)-(4,4-difhrorocyclohexyl)(4-(difluoromethyl)-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. To a solution of (4S)-4-((tert- butoxycarbonyl)amino)-2-((2-((5)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-oxadiazole-

[0518] 3-carboxamido)methyl)imidazo[l ,2-b ]pyridazin-7-yl)methyl)-5,5,5-trifluoropentanoic acid (778 mg, 1.12 mmol, Step B) in DCM (22 mL), DIPEA (0.96 mL, 5.60 mmol) was added and the resulting mixture was stirred for 5 min at rt. HATU (745 mg, 1.96 mmol) was added in portions and the reaction mixture was stirred at rt 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 (2 x 10 mL), dried over anhydrous MgSO-i, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound (57% yield). MS (ESI) m / z: [M+H]+Found 678.2.

[0519] Step D: 1 -(tert-Butyl) 3-ethyl (5S)-3-((2-((5)-(4,4-difluorocyclohexyl)(4- (difluoromethyl)-1,2,5-oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)- 2-oxo-5-(trifluoromethyl)pyrrolidine-l,3-dicarboxylate. To a solution of tert-butyl (5S)-3-((2- ((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)- l ,2,5-oxadiazole-3- carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (300 mg, 0.44 mmol, Step C) in THF (4 mL) was added a solution of LiHMDS in THF (0.97 mL, 1 M, 0.97 mmol) dropwise at -78 °C under a positive N2 atmosphere. The resulting solution was stirred at -78 °C for 30 min. A solution of ethyl chloroformate (0.055 mL, 0.58 mmol) in THF (2 mL) was then added dropwise over 5 min at -78 °C. The reaction mixture was then allowed to warm to rt over 1 h. A solution of AcOH in EtOAc (4 mL, 0.11 M) was added dropwise at 0 °C, followed by the dropwise addition of water (10 mL). The mixture was diluted with EtOAc (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0-70% EtOAc / hexanes) to provide the title compound (47% yield). MS (ESI) m / z: [M+H]+Found 750.2.

[0520] Step E: A-((S)-(4,4-Difluorocyclohexyl)(7-(((35,5S)-3-(methylcarbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4- (difluoromethyl)-1,2,5-oxadiazole-3-carboxamide. To a solution of 1 -(tert-Butyl) 3-ethyl (5S)-3- ((2-((5)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-oxadiazole-3- carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine- 1,3 -di carboxy late (30 mg, 0.04 mmol, Step D) in THF (0.2 mL) was added a solution of methylamine (60 pL, 0.12 mmol, 2.0 M in THF) at rt. The mixture was cooled to 0 °C and trimethylaluminum solution (4.7 mL, 9.3 mmol, 2.0 M in THF) was added dropwise. The resulting solution was heated at 70 °C for 1.5 h. The reaction was cooled to rt and quenched with IPA (0.5 mL) followed by MeOH (0.5 mL) and saturated aqueous Na2SO4 solution (1 mL) and the mixture was stirred at rt for 30 min. The reaction mixture was filtered through diatomaceous earth, and the filtrate extracted with EtOAc (2 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 followed by 0-5% MeOH / EtOAc) to provide a mixture of diastereomers (90:10 dr). The diastereomers were separated by chiral SFC (Stationary phase: Chiralcel Whelk 01 SS, 5 pm, 250 x 21 mm, Mobile phase: 20% methanol with 0.2% diethylamine, 80% CO2). The first eluting isomer was designated as the (3R ) isomer, N-((S)-(4,4- difluorocyclohexyl)(7-(((3R 5R )-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4-(difluoromethyl)-1,2,5-oxadiazole-3- carboxamide. The second eluting isomer, the title compound, (A-((5)-(4,4-difluorocyclohexyl)(7- (((35,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- b ]pyridazin-2-yl)methyl)-4-(difluoromethyl)-1,2,5-oxadiazole-3-carboxamide), which was the major diastereomer in the mixture was obtained in 37% yield.1H NMR (500 MHz, MeOH-<A) 5 8.27 (d, J= 2.1 Hz, 1H), 8.11 (s, 1H), 7.78 (d, J= 2.0 Hz, 1H), 7.33 (t, J= 52.4 Hz, 1H), 5.26 (d, J= 8.6 Hz, 1H), 4.56 (s, 1H), 4.24 - 4.16 (m, 1H), 3.30 - 3.28 (m, 1H), 3.05 (dd, J= 14.1, 8.6 Hz, 1H), 2.77 (s, 3H), 2.25 (q, J= 10.9 Hz, 1H), 2.16 - 1.97 (m, 4H), 1.87 - 1.60 (m, 4H), 1.53 - 1.38 (m, 4H). MS (ESI) m / z: [M+H]+Found 635.2.

[0521] Example 4: A-((5)-(4,4-Difluorocyclohexyl)(7-(((35,5S)-3-(methylcarbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4-(l,l- difluoroethyl)-!, 2, 5-oxadiazole-3-carboxamide

[0522] Step A: Ethyl (5S)-3-((2-((5)-(4,4-difluorocyclohexyl)(4-(l,l-difluoroethyl)-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. To a solution of ethyl (5S)-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate (25 mg, 0.050 mmol, Intermediate 5) in DCM (0.25 mL) was added DIPEA (0.051 mL, 0.30 mmol). Then a solution of 4-( 1,1 -difluoroethyl)- 1,2,5 - oxadiazole-3-carboxylic acid (15 mg, 0.084 mmol, Intermediate 8) in ethyl acetate (0.25 mL) was added to the reaction mixture. The resulting mixture was stirred for 5 min at rt, then T3P (0.089 mL, 0.15 mmol, 50 wt% in EtOAc) was added in one portion and the mixture was stirred at rt for 45 min. The reaction mixture was concentrated to dryness and purified by silica gel chromatography (0-100% (10% MeOH in EtOAc) / hexanes) to provide the title compound as an off-white solid (70% yield). MS (ESI) m / z: [M+H]+Found 664.1 Step B: Lithium (5S)-3-((2-((5)-(4,4-difluorocyclohexyl)(4-(l,l-difluoroethyl)-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. To a solution of ethyl (5S)-3-((2-((5)-(4,4- difluorocyclohexyl)(4-(l , 1 -difluoroethyl)- 1 ,2,5-oxadiazole-3-carboxamido)methyl)imidazo[l ,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (23 mg, 0.035 mmol, Step A) in THF (0.25 mL) and water (0.15 mL) was added solid LiOH (3.4 mg, 0.14 mmol) in one portion. The reaction mixture was stirred at rt for 45 min. The mixture was then concentrated to dryness to provide the title compound as a white solid that was used without further purification. MS (ESI) m / z: [M+H]+Found 636.1.

[0523] Step C: A-((5)-(4,4-Difluorocyclohexyl)(7-(((35,5S)-3-(methylcarbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4-(l,l- difluoroethyl)-1,2,5-oxadiazole-3-carboxamide. To a solution of lithium (5S)-3-((2-((5)-(4,4- difluorocyclohexyl)(4-(l , 1 -difluoroethyl)- 1 ,2,5-oxadiazole-3-carboxamido)methyl)imidazo[l ,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (70.0 mg, 0.109 mmol, Step B) in DMA (0.59 mL) were added methylamine (2 M in THF, 0.20 mL, 0.40 mmol) followed by TCFH (63.8 mg, 0.227 mmol). The resulting mixture was stirred at rt for 1 h after which the reaction mixture was purified directly by preparative HPLC (0-100% ACN / 20 mM NH4OH) to afford the title compound as a mixture of diastereomers. The diastereomers were separated by chiral SFC (Stationary phase: Whelk 01 SS, 5 pm, 250 x 21 mm, Mobile phase: 20% methanol, 80% CO2). The first eluting isomer was the (37?) isomer, N-((S)-(4,4- difluorocyclohexyl)(7-(((3 R,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[ 1 ,2-Z>]pyridazin-2-yl)methyl)-4-( 1 , 1 -difluoroethyl)- 1 ,2, 5-oxadiazole-3- carboxamide. The title compound that was the second eluting isomer and the major isomer and the (35) isomer (38% yield), was, N-(( 5)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3- (methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)methyl)-4-(l,l-difluoroethyl)-1,2,5-oxadiazole-3-carboxamide. 'H NMR (500 MHz, MeOH- d4) δ 8.32 - 8.29 (m, 1H), 8.11 (s, 1H), 7.82 - 7.79 (m, 1H), 5.35 - 5.24 (m, 1H), 4.31 - 4.16 (m, 1H), 3.35 - 3.34 (m, 3H), 3.34 - 3.31 (m, 2H), 3.15 - 3.01 (m, 1H), 2.80 (s, 3H), 2.32 - 1.95 (m, 5H), 1.91 - 1.72 (m, 2H), 1.73 - 1.65 (m, 1H), 1.59 - 1.40 (m, 2H). MS (ESI) m / z: [M+H]+Found 649.2. Example 5: 4-Cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7-(((3A,5S)-3-( N-methylacetamido)- 2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)- 1 ,2,5- oxadiazole-3 -carboxamide

[0524] Step A: 4-Cyclopropyl-A-((1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(((E)- (dimethylamino)methylene)amino)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. N-((1 S)-(7- (((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-l ,2, 5 -oxadiazole-3 -carboxamide (100 mg, 0.137 mmol, Intermediate 11) was added 1:1 DMF:DMA (3.0 mL) and the mixture was then evacuated and refilled with N2. The mixture was stirred until homogeneous and then heated at 80 °C for 2 h. The reaction mixture was cooled to rt and concentrated to dryness to provide the title compound as a brown oil (73% yield) that was used without further purification. MS (ESI) m / z: [M+H]+Found 638.2.

[0525] Step B: 4-Cyclopropyl-N-((1S')-(4,4-difluorocyclohexyl)(7-(((5S')-3-(methylamino)-2- oxo-5-(trifhioromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5- oxadiazole-3-carboxamide. 4-Cyclopropyl-A-((1S')-(4,4-difluorocyclohexyl)(7-(((5S)-3-(((E )- (dimethylamino)methylene)amino)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (90.0 mg, 0.141 mmol, Step A), Pd / C (40.0 mg, 10 wt %) and Pd(OH)2 / C (40.0 mg, 20 wt %) were suspended in MeOH (5.0 mL) in a flask that was subsequently evacuated and refilled with hydrogen. The resulting mixture was stirred at rt for 1 h under one atmosphere of hydrogen. The reaction mixture was then filtered through a pad of diatomaceous earth, and the filtrate was dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a white solid. The solid was purified by silica gel chromatography (0-6% MeOH / DCM) to provide the title compound as a white solid (13% yield). MS (ESI) m / z: [M+H]+Found 597.3. Step C: 4-Cyclopropyl-A-((S)-(4,4-difhiorocyclohexyl)(7-(((5S)-3-(7V-methylacetamido)- 2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)- 1 ,2,5- oxadiazole-3 -carboxamide. A mixture of 4-cyclopropyl-A-((1S')-(4,4-difluorocyclohexyl)(7- (((5S)-3-(methylamino)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2- b ]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide(20 mg, 0.034 mmol, Step B) and NMM (10 pL, 0.091 mmol) in DCM (2 mL) was cooled to 0 °C in an ice water bath. Acetyl chloride (4 pL, 0.056 mmol) was then added and the resulting mixture was stirred at rt for 1 h. The reaction mixture was poured over water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (3 x 1 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a yellow oil. The oil was purified by preparative HPLC (XSelect CSH Cl 8, 5 pm, 250 x 19 mm, 32-57% ACN / H2O (with 0.1% LA)) to provide, the title compound (white solid) as the major isomer (17% yield).JH NMR (400 MHz, DMSO- de) 59.54 (br s, 1H), 8.66 (br s, 1H), 8.32 (d, J= 1.5 Hz, 1H), 8.21 - 8.20 (m, 1H), 7.91 (d, J = 1.2 Hz, 1H), 5.22 - 5.20 (m, 1H), 4.17 - 4.10 (m, 1H), 3.24 - 3.21 (m, 2H), 3.03 (s, 3H), 2.45 - 2.39 (m, 1H), 2.29 - 2.14 (m, 3H), 2.07 - 2.03 (m, 5H), 1.86 - 1.72 (m, 3H), 1.61 - 1.58 (m, 1H), 1.43 - 1.23 (m, 2H), 1.12 - 1.08 (m, 2H), 0.97 - 0.93 (m, 2H). MS (ESI) m / z: [M+H]+Found 639.2.

[0526] Example 6: N-((N)-(4,4-Difluorocyclohexyl)(7-(((37?,5S)-3-(l-fluorocyclopropane-l- carboxamido)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)methyl)-4-methoxy-1,2,5-oxadiazole-3-carboxamide

[0527] A mixture of N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- oxadiazole-3 -carboxamide (25 mg, 0.044 mmol, Intermediate 12), 1 -fluorocyclopropane- 1- carbonyl chloride (9.5 mg, 0.078 mmol) and NMM (15 pL, 0.14 mmol) in DCM (2 mL) was stirred at rt for 30 min. Then, the reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (XBridge OBD Cl 8, 5 pm, 150 x 30 mm, 29-59% ACN / H2O (with 10 mM NH4HCO3)) to provide the title compound (white solid) as the major isomer (49% yield).JH NMR (400 MHz, DMSO- d6) 8 9.33 (br s, 1H), 8.90 (br s, 1H), 8.71 (br s, 1H), 8.33 (d, J= 2 Hz, 1H), 8.20 (s, 1H), 7.97 (d, J= 1.6 Hz, 1H), 5.17 - 5.15 (m, 1H), 4.31 - 4.26 (m, 1H), 4.08 (s, 3H), 3.21 - 3.15 (m, 2H), 2.48 - 2.44 (m, 1H), 2.33 - 2.19 (m, 2H), 2.18 - 2.02 (m, 2H), 1.99 - 1.70 (m, 3H), 1.64 - 1.58 (m, 1H), 1.38 - 1.34 (m, 3H), 1.30 - 1.22 (m, 1H), 1.21 - 1.13 (m, 2H). MS (ESI) m / z: [M+H]+Found 659.1.

[0528] The examples shown in Table 1 were prepared in a manner analogous to A-((6')-(4,4- difluorocyclohexyl)(7-(((37?,58)-3-(l-fluorocyclopropane-l-carboxamido)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)-4-methoxy-1,2,5- oxadiazole-3-carboxamide (Example 6) using the appropriate carboxylic acid chloride in place of 1 -fluorocyclopropane- 1 -carbonyl chloride and using the appropriate amine in place of N-((1S')- (7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5-oxadiazole-3-carboxamide as described in Table 2.

[0529] Table 1 : Table 2: Example 7. The absolute configuration of Example 7 was confirmed with further 2D-NMR correlation between the methine proton 33a and methylene proton 32b was observed when compared to the NOESY correlation between proton 33a and 32a, confirming that protons 33a and 32b are on the same side of the lactam ring. Key NOESY correlations were observed between the amine proton on the N-36 position and the methylene proton 32b, confirming that the protons 33a and 32b, and the N-36 proton are on the same side of the lactam ring. NOESY correlations were also observed between methylene protons 30a, 30b, and 32a, confirming that the C-30 sidechain are on the same side of the lactam ring as the proton 32a, which is opposite to the side of the protons 33a, 32b, and N-36. These correlations confirmed the relative cis stereochemistry between the C-30 sidechain and the C-39 sidechain.

[0530] Example 10. The absolute configuration of Example 10 was confirmed with further 2D-NMR analysis as shown here: . Key HOESY correlations were observed from the CF3 group on the C-33 position to the methylene protons 32a and 32b with the HOESY correlation between the CF3 group and 32a being stronger, confirming that the CF3 group and the proton 32a are on the same side of the lactam ring. Key NOESY correlations were observed between the protons 33a and 32b, confirming that they are on the same side of the lactam, which is opposite to the side of the CF3 group and the proton 32a. An additional NOESY correlation was observed between the proton 32a and the methylene protons 51 and 52 confirming that the C-30 side chain and the proton 32a are on the same side of the lactam ring. These correlations confirmed the relative cis stereochemistry between the C-30 sidechain and the C-42 sidechain.

[0531] Example 11. The absolute configuration of Example 11 was confirmed with further 2D-NMR analysis as shown here: Key NOESY correlations were observed between the methine proton 33a, methylene proton 32b and the amine proton at the N-36 position, confirming that all three protons are on the same side of the lactam ring. Additional key NOESY correlations were observed between the methylene protons 30a and 30b and methylene proton 32a, whichconfirmed the C-30 sidechain and the proton 32a are on the same side of the lactam ring, which is opposite to the side of the proton 33a, the proton 32b, and the amine N-36 proton. These correlations confirmed the relative cis stereochemistry between the C-30 sidechain and the C-40 sidechain.

[0532] Example 13. The absolute configuration of Example 13 was confirmed with further 2D-NMR analysis as shown here: Key NOESY correlations were observed between the proton 32a and the methylene protons 30a and 30b, as shown above, confirming that the C-30 sidechain and proton 32a are on the same side of the lactam ring. Stronger NOE correlations between the proton 33a and the proton 32b and between the 32b proton and the amine proton on the N-36 position confirmed that the protons 33a, 32b, and the N-36 sidechain are all on the same side of the lactam, which is opposite to the side of the C-30 sidechain and proton 32a. These correlations confirmed the relative trans stereochemistry between the C-30 sidechain and the C-39 sidechain.

[0533] Example 15. The absolute configuration of Example 15 was confirmed with further 2D-NMR analysis as shown here: . Key NOESY correlations were observed between the methine proton 37a and the methylene protons 36a and 36b and between the protons at the C-4 position and the protons 36a and 36b. Compared to the proton 36a, the proton 36b showed stronger NOE correlations with the respective proton 37a and the protons at the C-4 position, which confirmed that the proton 37a, the proton 36b, and the C-4 sidechain are all on the same side of the lactam ring. Additional key NOESY correlations observed between the methine proton 37a and the protons at the C-4 position, further confirming they are on the same side of the lactam ring. Key NOESY correlations were also observed between the methylene protons 6a and 6b and the methylene proton 36a, which confirmed that the proton 36a and the C-6 sidechain are on the same side of the lactam ring, which is opposite to the side of the C-4 sidechain and proton 37a. These correlations confirmed the relative cis stereochemistry between the C-6 sidechain and the C-43 sidechain.

[0534] Example 16: A-((5)-(7-(((35,5S)-3-Carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide.

[0535]

[0536] Step A: tert-Butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-cyano-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. tert-Butyl (5S)-3-((2-((5)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2- oxo-5-(trifluoromethyl)pyrrolidine-l -carboxylate (700 mg, 1.11 mmol, Intermediate 3) and THF (5 mL) were added to a flask which was subsequently evacuated and refilled with N2 three times.

[0537] The solution was cooled to -78 °C and then LiHMDS (3.3 mL, 3.3 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-l,2-benziodoxole-l-(3 H)-carbonitrile (605 mg, 2.22 mmol) in THF (5 mL) was added dropwise over 5 min. The resulting mixture was warmed to -20 °C over 10 min and then stirred at -20 °C for 4 h. The pH of the reaction mixture was then adjusted to pH 4-5 by the addition of HO Ac (0.1 M in EtOAc). The mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NH4Q (3 x 50 mL). The organic layer was 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 as a yellow solid (34% yield). MS (ESI) m / z: [M+H]+Found 657.4.

[0538] Step B: tert-Butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3-carbamoyl-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate. A mixture of tert-butyl (5S)-3-((2-((S)-((tert- butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-3- cyano-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate (200 mg, 0.305 mmol, Step A), Parkin’s Catalyst (6.5 mg, 0.015 mmol), EtOH (5 mL) and H2O (1 mL) was heated at 100 °C for 1 h. The reaction mixture was cooled to rt and concentrated to dryness to afford a yellow oil. The oil was purified by silica gel chromatography (30-60% EtOAc / petroleum ether) to provide the title compound as a yellow solid (82% yield). MS (ESI) m / z: [(M-100)+H]+Found 575.3. Step C: (5S)-3-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin- 7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxamide dihydrochloride. The title compound (94% yield) was prepared as described for the synthesis of Intermediate 10, Step B using tert-butyl (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[l,2-b>]pyridazin-7-yl)methyl)-3-carbamoyl-2-oxo-5- (trifluoromethyl)pyrrolidine-l -carboxylate (Step B) in place of tert-butyl (5S)-3-azido-3-((2-((5)- ((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[ l ,2-b ]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-l-carboxylate. MS (ESI) m / z: [M+H]+Found 475.2.

[0539] Step D: A-((6')-(7-(((56')-3-Carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3-carboxamide. The title compound was prepared as described for the synthesis of Intermediate 11 Step A using (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxamide dihydrochloride (Step C) in place of (5S)-3-((2-((5)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidin-2-one hydrochloride and lithium 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate in place of 4-cy cl opropyl- 1,2,5 -oxadiazole-3- carboxylic acid. The residue was purified by preparative HPLC (XBridge Prep OBD Cl 8, 5 pm, 150 x 30 mm, 34-50% ACN / H2O (with NH4HCO3 + 0.05% NH3)) to provide the title compound (white solid) as the major isomer (28% yield).1H NMR (300 MHz, DMSO-d6) 8 9.48 (d, J= 9.0 Hz, 1H), 9.01 (s, 1H), 8.36 (d, J= 1.8 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 5.22 - 5.16 (m, 1H), 4.27 - 4.25 (m, 1H), 3.17 - 3.12 (m, 1H), 2.90 - 2.83 (m, 1H), 2.50 - 2.30 (m, 3H), 2.07 - 1.87 (m, 5H), 1.81 - 1.54 (m, 2H), 1.45 - 1.33 (m, 1H), 1.31 - 1.21 (m, 1H), 1.15 - 1.06 (m, 2H), 0.99 - 0.91 (m, 2H). MS (ESI) m / z: [M+H]+Found 611.2.

[0540] Example 17: 4-Cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2- oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[l,2-b ]pyridazin-2-yl)methyl)-1,2,5- oxadiazole-3 -carboxamide.

[0541]

[0542] A mixture of (3A,5S)-3-((2-((5)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3 -carboxylic acid (50 mg, 0.082 mmol, Intermediate 6), methanamine hydrochloride (7 mg, 0.1 mmol), EDCI (47 mg, 0.25 mmol), HOBt (22 mg, 0.16 mmol) and NMM (41 mg, 0.41 mmol) in DCM (10 mL) was stirred at rt for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mb). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford a yellow oil. The oil was purified by preparative HPLC (SunFire Cl 8 OBD, 5 pm, 250 x 19 mm, 37-67% ACN / H2O (with 0.1% FA)) to provide the title compound as the major isomer that was a white solid (42% yield).JH NMR (300 MHz, DMSO-d6 ) 5 9.50 (d, J= 9.0 Hz, 1H), 9.02 (s, 1H), 8.30 (d, J= 1.8 Hz, 1H), 8.22 (s, 1H), 7.86 - 7.82 (m, 2H), 5.22 - 5.17 (m, 1H), 4.30 - 4.23 (m, 1H), 3.30 (s, 1H), 3.14 (d, J= 14.1 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.63 (d, J= 4.5 Hz, 3H), 2.30 - 2.25 (m, 2H), 2.08 - 1.87 (m, 5H), 1.78 - 1.58 (m, 2H), 1.45 - 1.22 (m, 2H), 1.14 - 1.08 (m, 2H), 0.98 - 0.93 (m, 2H). MS (ESI) m / z: [M+H]+Found 625.2. The absolute configuration of Example 17 was confirmed with further 2D-NMR analysis as shown here: . The observed NOESY correlation between the methine proton 25 and the protons 31b was stronger than that between the proton 35 and 31a, which confirmed that the proton 25 and the proton 31b are on the same side of the lactam ring. Additional key NOESY correlations were observed between the methine proton 31a and the protons 46 and 47 at the C-10 position, confirming that the methine proton 31a and the C-10 sidechain are on the same side of the lactam ring, which is opposite to the side of the proton 25 and the proton 31b. These correlations confirmed the relative cis stereochemistry between the C- 10 sidechain and the C-27 sidechain.

[0543] Example 18: 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((35,5S)-2-oxo-5- (trifluoromethyl)-3-(ureidomethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)- 1 ,2, 5-oxadiazole-3 -carboxamide.

[0544] A mixture of A-((S)-(7-(((35,5S)-3-(aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3- yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- oxadiazole-3 -carboxamide (57 mg, 0.096 mmol, Intermediate 17), TEA (36 μL, 0.26 mmol) and trimethylsilyl isocyanate (15 mg, 0.13 mmol) in DCM (5 mL) was stirred at rt for 1 h. The reaction mixture 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 to afford a white solid. The solid was purified by preparative HPLC (XSelect CSH C18, 5 pm, 150 x 19 mm, 35-51% ACN / H2O (with 0.1% FA)) to provide the title compound (white solid) as the major isomer (16% yield).JH NMR (300 MHz, DMSO- d6) 5 9.49 (br s, 1H), 8.75 (br s, 1H), 8.32 (d, J= 1.8 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J= 1.5 Hz, 1H), 6.24 - 6.19 (m, 1H), 5.62 (br s, 2H), 5.22 - 5.17 (m, 1H), 4.17 - 4.06 (m, 1H), 3.28 - 3.26 (m, 1H), 3.22 - 3.05 (m, 1H), 2.95 - 2.90 (m, 1H), 2.79 - 2.74 (m, 1H), 2.38 - 2.23 (m, 2H), 2.22 - 2.16 (m, 1H), 2.07 - 1.96 (m, 2H), 1.88 - 1.80 (m, 3H), 1.76 - 1.70 (m, 1H), 1.64 - 1.57 (m, 1H), 1.45 - 1.22 (m, 2H), 1.15 - 1.06 (m, 2H), 0.97 - 0.92 (m, 2H). MS (ESI) m / z: [M+H]+Found 640.1. Example 19: A-[(S)-[7-[[(35,5S)-3-(Cyclopropylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin- 3-yl]methyl]imidazo[1,2-b ]pyridazin-2-yl]-(4,4- difluorocyclohexyl)methyl]-4-(difluoromethyl)- 1 ,2, 5-oxadiazole-3 -carboxamide.

[0545] Step A: Ethyl (3A,5S)-3-((2-((5)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. A mixture of 1 -(tert-butyl) 3-ethyl (5S)-3-((2-((5)- (4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-oxadiazole-3- carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-l,3-dicarboxylate (30 mg, 0.04 mmol, Example 3 Step D) and TFA (0.306 mL, 4.0 mmol) in DCM (0.8 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to dryness to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 650.8.

[0546] Step B: Lithium (3A,5S)-3-((2-((S)-(4,4-difhiorocyclohexyl)(4-(difluoromethyl)-1,2,5- oxadiazole-3-carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. To a mixture of ethyl (3A,5S)-3-((2-((S)-(4,4- difhrorocyclohexyl)(4-(difluoromethyl)-1,2,5-oxadiazole-3-carboxamido)methyl)imidazo[l,2- b ]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (26 mg, 0.040 mmol, Step A) in anhydrous THF (0.8 mL) and water (8 μL, 0.4 mmol) was added Li OH (6 mg, 0.2 mmol). The resulting mixture was stirred at rt for 2 h, then additional LiOH (3 mg, 0.1 mmol) was added. The mixture was stirred at rt for 2 h and then concentrated to dryness to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 622.0.

[0547] Step C: A-[(S)-[7-[[(3S,5S)-3-(Cyclopropylcarbamoyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl]methyl]imidazo[1,2-b ]pyridazin-2-yl]-(4,4- difhrorocyclohexyl)methyl]-4-(difluoromethyl)-1,2,5-oxadiazole-3-carboxamide. To a mixture of lithium (3R ,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-oxadiazole-3- carboxamido)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5-

[0548] (trifluoromethyl)pyrrolidine-3 -carboxylate (25.1 mg, 0.04 mmol, Step B) in anhydrous N,N- dimethylacetamide (0.8 mL) were added cyclopropylamine (8.3 μL, 0.12 mmol) and TCFH (22.5 mg, 0.080 mmol). The resulting mixture was stirred at rt for 3 h, then additional TCFH (25 mg, 0.089 mmol) and cyclopropylamine (10 pL, 0.14 mmol) were added. The reaction mixture was stirred at rt overnight. Additional TCFH (20 mg, 0.07 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was purified directly by preparative HPLC (10-100% MeCN (0.05% TFA) in H2O (0.05% TFA)). The major isomer obtained was the title compound as its TFA salt. The white TFA salt was then dissolved in MeOH and filtered through a basic silica cartridge to provide the title compound, in its free base form, as a white solid (30% yield).1H NMR (400 MHz, MeOH-d4) 5 8.36 (d, J= 2.0 Hz, 1H), 8.19 (s, 1H), 7.85 - 7.82 (m, 1H), 7.33 (t, J= 52.4 Hz, 1H), 5.27 (d, J= 8.6 Hz, 1H), 4.28 - 4.18 (m, 1H), 3.35 - 3.34 (m, 2H), 3.10 - 3.01 (m, 1H), 2.68 - 2.62 (m, 1H), 2.32 - 2.22 (m, 1H), 2.15 - 2.00 (m, 4H), 1.88 - 1.62 (m, 3H), 1.54 - 1.37 (m, 2H), 0.75 - 0.69 (m, 2H), 0.55 - 0.45 (m, 2H). MS (ESI) m / z: [M+H]+found 661.0.

[0549] Example 20: 4-Cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((35,5S)-3-(2-(dimethylamino)- 2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)methyl)-1,2,5-oxadiazole-3-carboxamide.

[0550] To a solution of 2-((35,5S)-3-((2-((S)-(4-Cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difhiorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)acetic acid (100 mg, 0.16 mmol, Intermediate 18) in DMF (1.5 mL) were added dimethylamine (0.13 mL, 0.26 mmol, 2 M in MeOH) and DIPEA (0.083 mL, 0.48 mmol), and the resulting mixture was stirred at rt for 5 min. Then, HATU (79 mg, 0.21 mmol) was added and the resulting mixture was stirred at rt for 1 h. Additional dimethylamine (0.13 mL, 0.26 mmol, 2 M in MeOH), DIPEA (0.083 mL, 0.48 mmol) and HATU (79 mg, 0.21 mmol) were added and the mixture was stirred for 30 min. The reaction was filtered, subjected directly to basic preparative HPLC (10-100% ACN / water (with 20 mM NH4OH)) and lyophilized. The lyophilized material was purified by SFC (Stationary phase: Whelk 01 SS, 5 pm, 250 x 21 mm, Mobile phase: 30% ((1:1) methanol : IPA (with 0.2% isopropylamine)), 70% CO2) to afford the title compound that was the major isomer (49% yield).JH NMR (500 MHz, CDCh) 5 8.20 (d, J= 2.1 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 1.8 Hz, 1H), 5.80 (s, 1H), 5.34 - 5.29 (m, 1H), 4.38 - 4.29 (m, 1H), 3.11 (d, J= 14.0 Hz, 1H), 3.01 (s, 3H), 2.93 (s, 3H), 2.92 - 2.90 (m, 1H), 2.62 - 2.58 (m, 2H), 2.52 (dd, J= 9.8, 14.1 Hz, 1H), 2.23 - 2.16 (m, 2H), 2.11 - 2.05 (m, 1H), 2.01 (d, J= 14.4 Hz, 1H), 1.72 - 1.65 (m, 2H), 1.35 (s, 2H), 1.28 (br s, 2H), 1.22 (d, J= 6.1 Hz, 2H), 1.20 - 1.17 (m, 1H), 1.17 - 1.14 (m, 1H), 1.12 - 1.07 (m, 1H). MS (ESI) m / z: [M+H]+Found 653.2. The absolute configuration of Example 20 was confirmed with further 2D-NMR analysis as shown here: . Key HOESY correlations were observed between the CF3 group on the C-33 position and the methylene proton 32a confirming that the CF3 group and the proton 32a are on the same side of the lactam ring. Key NOESY correlations were observed between the proton 33a, the proton 32b, and the protons on the C-36 position, confirming that the protons 33a and 32b and the C-36 sidechain are on the same side of the lactam, which is opposite to the side of the CF3 group and the proton 32a. An additional NOESY correlation was observed between the protons 32a, 30a, and 30b, confirming that the C-30 side chain and the proton 32a are on the same side of the lactam ring. These correlations confirmed the relative cis stereochemistry between the C-30 sidechain and the C-39 sidechain. Example 21 : 4-Cyclopropyl-A-((5)-(4,4-difluorocyclohexyl)(7-(((3A,5S)-3-(methylcarbamoyl)- 2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2-yl)methyl)- 1 ,2,5- oxadiazole-3 -carboxamide.

[0551] Step A: 1 -(tert-Butyl) 3-ethyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazine-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine- 1,3 -di carboxy late. tert-Butyl (5)-((7-(bromomethyl)imidazo[l,2- b ]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (106 mg, 0.230 mmol, Intermediate 1) and 1 -(tert-butyl) 3-ethyl (5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-l,3-dicarboxylate (74.7 mg, 0.230 mmol, Intermediate 19) were dissolved in DMF (1 mL) and then K2CO3 (47.6 mg, 0.350 mmol) was added in one portion. The reaction was stirred for 3.5 h at rt. The reaction mixture was then diluted with brine (3 mL) and extracted with EtOAc (4 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 704.2.

[0552] Step B: Ethyl (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. 1 -(tert-Butyl) 3- ethyl (5S)-3-((2-((5)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine- l ,3-dicarboxylate (161 mg, 0.230 mmol, Step A) was dissolved in DCM (0.5 mL) and then TFA (1.5 mL, 19.6 mmol) was added in one portion. The reaction was stirred at rt for 2 h, then concentrated and azeotroped with acetonitrile to provide the title compound that was used without further purification. MS (ESI) m / z: [M+H]+Found 504.2.

[0553] Step C: Ethyl (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazine-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. To a solution of ethyl (5S)-3-((2-((5)-amino(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazine-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate (115 mg, 0.230 mmol, Step B) in acetonitrile (0.5 mL) and DIPEA (0.3 mL, 1.74 mmol) was added 2,5-dioxopyrrolidin-l-yl 4-cyclopropyl- 1,2,5- oxadiazole-3-carboxylate (68.9 mg, 0.270 mmol, Intermediate 9) in one portion. The resulting mixture was stirred for 2.5 h at rt. The reaction mixture was then concentrated, and the yellow residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound as a white solid (73% yield). MS (ESI) m / z: [M+H]+Found 640.2.

[0554] Step D: Lithium (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4- difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazine-7-yl)methyl)-2-oxo-5- (trifluoromethyl)pyrrolidine-3-carboxylate. To a mixture of ethyl (5S)-3-((2-((5)-(4-cyclopropyl- 1,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b ]pyridazin-7- yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (107 mg, 0.170 mmol, Step C) in THF (1 mL) and water (0.21 mL) was added LiOH (13.6 mg, 0.57 mmol) in one portion and the resulting mixture was stirred at rt for 3 h. Then, additional LiOH (5.6 mg, 0.23 mmol) was added and the reaction mixture was stirred at rt for 19 h. The reaction was then concentrated and azeotroped with THF to provide the title compound as a white solid that was used without further purification. MS (ESI) m / z: [M+H]+Found 612.2.

[0555] Step E: 4-Cyclopropyl-A-((S)-(4,4-difluorocyclohexyl)(7-(((3A,5S)-3- (methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b ]pyridazin-2- yl)methyl)-1,2,5-oxadiazole-3-carboxamide. To a solution of lithium (5S)-3-((2-((5)-(4- cyclopropyl-1,2,5-oxadiazole-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b ]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (84 mg, 0.14 mmol, Step D) in anhydrous DMA (1.0 mL) were added methylamine (2 M in THF, 0.69 mL, 1.38 mmol) in one portion followed immediately by TCFH (95 mg, 0.34 mmol) in one portion and the resulting mixture was stirred at rt for 1 h. The reaction mixture was filtered, concentrated, and the residue purified by preparative HPLC (XB ridge Cl 8, 5 pm, 100 x 50 mm, 0-100% MeCN / H2O (20 mM NH4OH)). The diastereomers were separated by chiral SFC (Stationary phase: Chiralpak IB N3, 5 pm, 250 x 30 mm, Mobile phase: 20% MeOH (with 0.2% diethylamine), 80% CO2) to afford the title compound that was the major isomer as the second- eluting isomer (19% yield). 'H NMR (400 MHz, MeOH-A) 8 8.31 (d, J= 2.1 Hz, 1H), 8.15 (s, 1H), 7.87 - 7.80 (m, 1H), 7.80 - 7.71 (m, 1H), 5.27 (d, J= 8.6 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.27 - 3.25 (m, 2H), 2.86 - 2.80 (m, 1H), 2.80 - 2.76 (m, 3H), 2.54 - 2.46 (m, 1H), 2.44 - 2.37 (m, 1H), 2.29 - 1.99 (m, 5H), 1.89 - 1.65 (m, 3H), 1.56 - 1.32 (m, 3H), 1.18 - 1.11 (m, 2H), 1.07 - 1.01 (m, 2H). MS (ESI) m / z: [M+H]+Found 625.2.

[0556] IN VITRO BIOLOGICAL DATA

[0557] IL-17A(FLAG-tagged): IL-17RA(His-tagged) binding disruption Eu-HTRF assay

[0558] An antibody directed against the FLAG tag of IL-17A (SEQ ID NO: 1 as described in U.S. Patent No. 11,691,979) is labeled with the HTRF donor chromophore (Europium- cry ptate). IL- 17A is present as a dimer that is “locked into” this quaternary structure due to the formation of loop-spanning intramolecular disulfide bridges. The construct of IL-17RA used in the assay excludes the outer-membrane portion of the receptor and is fused to a C-terminal 1 OxHis tag (SEQ ID NO:2 as described in U.S. Patent No. 11,691,979). An antibody directed against the His tag of the IL-17RA chimera is labeled with the HTRF acceptor chromophore (“D2”). The fluorescenceresonance energy transfer (FRET) depends on the vicinity of the donor chromophore to the acceptor, and interruption of the binding between the IL-17A and IL-17RA causes the reduction / loss of FRET. Therefore, this assay allows to evaluate the compound effect on the binding IL-17A and IL-17RA by monitoring the fluorescence intensity of donor vs acceptor. The assay is run as described below.

[0559] 40 nl of 2-fold serial diluted compound solution for total 22 dilution points is added into each well of a 1536-well, white, low-volume, non-binding plate (Greiner #782904), then 2 pl of FLAG tagged IL-17A at 2x final concentration (1 nM) in solution of PBS+ 0.01% Triton-XlOO is added to each well. The assay plate is briefly centrifuged then incubated for 1 h at rt. A mixed solution is prepared containing 2x 5nM 1 OHISxIL- 17RA, 2x 2.5nM Eu-anti-FLAG (CISBIO), 2x 5nM D2-anti-HIS (CISBIO) in PBS + 0.01% Triton-XlOO + 200 mM Potassium Fluoride (Sigma 60238) and 2 pl of mix is added to each well of the assay plate. The plate is briefly centrifuged then incubated for 2 h at rt. The HTRF intensities at the wavelength of donor (615 nm) and acceptor (665 nm) are measured using BMG Pherastar. The ratio between intensities at two wavelengths is calculated and plotted against the compound concentration and the data is fitted to a one-site competition model to yield IC5o of the compound.

[0560] IL-17A acts directly on keratinocytes through binding to dimeric receptor IL-17RA / RC and drives the production of a number of inflammatory mediators known to be elevated in psoriasis lesional tissue. IL-17A small molecule inhibitors that block the IL-17A to interact with IL-17R would inhibit the IL-17A signaling in its targeted cells such as keratinocytes. The compound functional activity is evaluated for its impact on IL-17A-induced G-CSF production in human normal keratinocyte (NHK).

[0561] N H K assay

[0562] Adult normal human keratinocytes are cultured in keratinocyte growth medium (Lonza) in a flask till reaching ~ 90% confluence, then cells are transferred to a 384- well plate at density of 3000-4000 cell / well. Recombinant human IL-17A (Gibco PHC9174) is pre-incubated with titrated compound or DMSO for 1 h at rt then added to the cell culture plate. The final concentration of IL-17A is 5 ng / mL and DMSO is 0.2%, in the culture containing 5% FBS. Cells are cultured / treated for 24 h at 37 °C. Supernatants are collected and G-CSF production is measured through HTRF technology using Human G-CSF Kit (CisBio). G-CSF concentration was extrapolated from the standard curve and IC5o is determined using GraphPad Prism. Cell viability is also evaluated using CellTiter-Glo kit (Promega) and effect of compound on cell viability is compared to DMSO control.

[0563] In cases where the compound was tested more than once, the IC5o value was calculated as a simple average of the measured values. The average was then used to categorize the compound within one of the following ranges.

[0564] A: IC50 <0.1 pM;

[0565] B: 0.1 pM <IC5o< 1.0 pM;

[0566] C: ICo > 1 μM

[0567] - Not available

[0568] Table 3 Table 4

[0569] As shown in Table 4, unexpectedly and surprisingly, Example 17, with an (S)-configuration on the C-3 position, showed a more than 150-fold increase in HTRF potency and more than 265 fold increase in NHK potency when compared to its C-3 epimer, Example 21 with an ( R)- configuration at the C-3 position. This unexpected and surprising result demonstrated the significantly higher potency of the compounds of Formula 1-1: as described and provided here, with an absolute configuration as indicated herein for the C-3 carbon next to the carbonyl of the lactam ring (e.g., the (S)-configuration of the C-3 carbon of Examples 17). Additionally, Example 17, as the cis- isomer where the CF3 side chain at the C-5 position and the C-6 side chain at the C-3 position are on the same side of the lactam ring as indicated above, showed an unexpected and surprising potency increase of more than 150-fold as indicated above, when compared to its corresponding / ra / ?.s-isomer, Example 21, where the CF3 side chain at the C-5 position and the C-6 side chain at the C-3 position are on the opposite sides of the lactam ring. This unexpected and surprising result showed the significantly higher potency of the compounds of Formula Ib-1 : including but not limited to compounds of Formula la- 3 , as described and provided here, containing a cis- configuration as shown herein where the R1sidechain (e.g., -CF3) at the C-5 position and the C-6 sidechain at the C-3 position are on the same side of the lactam ring.

[0570] While the foregoing specification teaches the principles of the present disclosure, with examples provided for the purpose of illustration, it will be understood that the practice of the compounds and methods disclosed herein encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents.

[0571] Any and all journal articles, patent applications, issued patents, or other cited references herein are incorporated by reference in their entirety.

Claims

We Claim:

1. A compound having a formula of Formula (I), Formula (1-1), or Formula (1-2):wherein: each R1is independently a -C(1-3)alkyl that is unsubstituted or substituted with one to six Rlagroups; each Rlais independently a halo;R2isR3is -C(3-8)cycloalkyl that is unsubstituted or substituted with one to six halo atoms;R4is a 5 -membered heteroaryl that is unsubstituted or substituted with one to two R4agroups; each R4ais independently a -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, and -C(o-2)alkyl-C(3- 6)cycloalkyl are unsubstituted or substituted with one to six halo atoms;R5is H, -C(1-3)alkyl, or -C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R5agroups; each R5ais independently a halo;R6is H or -C(1-3)alkyl;R7is H or -C(1-3)alkyl;R8is NH2, -C(1-3)alkyl, -C(3-5)cycloalkyl, -O-C(1-3)alkyl or -O-C(3-5)cycloalkyl, wherein the -C(1-3)alkyl and -C(3-5)cycloalkyl are unsubstituted or substituted with one to six R8agroups;each R8ais independently a halo, -O-C(1-3)alkyl, or -O-C(3-5)cycloalkyl; each m is independently 0, 1 , or 2; and each n is independently 0 or 1.

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

3. The compound of claim 1-2 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound having a formula of Formula (lb), Formula (Ib-1 ), or Formula (Ib-2)4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R1is -C(Rla)3.

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein the compound Formula (I) is a compound of Formula (la-3)6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R2is7. The compound of any one of claims 1 -6 or a pharmaceutically acceptable salt thereof, wherein n is 0.

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R5is -CH3and R6is H.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R3is10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R4is11. The compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R4ais12. A compound selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

13. A compound as claimed in claim 12, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

14. A compound as claimed in claim 12, wherein the compound is selected from the groupor a pharmaceutically acceptable salt thereof.

15. A compound as claimed in claim 12, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

16. A compound as claimed in claim 12, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

17. A compound selected from the group consistingor a pharmaceutically acceptable salt thereof.

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

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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