Lactam-containing imidazopyridazine IL-17 inhibitor compound

Abstract

This application relates to a compound having the following formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 4 , n, and m are as defined herein, and methods for the manufacture and use of the compounds disclosed herein for treating or ameliorating syndromes, disorders, and / or diseases mediated by IL-17 are disclosed. 【Chemical 1】 TIFF2026514378000387.tif21128

Description

[Technical Field]

[0001] (Reference to electronically submitted sequence listings) This application includes a sequence listing submitted electronically via EFS-Web as an ST.26 XML format sequence listing with the filename "PRD4255WOPCT1-SeqListing.xml", created on March 12, 2024, and having a size of 3KB. The sequence listing submitted via EFS-Web is part of this specification and is incorporated herein by reference in its entirety. [Background technology]

[0002] Interleukin-17 ("IL-17"), also known as IL-17A, and CTLA-8 are primarily produced by CD4+ Th17 cells, but are also produced by other immune cells such as CD8+ T cells, γδ 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 the dimer receptor complexes IL-17RA and IL-17RC. IL-17RA is expressed particularly at high levels and ubiquitously depending on hematopoietic cell type, while IL-17RC is preferentially expressed by non-hematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A / IL-17R signaling induces de novo gene transcription by triggering the NF-κB, C / EBP, and MAPK pathways via ACT1-TRAF6-TRAF4. This can also stabilize target mRNA transcription via 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-α, and IL-1β, which recruit lymphocytes to injury or inflammation sites, activate them, and maintain a pro-inflammatory state.

[0003] As discussed below in this disclosure, preclinical and clinical data demonstrate the important pathological role of IL-17A in several autoimmune and inflammatory diseases.

[0004] In summary, animal and human studies have shown that IL-17A plays a crucial role in the pathogenesis of several of the diseases and / or conditions described above. The importance of targeting IL-17A is demonstrated by the transformative efficacy of injectable IL-17A neutralizing antibodies in patients.

[0005] Despite the advances achieved with injectable IL-17A antagonist antibodies, the development of oral small molecule IL-17A inhibitors has long been urgently needed because they have the potential to broaden treatment options for many patients without the use of biologics. In addition, safe and effective small molecule IL-17A inhibitors can offer patients significant advantages over injectable IL-17A neutralizing antibodies, such as convenient dosing regimens and cost savings, and ultimately, can provide effective long-term disease management.

[0006] However, the development of oral small molecule therapies remains challenging. For example, none of the oral small molecule IL-17A inhibitors have yet progressed to late-stage clinical trials, with only two (NCT04586920 and NCT04883333) having progressed to Phase I clinical trials as of September 28, 2021. In addition, as of December 2021, one of these clinical trials (NCT04586920) has been suspended for safety review. Therefore, new small molecule IL-17A regulators (e.g., inhibitors) are needed. [Overview of the project] [Means for solving the problem]

[0007] This application is for formula I:

[0008] [ka] Disclosed are compounds of or pharmaceutically acceptable salts thereof, wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3 , R 4 n and m are as defined herein. In some embodiments, the compounds of formula I described and provided herein have the formula Ig-1:

[0009] [ka]

[0010] In some embodiments, the compounds of formula I described and provided herein have formulas Ib-8:

[0011] [ka]

[0012] This application also discloses a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] This application also discloses a method for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment and / or improvement. In some embodiments, the inflammatory syndrome, disorder, or disease mediated by IL-17A 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 disease, multiple myeloma, and systemic lupus erythematosus. [Modes for carrying out the invention]

[0014] definition The discussions of documents, operations, materials, devices, articles, etc., contained herein are for contextual purposes only. Such discussions do not imply that any or all of these things constitute prior art to any compound or method disclosed or claimed.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in the field to which the disclosed patent pertains. Otherwise, any particular term used herein has the meanings set forth herein.

[0016] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple reference subjects unless otherwise clearly indicated by the context.

[0017] To assist readers of this application, this description is divided into various paragraphs or sections, or directed to various embodiments of this application. These divisions should not be considered to separate the substance of one paragraph or section or embodiment from the substance of another paragraph or section or embodiment. On the contrary, those skilled in the art will understand that this description has broad applications and encompasses all possible combinations of sections, paragraphs, and sentences. Any consideration of embodiments is intended to be illustrative only and is not intended to imply that the scope of this disclosure, including the claims, is limited to these embodiments.

[0018] In relation to the methods of the present invention, the term "administering" means a method for therapeutically or preventively preventing, treating, or improving a syndrome, disorder, or disease described herein by using the compounds of the present disclosure or pharmaceutically acceptable salts thereof, compositions thereof, or pharmaceuticals thereof. Such methods include administering therapeutically effective amounts of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, compositions thereof, or pharmaceuticals thereof at different points in time during the course of treatment, or simultaneously or sequentially as a combination therapy.

[0019] The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, that will be treated or is being treated by a method according to one embodiment of this application. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, and humans, more preferably humans.

[0020] The terms “therapeutic effective amount” or “effective amount” mean the amount of an active compound or drug that elicits a biological or medical response in a tissue system, animal or human, including preventing, treating or improving the symptoms of a syndrome, disorder or disease being treated, as sought by researchers, veterinarians, physicians or other clinicians.

[0021] "Pharmacologically acceptable" means that it has been approved or is eligible for approval by a federal or state regulatory authority, or by the corresponding authority in a country other than the United States, or that it is listed in the United States Pharmacopeia or any other commonly recognized pharmacopoeia for use in animals, more specifically in humans.

[0022] "Pharmacologically acceptable salt" is intended to mean a salt of a free acid or base of a compound disclosed herein that is non-toxic, bioacidable, or otherwise biosuitable for administration to a subject. See, for general information, GSPaulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J.Med.Chem., 2007, 50:6665-72, SMBerge, et al., "Pharmaceutical Salts," J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without causing excessive toxicity, irritation, or allergic reactions. Since the compounds of this disclosure may have functional groups of a sufficiently acidic group, a sufficiently basic group, or both, they can react with a wide range of inorganic or organic bases, as well as inorganic and organic acids, to produce pharmaceutically acceptable salts.

[0023] As used herein, “IL-17” or “IL-17A” refers to interleukin-17A. It is also known as IL17, CTLA8, or CTLA-8. Interleukin-17A is a pro-inflammatory cytokine. This cytokine is produced by immune cells in response to their stimulation. An exemplary amino acid sequence of human IL-17 is shown in GenBank acceptance number NP_002181.1, which may be encoded by nucleic acid sequences such as the nucleic acid sequence in GenBank acceptance number NM_002190.3.

[0024] As used herein, the term “modulator” refers to any drug or molecule, including small molecule compounds, that can bind to IL-17.

[0025] As used herein, the term “composition” is intended to encompass products containing specific components in specific amounts, as well as any products obtained directly or indirectly from specific combinations of specific components in specific amounts.

[0026] As used herein, the terms “treat,” “treating,” or “treatment” any disease, condition, syndrome, or disorder mean, in one embodiment, improving the disease, condition, syndrome, or disorder (i.e., delaying, stopping, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, “treat,” “treating,” or “treatment” means reducing or improving at least one physiological or biochemical parameter associated with or causing the disease, condition, syndrome, or disorder, including those that may not be recognizable to the patient. In a further embodiment, “treat,” “treating,” or “treatment” means modulating the disease, condition, syndrome, or disorder either physically (e.g., stabilization of recognizable symptoms) or physiologically (e.g., stabilization of physical parameters), or both.

[0027] As used herein, the terms “prevent” or “prevention” mean, if the onset of a disability or disease has not occurred, that there will be no onset of a disability or disease, or, if the onset of a disability or disease has already occurred, that there will be no further onset of a disability or disease. The individual’s ability to prevent some or all of the symptoms associated with a disability or disease is also taken into consideration. In one embodiment, “prevent” or “prevention” means preventing or delaying the onset, onset, or progression of a disease, condition, syndrome, or disability.

[0028] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. For example, an alkyl group may have 1 to 12 carbon atoms (i.e., (C1-C 12 ) alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6) alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH(CH3)CH2CH2CH3), 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) 10 CH3), and dodecyl (-(CH2) 11 CH3), but are not limited thereto. Any alkyl group may be unsubstituted or substituted.

[0029] The term "C (a~b) " (where a and b are integers referring to the indicated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical, or the alkyl portion of a radical that appears as the root of a prefix containing an alkyl having a to b (including the boundary values) carbon atoms. For example, C (1~4) means a radical containing 1, 2, 3, or 4 carbon atoms.

[0030] The term "alkylene" refers to 1 to 12 carbon atoms (i.e., (C1-C12 This refers to a linear or branched saturated divalent hydrocarbon moiety derived from an alkane, having 1 to 6 carbon atoms (i.e., (C1-C6)alkylene), 1 to 4 carbon atoms (i.e., (C1-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 one embodiment, the alkylene is C (1~4) This refers to alkylene. In another embodiment, alkylene is C (1~2) This refers to alkylene.

[0031] The term "cycloalkyl" refers to a group of 3 to 8 carbon atoms (i.e., C (3~8) Cycloalkyl), preferably 3 to 6 carbon atoms (i.e., C (3~6) This refers to saturated or partially unsaturated whole-carbocyclic systems having a cycloalkyl group, where the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bicyclic form. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically described herein, the cycloalkyl group may be unsubstituted or substituted. Some cycloalkyl groups may exist as spirocycloalkyl groups, where two cycloalkyl rings are condensed via a single carbon atom; for example, but are not limited to, a spiropentyl group.

[0032] [ka] For example, although not limited to them, examples of spirohexyl groups include:

[0033] [ka] Examples include, for instance, the cycloheptyl group, although this is not an exhaustive list.

[0034] [ka] Examples include, for instance, the cyclooctyl group, although this is not an exhaustive list.

[0035] [ka] Examples include: Unless otherwise specifically described herein, the siprocycloalkyl group may be unsubstituted or substituted. Other bicyclic cycloalkyl ring systems include:

[0036] [ka] These are some examples.

[0037] The term "heterocyclyl" refers to a single saturated or partially unsaturated ring having 3-12, 3-10, 3-8, or 3-6 ring members, which contains a carbon atom and at least one other atom selected from the group consisting of N, O, and S. The terms "heterocyclyl" and "heterocycloalkyl" include cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Exemplary heterocycles include, but are not limited to, oxetanyl, azilidinyl, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise stated, the heterocyclyl group is bonded to its pendant group by any heteroatom or carbon atom that results in a stable structure. In one embodiment, heterocyclyl refers to a heterocyclyl with 3 to 10 members. In another embodiment, heterocyclyl refers to a heterocyclyl with 3 to 8 members. In yet another embodiment, heterocyclyl refers to a heterocyclyl with 3 to 6 members.

[0038] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes single aromatic rings having 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, pyridadinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0039] The terms "halogen" or "halo" refer to bromo (-Br), chloro (-Cl), fluoro (-F), or iodine (-I).

[0040] If the compounds disclosed herein have at least one stereocenter, they may exist as enantiomers (optical isomers) or diastereomers (diastereoisomers) accordingly. All such isomers and mixtures thereof are understood to be included within the scope of this disclosure.

[0041] A diastereoisomer is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0042] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "scalemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0043] If the process for preparing the compounds according to this disclosure results in a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. These compounds may be prepared in racemic form, and the scalmic mixture or individual enantiomers may be prepared by either enantiospecific synthesis or degradation. These compounds may be degraded, for example, by standard techniques, to the formation of diastereomer pairs by forming salts with optically active acids such as (-)-di-p-thuloyl-D-tartaric acid and / or (+)-di-p-thuloyl-L-tartaric acid, followed by fractional crystallization and regeneration of free bases, to their constituent enantiomers. These compounds may also be degraded by the formation of diastereomer esters or amides, followed by chromatographic separation and removal of chiral auxiliary groups. Alternatively, these compounds may be degraded using a chiral column by HPLC or SFC. In some cases, 1 This results in complex multiline and peak integration in the 1H NMR spectrum. 1Rotational isomers of the compound, observable by 1H NMR, may also exist.

[0044] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers whose absolute configuration is known are denoted by the prefixes R and S, assigned by standard sequencing rules, preceded by the appropriate locant as needed (Pure & Appl. Chem. 45, 1976, 11-30). A particular example is (R * ) or (S * (R * ) or (S * When (R) is used in the name or chemical description of a compound, it is intended to convey that the compound is a pure single isomer at its stereocenter, however the absolute configuration of that stereocenter has not been established. Therefore, (R) * A compound designated as (R) refers to a compound that is a pure single isomer at its stereocenter having either the absolute configuration of (R) or (S), and (S * A compound designated as ) refers to a compound that is a pure single isomer in its stereocenter having either the (R) or (S) absolute configuration. For example, 4-cyclopropyl-N-((S)-(7-(((R)-5,5-difluoro-2-oxopiperidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide:

[0045] [ka] It is one of the following:

[0046] [ka] It refers to a compound that is [a certain compound].

[0047] During any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect a sensitive or reactive group in any of the molecules involved. This may be achieved by conventional protecting group means, such as those described in Protective Groups in Organic Chemistry, ed. JFWMcOmie, Plenum Press, 1973, and TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting group can be removed at a later, convenient step using methods known in the art.

[0048] Furthermore, wherever references are made within the scope of this disclosure, particularly with respect to the compounds of this disclosure or their pharmaceutically acceptable salts, any element is intended to include all isotopes and isotopic mixtures of that element, either naturally occurring or synthetically produced, in either naturally occurring or isotopically abundant forms. For example, references to hydrogen are, within that scope, 1 H, 2 H (i.e., deuterium or D), and 3 It contains H (i.e., tritium or T). In some embodiments, the compounds described herein are 2 It contains the H (i.e., deuterium) isotope. For example, -C (1~6) The groups represented as alkyl include not only -CH3 but also CD3, and not only -CH2CH3 but also -CD2CD3, etc. Similarly, references to carbon and oxygen are within their respective ranges. 12 C, 13 C, and 14 C, and 15 O and 16 O, and 17 O and 18 Contains O. These isotopes may be radioactive or non-radioactive. The radiolabeled compounds of this disclosure are 3 H, 11 C, 18 F,35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 It may also contain a radioactive isotope selected from the group including Br. Preferably, this radioactive isotope is 3 H, 11 C, and 18 It is selected from group F.

[0049] compound This application is for formula I:

[0050] [ka] The compound, Or disclose a pharmaceutically acceptable salt thereof, During the ceremony, R 1a and R 1b These are H and -C, respectively, independently. (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0051] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded, or R 1a and R 1c Together, C (1~2)Form an alkylene crosslink, R 1c is H, halo, -OH, -C (1~3) alkyl, -C (1~3) alkyl - CN, -C (3~5) cycloalkyl, -C (1~3) alkyl - O - C (1~3) alkyl, or -C (1~3) alkyl - N(C (1~3) alkyl)2, wherein -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 R 1aa groups, R 1d is, independently for each occurrence, -OH, halo, -C (1~3) alkyl, -C (3~5) cycloalkyl, -C (1~3) alkyl - O - C (1~3) alkyl, or -C (1~3) alkyl - N-(C (1~3) alkyl)2, wherein -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 R 1aa groups, R 1aa is, independently for each occurrence, halo, R 2 is H, -OH, -C (1~3) alkyl, -C (3~5) cycloalkyl, -C (1~3) alkyl - O - C (1~3) alkyl, -C<x (1~3) alkyl - O - C (3~5) cycloalkyl, or 4 - 6 membered heterocyclyl, wherein -C (1~3) alkyl, -C (3~5) cycloalkyl, -C (1~3) alkyl - O - C (1~3) alkyl, and -C (1~3) alkyl - O - C (3~5) cycloalkyl groups are unsubstituted or substituted with 1 to 6 R 2aa groups, R 2aa is, independently for each occurrence, halo, -OH, or -CN, R 2b is H or -C(1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 Each of these is either unsubstituted or substituted with 1 to 6 halo atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.

[0052] This application also includes formula I:

[0053] [ka] Compound of formula I, Or disclose a pharmaceutically acceptable salt thereof, During the ceremony, R 1a and R 1b These are H and -C, respectively, independently. (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl or

[0054] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently -OH, halo, and -C. (1~3) Alkyl, -C (3~5)Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N-(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1aa Each occurrence is independently a halo, R 2 H, -OH, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) A cycloalkyl or 4-6 membered heterocycline, wherein -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl and -C (1~3) Alkyl-OC (3~5) Cycloalkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa It is substituted with the base, R 2aa Each occurrence is independently a halo, -OH, or -CN. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, or -C (3~6) It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 halo atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.

[0055] In some embodiments, the compound of formula I described and provided herein, or a pharmaceutically acceptable salt thereof, is of formula Ig-1:

[0056] [ka] It holds.

[0057] In some embodiments, the compounds of formula I described and provided herein, or pharmaceutically acceptable salts thereof, are of formula Ib-8:

[0058] [ka] It holds.

[0059] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R1a and R 1b These are H and -C, respectively, independently. (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0060] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups.2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each occurrence is independently fluorine, -OH, or -CN. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 Each of these is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6)The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.

[0061] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0062] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded. R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3)Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each instance is independently either fluorine or -OH. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6)Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is 0, 1, 2, 3, or 4.

[0063] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0064] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded. R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each instance is independently either fluorine or -OH. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl or -C (3~8) It is a cycloalkyl group, each of which is unsubstituted or substituted with 1 to 6 fluorine atoms, or R 3 is -C (1~10) Alkyl or -C (3~6) It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl, n is 1, 2, or 3, and m is 0, 1, or 2.

[0065] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1aaEach instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa It is substituted with the base, R 2aa Each instance is independently fluorine, R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (4~10) They are alkyl or cyclohexyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1, 2, or 3, and m is 0, 1, or 2.

[0066] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R 1a is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aaIt is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is alkyl, R 2b is H or -C (1~3) It is alkyl, R 3 is -C (4~10) They are alkyl or cyclohexyl, each substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1 or 2, and m is 0, 1, or 2.

[0067] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R 1a is -C (1~3) It is an alkyl group, and in the formula, -C (1~3)Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with the base, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, R 1aa Each instance is independently fluorine, R 2a is H or -OH, R 2b H is, R 3 -C substituted with 1-3 fluorine atoms (4~8) Alkyl, or

[0068] [ka] And, R 4 teeth,

[0069] [ka] And, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1 and m is 0.

[0070] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, wherein, R1a is -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with the base, R 1b is H or -C (1~3) It is alkyl, R 1c is -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, R 1aa Each instance is independently fluorine, R 2a is H or -OH, R 2b H is, R 3 -C substituted with 1-3 fluorine atoms (4~8) Alkyl, or

[0071] [ka] And, R 4 teeth,

[0072] [ka] And, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1 and m is 0.

[0073] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ia-1:

[0074] [ka]

[0075] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ia-2:

[0076] [ka]

[0077] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where n is 1.

[0078] In some embodiments, disclosed herein are compounds of formula I having a formula selected from formulas Ib-1 to Ib-7, or pharmaceutically acceptable salts thereof:

[0079] [ka]

[0080] In some embodiments, disclosed herein are compounds of formula I having a formula selected from formulas Ib-1a to Ib-7a, or pharmaceutically acceptable salts thereof:

[0081] [ka]

[0082] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ib-2:

[0083] [ka]

[0084] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ib-3:

[0085] [ka]

[0086] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ib-4:

[0087] [ka]

[0088] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ib-8:

[0089] [ka]

[0090] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where n is 2.

[0091] In some embodiments, disclosed herein are compounds of formula I having a formula selected from formulas Ic-1 to Ic-7, or pharmaceutically acceptable salts thereof:

[0092] [ka]

[0093] In some embodiments, disclosed herein are compounds of formula I having a formula selected from formulas Ic-1a to Ic-7a, or pharmaceutically acceptable salts thereof:

[0094] [ka]

[0095] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ic-2:

[0096] [ka]

[0097] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ic-5:

[0098] [ka]

[0099] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ic-7:

[0100] [ka]

[0101] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where n is 3.

[0102] In some embodiments, disclosed herein are pharmaceutically acceptable salts having a formula selected from formulas Id-1 to Id-2:

[0103] [ka]

[0104] In some embodiments, disclosed herein are compounds of formula I having a formula selected from formulas Id-1a to Id-2a, or pharmaceutically acceptable salts thereof:

[0105] [ka]

[0106] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0107] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0108] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 3 fluorine atoms.

[0109] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 3 fluorine atoms.

[0110] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H, -CH3, or -CF3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a It is -CF3.

[0111] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0112] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0113] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C(1~3) Alkyl groups are either unsubstituted or substituted with 1 to 3 fluorine atoms.

[0114] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H, -CH3, or -CF3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H or -CH3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1b is H. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 1b It is -CH3.

[0115] In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where R 1a and R 1b Together with the carbon atoms to which they bond, spiroC (3~5) Cycloalkyl, or

[0116] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which the atom is bonded.

[0117] In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where R 1a and R 1b Together with the carbon atoms to which they are bonded, they form a spirocyclopropyl or

[0118] [ka] It forms, and in the formula, · is R1a and R 1b This indicates the carbon atom to which the atom is bonded.

[0119] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 1a and R 1c Together, C (1~2) An alkylenyl crosslink is formed. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a and R 1c These together form a -CH2-bridge. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a and R 1c They combine to form a -CH2CH2-bridge.

[0120] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl is either unsubstituted or substituted with 1 to 6 fluorine atoms, and R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0121] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl, R 1b This is H, -CH3, or -CF3.

[0122] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1a is H, -CH3, or -CF3, and R 1b This is either H or -CH3.

[0123] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base.

[0124] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) It is alkyl(2).

[0125] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3)Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base.

[0126] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) It is alkyl(2).

[0127] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) It is alkyl(2).

[0128] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) It is alkyl(2).

[0129] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c H, -OH, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C(1~3) It is alkyl(2).

[0130] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -OH, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) It is alkyl(2).

[0131] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c H, -C (1~3) Alkyl-CN, or -C (1~3) Alkyl-OC (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -C (1~3) Alkyl-CN or -C (1~3) Alkyl-OC (1~3) It is alkyl.

[0132] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is H, fluorine, -OH, -CH3, -CH2CN, -CH2OCH3, or -CH2N(CH3)2. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c These are fluorine, -OH, -CH3, -CH2CN, -CH2OCH3, or -CH2N(CH3)2.

[0133] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is H. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R1c is a halo. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is fluorine. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 1c is -OH. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 1c is -C (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -CH3. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 1c is -C (1~3) It is alkyl-CN. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -CH2CN. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -C (1~3) Alkyl-OC (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -CH2OCH3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c is -C (1~3) Alkyl-N(C (1~3) Alkyl)2. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1c It is -CH2N(CH3)2.

[0134] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0135] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 3 fluorine atoms.

[0136] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d Each occurrence is independently F, -CH3, or -CF3.

[0137] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d is F. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where R 1dIt is -CH3.

[0138] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1d It is -CF3.

[0139] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 1aa Each instance of this term is independently fluorine.

[0140] In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where n is 1, 2, or 3. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where n is 1. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where n is 2. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where n is 3.

[0141] In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where m is 0, 1, or 2. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where m is 0. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where m is 1. In some embodiments, disclosed herein is a compound of formula I or a pharmaceutically acceptable salt thereof, where m is 2.

[0142] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ie-1:

[0143] [ka] In the formula, R 1 teeth,

[0144] [ka] It is selected from the group consisting of the following.

[0145] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ie-:

[0146] [ka] In the formula, R 1 teeth,

[0147] [ka] It is selected from the group consisting of the following.

[0148] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0149] [ka] It is selected from the group consisting of the following.

[0150] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0151] [ka] It is selected from the group consisting of the following.

[0152] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R1 teeth,

[0153] [ka] It is selected from the group consisting of the following.

[0154] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0155] [ka] It is selected from the group consisting of the following.

[0156] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0157] [ka] It is selected from the group consisting of the following.

[0158] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0159] [ka] It is selected from the group consisting of the following.

[0160] In some embodiments, disclosed herein are compounds of formula Ie or pharmaceutically acceptable salts thereof, where R 1 teeth,

[0161] [ka] It is selected from the group consisting of the following.

[0162] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is H, -OH, or -C (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is either H or -OH.

[0163] In some embodiments, the formula disclosed herein is I A compound of or a pharmaceutically acceptable salt thereof, wherein R 2a is H. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 2a is -OH. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 2a is -C (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is -CH3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a It is -CH2CH3.

[0164] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5)It forms a cycloalkyl or a 4-6 membered heterocycle. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) It forms a cycloalkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a and R 1c These, together with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0165] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2aa In each instance, independently, is fluorine or -OH. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2aa Each instance of this term is independently fluorine.

[0166] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2b is H. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 2b is -C (1~3) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2b is -CH3. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2b It is -CH2CH3.

[0167] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a and R 2bThese atoms, together with the carbon atoms to which they are bonded, form a C=O group.

[0168] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is H, -OH, or -C (1~3) It is alkyl, R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These atoms, together with the carbon atoms to which they are bonded, form a C=O group.

[0169] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a H is R 2b H is R 2a is -OH, and R 2b H is R 2a is -CH3, R 2b H is R 2a is -CH2CH3, and R 2b H is R 2a is -OH, and R 2b is -CH3, or R 2a and R 2b These atoms, together with the carbon atoms to which they are bonded, form a C=O group.

[0170] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 2a is H or -OH, and R 2b H is H.

[0171] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula If:

[0172] [ka]

[0173] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8)シ Chloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 Each of these atoms is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0174] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) They are cycloalkyl groups, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0175] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (1~10) Alkyl or -C (3~8) They are cycloalkyl groups, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0176] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (4~10)They are alkyl or cyclohexyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0177] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (4~10) The compounds are alkyl or cyclohexyl, each of which is substituted with 1 to 6 fluorine atoms. In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 3 is -C (4~8) They are alkyl or cyclohexyl, each substituted with 1 to 6 fluorine atoms.

[0178] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 is -C (4~8) It is an alkyl group and contains 1 to 3 fluorine atoms or

[0179] [ka] It has been replaced with.

[0180] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 teeth,

[0181] [ka] That is the case.

[0182] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 teeth,

[0183] [ka] That is the case.

[0184] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 3 teeth,

[0185] [ka] That is the case.

[0186] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ig:

[0187] [ka]

[0188] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ig-1:

[0189] [ka]

[0190] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ig-2:

[0191] [ka]

[0192] In some embodiments, disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, One of the compounds of formulas Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, Ig-1, and Ig-2, Ih, Ih-1, and Ih-2, Ih-3, Ii, Ii-1, and Ii-2, Ii-3, Ij, Ij-1, and Ij-2, Ij-3, Ik, Ik-1, Ik-2, Ik-3, Im, Im-1, Im-2, and Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 is -C (3~6) They are cycloalkyl groups, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0193] In some embodiments, the formulas disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, and I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 is -C (3~5) They are cycloalkyl groups, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0194] In some embodiments, the formulas disclosed herein are those described above: Formula I, Formulas Ia-1 to Ia-7, Formulas Ib-1 to Ib-8, Formulas Ia-1a to Ia-7a, Formulas Ic-1 to Ic-7, Formulas Ic-1a to Ic-7a, Formulas Id-1 to Id-2, Formulas Id-1a to Id-2a, Formulas Ie-1 to Ie-2, Formulas Ic-1, Formula Ic-2, Formula Ic-3, Formula Ic-4, Formula Ic-5, Formula Ic-6, Formula Ic-7, Formula Id-1, Formula Id-2, Formula Ie, Formula If, Formula Ig, Formula I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 is -C (3~4) They are cycloalkyl groups, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0195] In some embodiments, the formulas disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, and I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 It is a cyclohexyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0196] In some embodiments, the formulas disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, and I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 It is cyclopentyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0197] In some embodiments, the formulas disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, and I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 It is cyclobutyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0198] In some embodiments, the formulas disclosed herein are the aforementioned formulas I, Ia-1 to Ia-7, Ib-1 to Ib-8, Ia-1a to Ia-7a, Ic-1 to Ic-7, Ic-1a to Ic-7a, Id-1 to Id-2, Id-1a to Id-2a, Ie-1 to Ie-2, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Ic-7, Id-1, Id-2, Ie, If, Ig, and I g-1, and any one of the compounds of formula Ig-2, formula Ih, formula Ih-1 and formula Ih-2, formula Ih-3, formula Ii, formula Ii-1 and formula Ii-2, formula Ii-3, formula Ij, formula Ij-1 and formula Ij-2, formula Ij-3, formula Ik, formula Ik-1, formula Ik-2, formula Ik-3, formula Im, formula Im-1, formula Im-2, and formula Im-3, or a pharmaceutically acceptable salt thereof, these compounds are described and provided herein, where R 3 It is a cyclopropyl compound, each of which is either unsubstituted or substituted with 1 to 5 fluorine atoms.

[0199] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ih:

[0200] [ka]

[0201] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ih-1:

[0202] [ka]

[0203] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ih-2:

[0204] [ka]

[0205] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ih-3:

[0206] [ka]

[0207] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ii:

[0208] [ka]

[0209] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ii-1:

[0210] [ka]

[0211] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ii-2:

[0212] [ka]

[0213] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ii-3:

[0214] [ka]

[0215] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 is one or two R 4a It is a five-membered heteroaryl substituted with a specific group.

[0216] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 This is a 5-membered heteroaryl compound containing 1 to 3 heteroatoms selected from O and N (where the 5-membered heteroaryl is unsubstituted or contains 1 to 2 R 4a (substituted with a group). In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, where R 4 However, a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N (where the 5-membered heteroaryl contains 1 R 4a (It is substituted with the base.)

[0217] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 These are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or has 1-2 R 4a It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 These are pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or has 1-2 R 4a It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 It is pyrazolyl or oxadiazolyl, each of which is unsubstituted or has 1-2 R 4aIt is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 However, it is pyrazolyl or oxadiazolyl, each of which contains one R 4a It is substituted with the base.

[0218] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 These are pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadizaoyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is unsubstituted or has 1-2 R 4a It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 The compound is pyrazolyl or 1,2,5-oxadiazolyl, each of which is unsubstituted or has 1-2 R compounds. 4a It is substituted with a group. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 It is pyrazolyl or 1,2,5-oxadiazolyl, each of which contains one R 4a It is substituted with the base.

[0219] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 teeth,

[0220] [ka] That is the case.

[0221] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 teeth,

[0222] [ka] That is the case.

[0223] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4 teeth,

[0224] [ka] That is the case.

[0225] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CH2F, -CHF2, and -CF3.

[0226] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl group.

[0227] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl group.

[0228] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl compound. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is -C (1~6) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is, -OC (1~6) It is alkyl. In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4a is -C (3~6) It is a cycloalkyl group.

[0229] In some embodiments, disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, where R 4ais -CH3, -CH(CH3)2, -OCH3, or cyclopropyl. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is -CH3. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is -CH(CH3)2. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is -OCH3. In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is cyclopropyl.

[0230] In some embodiments, what is disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is

[0231]

Chemical formula

[0236] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is

[0237] [Chemical formula] as follows.

[0238] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is

[0239] [Chemical formula] as follows.

[0240] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, having the formula according to Ij:

[0241] [Chemical formula]

[0242] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, having the formula according to Ij-1:

[0243] [Chemical formula]

[0244] In some embodiments, what is disclosed herein is a compound of formula I, or a pharmaceutically acceptable salt thereof, having the formula according to Ij-2:

[0245] [Chemical formula]

[0246] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ij-3:

[0247] [ka]

[0248] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ik:

[0249] [ka]

[0250] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ik-1:

[0251] [ka]

[0252] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ik-2:

[0253] [ka]

[0254] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Ik-3:

[0255] [ka]

[0256] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Im:

[0257] [ka]

[0258] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Im-1:

[0259] [ka]

[0260] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Im-2:

[0261] [ka]

[0262] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula Im-3:

[0263] [ka]

[0264] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula In:

[0265] [ka]

[0266] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula In-1:

[0267] [ka]

[0268] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula In-2:

[0269] [ka]

[0270] In some embodiments, disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, having the formula In-3:

[0271] [ka]

[0272] In some embodiments, disclosed herein are compounds of formula I that are deuterated isotopes containing 1 to 30 deuterium atoms, or pharmaceutically acceptable salts thereof. In some embodiments, disclosed herein are compounds of formula I that are deuterated isotopes containing 1 to 15 deuterium atoms, or pharmaceutically acceptable salts thereof. In some embodiments, disclosed herein are compounds of formula I that are deuterated isotopes containing 1 to 7 deuterium atoms, or pharmaceutically acceptable salts thereof.

[0273] In some embodiments, what is disclosed herein is a compound of formula I having the formula shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0274] [Table 1-1]

[0275] [Table 1-2]

[0276] [Table 1-3]

[0277] [Table 1-4]

[0278] [Table 1-5]

[0279] [Table 1-6]

[0280] [Table 1-7]

[0281] [Table 1-8]

[0282] [Table 1-9]

[0283] In some embodiments, what is disclosed herein is

[0284] [ka] A compound of formula I selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the following formula is disclosed herein:

[0286] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the following formula is disclosed herein:

[0288] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the following formula is disclosed herein:

[0290] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the following formula is disclosed herein:

[0292] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the following formula is disclosed herein:

[0294] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the following formula is disclosed herein:

[0296] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the following formula is disclosed herein:

[0298] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the following formula is disclosed herein:

[0300] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the following formula is disclosed herein:

[0302] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the following formula is disclosed herein:

[0304] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the following formula is disclosed herein:

[0306] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the following formula is disclosed herein:

[0308] [ka] A compound of formula I having, or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, disclosed herein are compounds of formula I having the formula shown in Table 2, or pharmaceutically acceptable salts thereof.

[0310] [Table 2-1]

[0311] [Table 2-2]

[0312] [Table 2-3]

[0313] [Table 2-4]

[0314] [Table 2-5]

[0315] In some embodiments, disclosed herein are pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration (e.g., tablets or capsules).

[0316] In some embodiments, disclosed herein are pharmaceutical compositions prepared by mixing a compound of formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

[0317] In some embodiments, disclosed herein is a process for preparing a pharmaceutical composition, comprising mixing a compound of formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

[0318] therapeutic use Preclinical and clinical data demonstrate the important pathological role of IL-17A in multiple autoimmune and inflammatory diseases.

[0319] In psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesioned skin and blood of patients with psoriasis and correlate with disease severity. IL-17A directly synergizes with other cytokines (such as TNFα, IFNγ, or IL-22) in keratinocytes, inducing an auto-amplified inflammatory response in the skin and leading to the formation of psoriatic plaques. Blockade of IL-17A using antibodies against IL-17A or IL-23 results in a complete reversal of molecular and clinical disease characteristics in the majority of psoriasis patients, clearly demonstrating the crucial 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 transformative efficacy against psoriasis, demonstrate IL-17A as an effective target for the treatment of psoriasis. (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).

[0320] In the case of psoriatic arthritis (PsA): IL-17A is mechanistically associated with PsA through NFκB activation, which induces transcription of several PsA-related genes, including the receptor activator of nuclear factor κB ligand (RANKL). RANKL induces differentiation of osteoclast precursor cells into activated osteoclasts, leading to bone resorption and subsequent joint deformation in PsA (Adamopoulos I. and Mellins E. Nature reviews Rheumatology 2015;11:189-94). PsA joints are rich in IL-17+CD8+ T cells, and the level of this T cell subset correlates with disease activity (Menon B. et al., Arthritis & Rheumatology 2014;66:1272-81). Synovial fibroblasts isolated from PsA patients secrete increased IL-6, CXCL8, and MMP3, including ex vivo elevated IL-17R expression, compared to patients with osteoarthritis. Both secukinumab and ixekizumab are FDA-approved drugs for PsA. In matched and adjusted indirect comparative analyses, secukinumab was associated with a higher ACR20 / 50 / 70 response rate than anti-TNFα antibodies in patients with active PsA (Mease P. et al., Eur. J. Rheumatol. 2019 Jul 1; 6(3): 113-121; Strand V. et al., J. Comp. Eff. Res. 2019, 8(7): 497-510; Nash P. et al., Rheumatol. Ther. 2018, 5(1): 99-122). In a recent one-on-one study, ixekizumab was superior to adalimumab in achieving simultaneous improvement of joint and skin disease in patients with PsA (ACR50 and PASI100), and in showing inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, P. et al. Ann Rheum Diss 2020;79:123-131). By attacking the same target, IL-17A small molecule inhibitors may exert similar or better efficacy than biologics in which small molecules are generally thought to have better tissue penetration.

[0321] In the case of rheumatoid arthritis (RA): IL-17A is recognized as important in 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. Furthermore, in rheumatoid arthritis, IL-17A acts locally on synovial cells and osteoblasts, contributing to synovitis and joint destruction. Robert and Miossec propose the use of synovial biopsy and / or biomarkers to accurately identify patients who would respond to IL-17A inhibition. Their paper concludes that IL-17 inhibitors should be considered today in the development of precision medicine in RA. (Robert M. and Miossec P.,Front.Med.,2019,5:364).

[0322] In the case of ankylosing spondylitis (AS): Various studies have reported increased levels of IL-17A and Th17, as well as other IL-17-producing cells, in AS blood samples (Wendling D. et al., Joint Bone Spine. 2007, 74:304-305; Shen H. et al., Arthritis Rheum. 2009; 60(6): 1647-56; Zhang L. et al., PLoS One. 2012; 7(4): e31000; Jansen D. et al., Rheumatology (Oxford). 2015 Apr; 54(4): 728-735). In situ analysis of AS spine has revealed an increase in IL-17A-producing cells in the bone of the intervertebral (articular) joints (Appel H. et al., Arthritis Res. Ther. 2011;13(3):R95). Two advanced IL-17A neutralizing antibodies, secukinumab and ixekizumab, which are FDA-approved for AS, have demonstrated superior efficacy to placebo, even in anti-TNF-deficient responders. In contrast, anti-IL-23 p40 and anti-IL-23 p19 biologics failed to demonstrate beneficial effects (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. et al., Ann. Rheum. Dis. 2018, 77(9):1295-1302), indicating that different mechanisms underlie the IL-23 / IL-17 pathway in AS, providing strong evidence to support the continued development of IL-17A inhibitors.

[0323] In the case of hidradenitis suppurativa (HS): Increases in IL-17 and IL-17-producing T helper cells have been reported in skin lesions of HS patients, and molecular proteomics and gene expression data indicate that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach C. et al., J.Am.Acad.Dermatol.2011;65(4):790; Kelly G. et al., British J.Dermatol.2015 Dec;173(6):1431-9; Moran B. et al., J.Invest.Dermatol.2017;137(11):2389; Thomi R. et al., JAMA Dermatol.2018;154(5):592). Seven out of nine patients (78%) with moderate to severe HS achieved HiSCR in an open-label pilot study using secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep;181(3):609-611), and further clinical trials using anti-IL-17 mAbs for HS are underway.

[0324] In the case of bullous pemphigoid (BP): IL-17 levels are elevated in the blister fluid and surrounding skin of BP patients (Le Jan S. et al., J.Invest.Dermatol.2014;134(12):2908-2917; Chakievska LJ Autoimmun.2019,96:104-112). Exome sequencing of BP patients revealed mutations in 12 IL-17-related genes in one-third of patients, providing a genetic link between the IL-17 pathway and BP (Chakievska LJ Autoimmun.2019,96:104-112). In experimental BP mice, IL-17A- / - mice were protected, and anti-IL-17A treatment significantly reduced skin lesions in wild-type mice (Chakievska LJ Autoimmun.2019,96:104-112). Phase 2 ixekizumab is ongoing in a previously untreated patient with refractory bisphosphonate (NCT03099538).

[0325] In the case of atopic dermatitis (AD): IL-17 has been found to be elevated in peripheral blood and lesions in AD patients, and Th17 cells infiltrate significantly more in acute lesions than chronic lesions, suggesting its role in the acute phase of AD (Koga C. et al., J. Invest. Dermatol. 2008, 128, 2625-2630). Molecular profile analysis from ustekinumab phase II suggests the possible involvement of the IL-23 / Th17 / IL-17 pathway in AD (Khattri S. et al., Exp. Dermatol. 2017 Jan;26(1):28-35).

[0326] In the case of vitiligo: Numerous studies in vitiligo patients have demonstrated increased frequency of Th17 cells in both circulation and lesions, and higher levels of IL-17, positively correlated with disease duration, severity, and activity (Singh R. et al., Autoimmun. Rev 2016, Apr;15(4):397-404). Mouse studies have demonstrated that desynthesis correlates with higher IL-17 expression / secretion, which modulates vitiligo development (Eby J. et al., Pigment Cell & Melanoma Res. 2014 Nov;27(6):1075-85).

[0327] In the case of multiple sclerosis (MS): IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF), and brain lesions and brain cells derived from MS patients (Lock, C. et al., Nat. Med. 2002, 8:500-508; Matusevicius, D. et al., Mult. Scler. 1999, 5:101-104; Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155). IL-17-producing T cells are abundant in active MS lesions (Tzartos, J. et al., Am. J. Pathol. 2008, 172:146-155, Willing A. et al., J. Immunol. 2018, 200(3):974-982). IL-17A levels were elevated in CSF in patients with relapsing-remitting MS (RRMS), and IL-17A combined with IL-6 correlated with the CSF / serum albumin index, a measure of BBB insufficiency, along with in vitro data showing that IL-17A reduced the expression of tight junction-related genes and disrupted monolayer integrity in blood-brain barrier (BBB) ​​cell lines, 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 initial results in a proof-of-concept study in MS patients (Havrdova, E. et al., J. Neurol. 2016, 263:1287-1295).

[0328] In asthma: IL-17 expression is increased in the lungs, sputum, bronchoalveolar lavage fluid, and serum of 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 has been reported to increase 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 antibodies modulate airway responsiveness, inflammation, tissue remodeling, and oxidative stress in a chronic mouse asthma model (Camargo LdN. et al., Front Immunol. 2018; 8:1835; dos Santos T. et al., Front. Physiol. 2018, 9:1183).

[0329] In the case of Chronic Obstructive Pulmonary Disease (COPD): Compared to current smokers without COPD and healthy subjects, an increase in Th17 cells was observed in patients with COPD, and an inverse correlation was found between Th17 cells and lung function (Vargas-Rojas M. et al., Respir. Med. 2011 Nov;105(11):1648-54). Three recent human COPD studies have shown that gene expression profiles in bronchial epithelium indicate that higher IL-17 characteristic expression is associated with a lack of response to inhaled corticosteroids, suggesting that there is a COPD subgroup that can benefit from IL-17 inhibitor therapy (Christenson S. et al., J. Clin. Invest. 2019;129(1):169-181).

[0330] In cases of uveitis: IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines and disrupts the retinal pigment epithelial barrier function (Chen Y. et al., PLoS One. 2011;6:e18139). IL-17 levels were elevated in the serum or aqueous humor of patients with uveitis (El-Asrar A. et al., 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 antibodies delayed the onset of ocular inflammation and significantly prevented the development of experimental autoimmune uveitis in rats (Zhang R. et al., Curr. Eye Res. 2009 Apr;34(4):297-303). Analysis of secondary efficacy data from a subcutaneous (sc) secukinumab phase 3 trial in uveitis suggested the favorable efficacy of secukinumab when concomitant immunosuppressant use was reduced (Dick A. et al., Ophthalmology 2013;120(4):777-87). Subsequent studies of intravenous secukinumab in uveitis demonstrated higher efficacy than sc administration and suggested the need for optimal exposure for efficacy, confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015,122(5),939-948). It has also been reported that ustekinumab, which blocks the IL-23 / IL-17 pathway, successfully treated patients with non-infectious uveitis who had severe congenital psoriasis and PsA and who had not responded to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep;30(5);e12527.).

[0331] In the case of multiple myeloma (MM): Serum IL-17A levels were significantly higher in MM patients and in patients with advanced disease compared to healthy subjects (Lemancewicz D. et al., Med.Sci.Monit. 2012;18(1):BR54-BR59). Weekly administration of secukinumab over four weeks following initial tumor detection in mice in a SCIDhu model of human myeloma resulted in significant suppression of tumor growth and reduced bone damage compared to isotyped control mice (Prabhala R. et al., Leukemia. 2016 February;30(2):379-389).

[0332] In the case of systemic lupus erythematosus (SLE): Increased serum or plasma IL-17 levels, proliferation of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidneys have been observed in SLE patients (Wong C. et al., Lupus. 2000; 9(8): 589-593; Wong C. et al., Clinical Immunology. 2008; 127(3): 385-393; Zhao XF. et al., Mol. Biol. Rep. 2010 Jan; 37(1): 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). An imbalance between Th17 cells and regulatory T (Treg) cells was observed in SLE patients, including those in the quiescent phase (Ma J. et al., Clin. Rheumatol. 2010; 29(11): 1251-1258; Dolff S. et al., Clin. Immunol. 2011, 141(2): 197-204). Overexpression of IL-17A using adenovirus increased the severity of lupus nephritis, while blockade of IL-17A using neutralizing antibodies reduced the severity of lupus nephritis (Wen, Z. et al., PLoS One. 2013, 8: e58161). In a Phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, demonstrated efficacy in patients with SLE (van Vollenhoven R. et al., Lancet 2018;392:1330-39). Human expression studies, animal models, and clinical trials have shown that IL-17 blockade may be a promising therapeutic strategy for SLE (Koga T. et al., Expert Rev. Clin. Immunol. 2019, 15(6)629-637).

[0333] Accordingly, this application also relates to a method for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof to a subject in need of treatment and / or improvement.

[0334] In some embodiments, disclosed herein are methods for treating or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment or improvement.

[0335] In some embodiments, disclosed herein are methods for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A 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 injury, multiple myeloma, and systemic lupus erythematosus.

[0336] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0337] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0338] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0339] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0340] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

[0341] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0342] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[0343] In some embodiments, disclosed herein are methods for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0344] In some embodiments, disclosed herein are methods for treating or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment or improvement, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0345] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[0346] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[0347] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is uveitis.

[0348] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary injury.

[0349] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or improvement, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[0350] In some embodiments, disclosed herein are methods for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment and / or improvement, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A 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 disease, multiple myeloma, and systemic lupus erythematosus, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally (for example, as a tablet or capsule).

[0351] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating and / or improving 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 injury, multiple myeloma, and systemic lupus erythematosus.

[0352] In some embodiments, disclosed herein is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for treating and / or improving 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 disease, multiple myeloma, and systemic lupus erythematosus.

[0353] In some embodiments, disclosed herein are methods for treating and / or improving IL-17-mediated inflammatory syndromes, disorders, or diseases, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof to a subject in need of such treatment and / or improvement.

[0354] In some embodiments, disclosed herein are methods for treating and / or improving an IL-17-mediated inflammatory syndrome, disorder, or disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof to a subject in need of such treatment and / or improvement, 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.

[0355] In some embodiments, disclosed herein are methods for treating or improving an inflammatory syndrome, disorder, or disease mediated by IL-17, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof to a subject in need of such treatment or improvement, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0356] In some embodiments, disclosed herein are methods for regulating IL-17 activity in mammals by administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0357] Also disclosed herein is a method for inhibiting the production of interleukin-17, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

[0358] Combination therapy Compounds of formula I or pharmaceutically acceptable salts thereof, compositions thereof, or pharmaceuticals thereof may also be used in combination with one or more additional therapeutic agents.

[0359] In some embodiments, one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, immunomodulators, and immunosuppressants.

[0360] In some embodiments, disclosed herein is a method for treating and / or improving an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject requiring treatment and / or improvement, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical product thereof to the subject in combination with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, or ankylosing spondylitis. 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.

[0361] Administration regimen The dosage administered is influenced by factors such as the route of administration, the recipient's health status, weight, and age, the frequency of treatment, and the presence of unrelated treatments being administered concurrently.

[0362] Furthermore, it will be apparent to those skilled in the art that the therapeutically effective dose of the compounds or their pharmaceutical compositions may vary depending on the desired effect. Therefore, the optimal dosage may be readily determined by those skilled in the art and will vary depending on the specific compound used, the method of administration, the strength of the preparation, and the progression of the disease. It will also be necessary to adjust the dosage to an appropriate therapeutic level based on factors relevant to the specific subject being treated, including age, weight, diet, and administration time. Therefore, the above dosages are examples of average cases. Naturally, there may be individual cases where larger or smaller dosage ranges are effective, and such cases are also within the scope of this disclosure.

[0363] Pharmaceutical composition Compounds of formula I, or pharmaceutically acceptable salts thereof, can be formulated in pharmaceutical compositions comprising any known pharmaceutically acceptable carrier. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion solvents, coatings, antimicrobial and antifungal agents, and isotonic agents. Exemplary excipients, which may also be components of the formulation, include fillers, binders, disintegrants, and lubricants.

[0364] The pharmaceutical compositions of this disclosure may be administered by any means necessary to achieve their intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. Alternatively, administration may be by oral route.

[0365] Furthermore, disclosed herein are methods for preparing pharmaceutical compositions, comprising mixing a pharmaceutically acceptable carrier with a compound of formula I or a pharmaceutically acceptable salt thereof. In addition, this application includes pharmaceutical compositions prepared by mixing a pharmaceutically acceptable carrier with any of the compounds of this disclosure.

[0366] Certain features of this disclosure are described in the context of separate embodiments for clarity, but it is further understood that these may also be presented in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for brevity may be provided separately or in any suitable subcombination.

[0367] This disclosure also provides the following non-limiting embodiments.

[0368] 1. Equation I

[0369] [ka] compounds or a pharmaceutically acceptable salt thereof During the ceremony, R 1a and R 1b These are H and -C, respectively, independently. (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0370] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded, or R 1a and R 1c Together, C (1~2)Forming alkylenyl crosslinks, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently -OH, halo, and -C. (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N-(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1aa Each occurrence is independently a halo, R 2 H, -OH, -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl, -C (1~3) Alkyl-OC (3~5) A cycloalkyl or 4-6 membered heterocycline, wherein -C (1~3) Alkyl, -C (3~5) Cycloalkyl, -C (1~3) Alkyl-OC (1~3) Alkyl and -C (1~3) Alkyl-OC (3~5) Cycloalkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5)forms a cycloalkyl or 4- to 6-membered heterocyclyl, R 2aa is, independently for each occurrence, halo, -OH, or -CN, R 2b is H or -C (1~3) alkyl, or R 2a and R 2b together with the carbon atom to which they are attached form a C=O, R 3 is -C (1~10) alkyl, -C (1~6) alkyl-O-C (1~6) alkyl, -C (1~6) alkyl-O-C (3~5) cycloalkyl, -C (1~6) alkyl-O-C (3~5) cycloalkyl-C (1~3) alkyl, -C (3~8) cycloalkyl, or -C (1~3) alkyl-(C (3~5) cycloalkyl) 1-2 where each is unsubstituted or substituted with 1 to 6 halo atoms, R 4 is unsubstituted or 5-membered heteroaryl substituted with 1 to 2 R 4a groups, R 4a is halo, -C (1~6) alkyl, -O-C (1~6) alkyl, -C (1~6) alkyl-O-C (1~6) alkyl, or -C (0~2) alkyl-C (3~6) cycloalkyl, wherein -C (1~6) alkyl, -O-C (1~6) alkyl, -C (1~6) alkyl-O-C (1~6) alkyl, and -C (0~2) alkyl-C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halo, -CH3, -CH2F, -CHF2, and -CF3, n is 1, 2, or 3, and A compound of formula I or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

[0371] 2. The compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, R 1a and R 1b These are H and -C, respectively, independently. (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0372] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each occurrence is independently fluorine, -OH, or -CN. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form C=O. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl-C (1~3) Alkyl, -C (3~8) Cycloalkyl, or -C (1~3) Alkyl-(C (3~5) Cycloalkyl) 1-2 Each of these is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6)Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0, 1, 2, 3, or 4.

[0373] 3. A compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0374] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded. R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3)Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independent of the halo, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each instance is independently either fluorine or -OH. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form a C=O group. R 3 is -C (1~10) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, -C (1~6) Alkyl-OC (3~5) Cycloalkyl, or -C (3~8) It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is, halo, -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl compound, in the formula -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl and -C (0~2) Alkyl-C (3~6) The cycloalkyl group is either unsubstituted or substituted with 1 to 6 substituents independently selected from fluorine, -CH3, -CH2F, -CHF2, and -CF3. n is 1, 2, or 3, and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0, 1, 2, 3, or 4.

[0375] 4. A compound described in any one of Embodiments 1 to 3 or a pharmaceutically acceptable salt thereof, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups, or R 1a and R 1c Together, C (1~2) Forming alkylenyl crosslinks, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa Substituted with or R 1a and R 1b Together with the carbon atoms to which they are bonded, spiro C (3~5) Cycloalkyl, or

[0376] [ka] A spiroheterocylyl is formed by selecting from the following, where · is R 1a and R 1b This indicates the carbon atom to which it is bonded. R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa Substituted with or R 2a and R 1c Together with the carbon atoms to which they are bonded, C (3~5) Forming a cycloalkyl or 4-6 membered heterocycle, R 2aa Each instance is independently either fluorine or -OH. R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form a C=O group. R 3 is -C (1~10) Alkyl or -C (3~8) It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (0~2) Alkyl-C (3~6) It is a cycloalkyl, n is 1, 2, or 3, and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0, 1, or 2.

[0377] 5. A compound described in any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl compound, in the formula -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 2aa It is substituted with the base, R 2aa Each instance is independently fluorine, R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b These, together with the carbon atoms to which they are bonded, form a C=O group. R 3 is -C (4~10) They are alkyl or cyclohexyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1, 2, or 3, and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0, 1, or 2.

[0378] 6. A compound described in any one of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, R 1a is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3)Alkyl groups are either unsubstituted or have 1 to 6 R groups. 1aa It is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or substituted with 1 to 6 R1aa groups. R 1aa Each instance is independently fluorine, R 2a is H, -OH, or -C (1~3) It is alkyl, R 2b is H or -C (1~3) It is alkyl, R 3 is -C (4~10) They are alkyl or cyclohexyl, each substituted with 1 to 6 fluorine atoms. R 4 is either unsubstituted or has 1-2 R 4a It is a 5-membered heteroaryl substituted with a group, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, -C (1~6) Alkyl-OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1 or 2, and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0, 1, or 2.

[0379] 7. A compound described in any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, R 1a is -C (1~3)It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with the base, R 1b is H, or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl groups are either unsubstituted or have 1-3 R groups. 1aa It is substituted with the base, R 1c H, halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) Alkyl)2, R 1aa Each instance is independently fluorine, R 2a is H or -OH, R 2b H is, R 3 -C substituted with 1-3 fluorine atoms (4~8) Alkyl, or

[0380] [ka] And, R 4 teeth,

[0381] [ka] And, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, or -C (3~6) It is a cycloalkyl, n is 1 and m is a compound or a pharmaceutically acceptable salt thereof, where m is 0.

[0382] 8. A compound described in any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the following

[0383] [ka] A compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of the following.

[0384] 9. A compound described in any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the following

[0385] [ka] A compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of the following.

[0386] 10. A compound described in any one of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the following

[0387] [ka] A compound or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of the following.

[0388] 11. A compound described in any one of Embodiments 1 to 4 or 8 to 10, or a pharmaceutically acceptable salt thereof, R 1a H, -C (1~3) Alkyl, or -C (3~5) It is a cycloalkyl, -C (1~3) Alkyl is either unsubstituted or substituted with 1 to 6 fluorine atoms, and R 1b is H or -C (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl compounds or pharmaceutically acceptable salts thereof that are unsubstituted or substituted with 1 to 6 fluorine atoms.

[0389] 12. A compound described in any one of Embodiments 1 to 5 or 8 to 11, or a pharmaceutically acceptable salt thereof, R 1a is H, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl, and R 1b A compound or a pharmaceutically acceptable salt thereof, wherein the compound is H, -CH3, or -CF3.

[0390] 13. A compound described in any one of Embodiments 1 to 6 or 8 to 11, or a pharmaceutically acceptable salt thereof, R 1a is H or -C (1~3) It is alkyl, -C (1~3) Alkyl compounds or pharmaceutically acceptable salts thereof that are unsubstituted or substituted with 1 to 3 fluorine atoms.

[0391] 14. A compound described in any one of Embodiments 1 to 6 or 8 to 13, or a pharmaceutically acceptable salt thereof, R 1a A compound or a pharmaceutically acceptable salt thereof, wherein the compound is H, -CH3, or -CF3.

[0392] 15. A compound described in any one of Embodiments 1 to 7 or 8 to 14, or a pharmaceutically acceptable salt thereof, R 1b is a compound or a pharmaceutically acceptable salt thereof, which is H or -CH3.

[0393] 16. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 7 or 8 to 15, wherein R 1c is halo, -OH, -C (1~3) Alkyl, -C (1~3) Alkyl-CN, -C (1~3) Alkyl-OC (1~3) Alkyl, or -C (1~3) Alkyl-N(C (1~3) A compound or a pharmaceutically acceptable salt thereof that is alkyl(2).

[0394] 17. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 7 or 8 to 15, wherein R 1c H, -C (1~3) Alkyl-CN, or -C (1~3) Alkyl-OC (1~3) A compound that is alkyl, or a pharmaceutically acceptable salt thereof.

[0395] 18. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 7 or 8 to 15, wherein R 1c A compound or a pharmaceutically acceptable salt thereof, wherein is H, fluorine, -OH, -CH3, -CH2CN, -CH2OCH3, or -CH2N(CH3)2.

[0396] 19. A compound described in any one of Embodiments 1 to 6 or 8 to 18, or a pharmaceutically acceptable salt thereof, R 1d Each occurrence is independently either a halo or -C. (1~3) It is an alkyl group, and in the formula, -C (1~3) Alkyl compounds or pharmaceutically acceptable salts thereof that are unsubstituted or substituted with 1 to 3 fluorine atoms.

[0397] 20. A compound described in any one of Embodiments 1 to 6 or 8 to 19, or a pharmaceutically acceptable salt thereof, R 1d A compound or a pharmaceutically acceptable salt thereof, in which each occurrence is independently F, -CH3, or -CF3.

[0398] 21. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 5, 8, 9, or 11 to 20, wherein n is 1 or 2.

[0399] 22. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 6, 8, or 11 to 21, wherein n is 1.

[0400] 23. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 6 or 8 to 22, wherein m is 0, 1, or 2.

[0401] 24. A compound according to any one of Embodiments 1 to 4, wherein formula Ie:

[0402] [ka] Compounds having a structure due to or a pharmaceutically acceptable salt thereof In the formula, R 1 teeth,

[0403] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0404] 25. The compound described in Example 24 or a pharmaceutically acceptable salt thereof, R 1 teeth,

[0405] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0406] 26. A compound or pharmaceutically acceptable salt thereof described in Embodiment 24 or 25, R 1 teeth,

[0407] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0408] 27. A compound described in any one of Embodiments 1 to 5 or 8 to 26, or a pharmaceutically acceptable salt thereof, R 2ais H, -OH, or -C (1~3) It is alkyl, and R 2b is H or -C (1~3) Alkyl, or R 2a and R 2b A compound or a pharmaceutically acceptable salt thereof in which these atoms, together with the carbon atoms to which they are bonded, form a C=O group.

[0409] 28. A compound described in any one of Embodiments 1 to 5 or 8 to 27, or a pharmaceutically acceptable salt thereof, R 2a is H and R 2b H is H, R 2a is -OH and R 2b H is H, R 2a is -CH3 and R 2b H is H, R 2a is -CH2CH3 and R 2b H is H, R 2a is -OH and R 2b is -CH3, or R 2a and R 2b A compound or a pharmaceutically acceptable salt thereof in which these atoms, together with the carbon atoms to which they are bonded, form a C=O group.

[0410] 29. A compound described in any one of Embodiments 1 to 6 or 8 to 28, or a pharmaceutically acceptable salt thereof, R 2a is H or -OH, and R 2b A compound or a pharmaceutically acceptable salt thereof, wherein H is present.

[0411] 30. A compound described in any one of Embodiments 1 to 3 or 8 to 29, or a pharmaceutically acceptable salt thereof, R 3 is -C (1~10) Alkyl or -C (3~8)A compound or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms.

[0412] 31. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 6 or 8 to 30, wherein R 3 is -C (4~8) A compound or a pharmaceutically acceptable salt thereof that is alkyl or cyclohexyl, each of which is substituted with 1 to 6 fluorine atoms.

[0413] 32. A compound described in any one of Embodiments 1 to 31 or a pharmaceutically acceptable salt thereof, R 3 teeth,

[0414] [ka] A compound or a pharmaceutically acceptable salt thereof.

[0415] 33. A compound described in any one of Embodiments 1 to 32 or a pharmaceutically acceptable salt thereof, R 3 teeth,

[0416] [ka] A compound or a pharmaceutically acceptable salt thereof.

[0417] 34. A compound described in any one of Embodiments 1 to 33 or a pharmaceutically acceptable salt thereof, R 3 teeth,

[0418] [ka] A compound or a pharmaceutically acceptable salt thereof.

[0419] 35. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 6 or 8 to 34, wherein R 4It is a 5-membered heteroaryl compound containing 1 to 3 heteroatoms selected from O and N, and the heteroaryl compound is either unsubstituted or contains 1 to 2 R atoms. 4a A compound or a pharmaceutically acceptable salt thereof that is substituted with a group.

[0420] 36. A compound described in any one of Embodiments 1 to 6 or 8 to 35, or a pharmaceutically acceptable salt thereof, R 4 It is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N, and the heteroaryl has 1 R 4a A compound or a pharmaceutically acceptable salt thereof that is substituted with a group.

[0421] 37. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 6 or 8 to 36, wherein R 4 This is one R 4a A compound or a pharmaceutically acceptable salt thereof that is pyrazolyl or oxadiazolyl substituted with a group.

[0422] 38. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 6 or 8 to 37, wherein R 4 teeth,

[0423] [ka] A compound or a pharmaceutically acceptable salt thereof.

[0424] 39. A compound described in any one of Embodiments 1 to 6 or 8 to 38 or a pharmaceutically acceptable salt thereof, R 4a is -C (1~6) Alkyl, -OC (1~6) Alkyl, or -C (3~6) A cycloalkyl compound or a pharmaceutically acceptable salt thereof.

[0425] 40. A compound described in any one of Embodiments 1 to 39 or a pharmaceutically acceptable salt thereof, R 4aA compound or a pharmaceutically acceptable salt thereof that is -CH3, -CH(CH3)2, -OCH3, or cyclopropyl.

[0426] 41. A compound described in any one of Embodiments 1 to 40 or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0427] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0428] 42. A compound described in any one of Embodiments 1 to 41 or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0429] [ka] A compound or a pharmaceutically acceptable salt thereof.

[0430] 43. A compound according to any one of Embodiments 1 to 7, having the following structure

[0431] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0432] 44. A compound according to any one of Embodiments 1 to 7, having the following structure

[0433] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0434] 45. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1, selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0435] 46. ​​A compound described in any one of Embodiments 45 or a pharmaceutically acceptable salt thereof,

[0436] [ka] Compounds selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0437] 47. A compound described in Embodiment 46, having the following structure:

[0438] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0439] 48. A compound described in Embodiment 46, having the following structure:

[0440] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0441] 49. A compound described in Embodiment 46, having the following structure:

[0442] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0443] 50. A compound described in Embodiment 46, having the following structure:

[0444] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0445] 51. A compound according to Embodiment 46, having the following structure:

[0446] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0447] 52. A compound described in Embodiment 46, having the following structure:

[0448] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0449] 53. A compound described in Embodiment 46, having the following structure:

[0450] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0451] 54. A compound described in Embodiment 46, having the following structure:

[0452] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0453] 55. A compound described in Embodiment 46, having the following structure:

[0454] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0455] 56. A compound according to Embodiment 46, having the following structure:

[0456] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0457] 57. A compound according to Embodiment 46, having the following structure:

[0458] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0459] 58. A compound described in Embodiment 46, having the following structure:

[0460] [ka] Compounds containing or a pharmaceutically acceptable salt thereof.

[0461] 59. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0462] 60. A pharmaceutical composition prepared by combining a compound described in any one of Embodiments 1 to 58 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0463] 61. A pharmaceutical composition according to Embodiment 59 or 60, or a pharmaceutically acceptable salt thereof, to be administered orally.

[0464] 62. The pharmaceutical composition according to Embodiment 61, or a pharmaceutically acceptable salt thereof, administered as a tablet or capsule.

[0465] 63. A process for preparing a pharmaceutical composition, comprising combining a compound described in any one of Embodiments 1 to 58 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

[0466] 64. A method for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of any one of Embodiments 1 to 58 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment and / or improvement.

[0467] 65. The method according to Embodiment 64, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigold, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[0468] 66. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriasis.

[0469] 67. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriatic arthritis.

[0470] 68. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is rheumatoid arthritis.

[0471] 69. The method according to embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is ankylosing spondylitis.

[0472] 70. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is hidradenitis suppurativa.

[0473] 71. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is bullous pemphigoid.

[0474] 72. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is atopic dermatitis.

[0475] 73. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is vitiligo.

[0476] 74. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0477] 75. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is systemic lupus erythematosus.

[0478] 76. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is asthma.

[0479] 77. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is uveitis.

[0480] 78. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is chronic obstructive pulmonary injury.

[0481] 79. The method according to Embodiment 65, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple myeloma.

[0482] 80. The method according to any one of Embodiments 64 to 79, wherein a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 58 is administered orally.

[0483] 81. The method according to any one of Embodiments 64 to 80, wherein a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 58 is administered as a tablet or capsule.

[0484] 82. Compounds described herein.

[0485] 83. The methods described herein. [Examples]

[0486] Abbreviation Throughout this specification and this application, the following abbreviations may be used. Å Angstrom Acetyl ACN Acetonitrile AIBN 2,2'-Azobis(2-methylpropionitrile) ATM atmosphere Boc tert-butyloxycarbonyl br broad Bu butyl CDI 1,1'-Carbonyldiimidazole δ NMR chemical shifts in parts per million from the standard to low magnetic field. d double line d day DBA dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCM Dichloromethane DEA (Diethylamine) DEAD Diethyl Azodicarboxylate DIPEA N,N-diisopropylethylamine (Hünig base) DMAP 4-(dimethylamino)pyridine DMF (N,N-dimethylformamide) DMP Dess-Martin Periodine DMSO (Dimethyl Sulfoxide) dr diastereomer ratio EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Eschenmoser salt N,N-dimethylmethyleneiminium iodide ESI Electrospray Ionization Et ethyl HCl ethyl acetate g grams h time HOBt 1-hydroxybenzotriazole HPLC (High-Pressure Liquid Chromatography) Hz (Hertz) Iso IPA Isopropanol J coupling constant (NMR spectroscopy) L (liters) LC (Reset Chromatography) LDA Lithium Diisopropylamide LiHMDS (Lithium Bis(Trimethylsilyl)amide) m millimeters or multiple lines m / z mass-to-charge ratio M + Parental molecular ions M Molar concentration (moles / liter) Me methyl min μ (micron) MOM Methoxymethyl MS mass spectrometry n Normal N normality (equivalent concentration) NMR nuclear magnetic resonance Nos 2-nitrobenzenesulfonyl p Para Ph Phenyl psi: pounds per square inch q quadruple line rt room temperature RuPhos Pd G3 (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate S,S-(salen)Co(III)(OAc) (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(III) acetate s single line SFC Supercritical Fluid Chromatography t triplet or tert T3P 1-Propanephosphonic Acid Anhydride TEA (Triethylamine) Tf Trifluoromethanesulfonic acid TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) Ts p-toluenesulfonyl w / v weight / volume

[0487] In some embodiments, what is provided herein are processes and intermediates useful for preparing the compounds of this disclosure or pharmaceutically acceptable salts thereof. In the scheme below, the term PG is intended to mean a “protecting group,” such as those described in TW Greene and PGMWuts, “Protective Groups in Organic Synthesis,” 3rd ed., John Wiley & Sons, 1999. For example, a group PG bonded to a nitrogen atom represents a nitrogen protecting group, such as tert-butyloxycarbonyl (Boc), toluenesulfonyl (tosyl, Ts), or nitrobenzenesulfonyl (nosyl, Ns).

[0488] NMR spectra were recorded in DMSO-d6 at 300 K using a Bruker 600 MHz instrument equipped with a 5 mm BBO probe or a 500 MHz instrument equipped with a 5 mm BBFO probe. 1For 1H NMR signal assignment and relative stereochemistry determination, 1D 1H, 1D 13C, and 2D correlation spectroscopy (COSY) are used. 1 H- 13 Heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), nuclear Overhauser effect spectroscopy (NOESY), and 1 H- 19 Spectra obtained using heteronuclear Overhauser effect spectroscopy (HOESY) were acquired using a standard pulse sequence available on TopSpin 4.1 (Bruker Inc.).

[0489] Scheme 1

[0490] [ka] The compound of formula I can be prepared according to scheme 1. Compound AI can be converted to compound A-II via a two-step sequence: i) reducing the aldehyde with a reagent such as sodium borohydride in a solvent such as DCM and MeOH to obtain the corresponding alcohol (structure not shown), and then ii) brominating the alcohol with a reagent such as CBr4 and PPh3 using an additive such as imidazole in a solvent such as DCM. Alternatively, the aldehyde AI can be reduced in a solvent such as THF, R 2aCompound A-II can be obtained by treating M with a drug such as MeMgBr, and then brominating it in a solvent such as DCM with a reagent such as CBr4 containing additives such as imidazole and PPh3. Compound A-III can be prepared by treating bromide A-II with lactam BI in a solvent such as THF in the presence of a base such as LiHMDS. Compound A-III can then be converted to the compound of formula I by deprotection of compound A-III, followed by amide bond formation with a primary amine. For example, if the protecting group (PG) is a Boc group, compound A-III can be treated in a solvent such as DCM with an acid such as TFA to obtain the corresponding amine (structure not shown). Primary amines and carboxylic acids (R 4 The formation of an amide bond in CO2H) can be achieved in a solvent such as DMF, MeCN, or DCM, with or without additives such as HOBt, in the presence of a base such as DIPEA or TEA, via the use of a coupling agent such as HATU, EDCI, or 2-chloro-1-methylpyridinium iodide, to obtain the compound of formula I. Alternatively, the formation of an amide bond in a primary amine can be achieved by treatment with an N-hydroxysuccinate ester in a solvent such as acetonitrile, in the presence of a reagent such as DIPEA, to provide the compound of formula I.

[0491] Scheme 2

[0492] [ka] The substituted lactam A-III can also be prepared as shown in Scheme 2. 1c A substituted lactam A-III can be obtained by treating compound A-IIIa, in which the base is H, with a chemical agent such as methyl iodide, chloromethyl methyl ether, bromoacetonitrile, N-fluorobenzenesulfonimide, or 3-phenyl-2-(phenylsulfonyl)-1,2-oxazyridine in the presence of a base such as LiHMDS or K2CO3 and a solvent such as THF or DMF.

[0493] Scheme 3

[0494] [ka] Compounds Ib and Ic may be prepared as shown in Scheme 3. Lactams A-IIIb can be prepared by treating aldehyde AI with lactam BI in a solvent such as THF and in the presence of a base such as LiHMDS. Then, compounds A-IIIb are converted to ketones A-V by treating them with a reagent such as DMP in a solvent such as DCM. Lactams A-VI are obtained by treating ketone AV with an alkylating reagent such as methyl iodide in the presence of a base such as K2CO3 and a solvent such as DMF. Then, R 2a By adding a suitable nucleophile such as M to lactam A-VI, the corresponding alcohol A-VII is obtained. Compounds A-VI and A-VII can be converted to the compound of formula I using the method described in Scheme 1 for the conversion of compound A-III to the compound of formula I.

[0495] Scheme 4a

[0496] [ka] Compound C-II can be prepared from compound CI by protecting the free amine with a protecting group (PG). For example, compound CI can be treated with a reagent such as TsCl or 4-nitrobenzenesulfonyl chloride in the presence of a base such as pyridine or DIPEA and a solvent such as DCM. Phosphonate C-IV may be prepared by several methods, two of which are described in scheme 4a.

[0497] Method 1: In a two-step procedure, alcohol C-II is cyclized to form an aziridine (structure not shown) by treatment with a reagent such as DIAD or DEAD, an additive such as PPh3, and a solvent such as THF. Subsequently, compound C-III can be obtained by forming a phosphonic acid ester through reaction with a base such as triethyl phosphonoacetate, KOtBu, and a solvent such as THF. Phosphonate C-IV can be prepared by treating compound C-III with a reagent such as AlMe3 in a solvent such as IPA, MeOH, and toluene.

[0498] Method 2: Phosphonic acid ester C-III can be prepared by treating alcohol CI with NoSc 1 in a solvent such as DCM and in the presence of a base such as DIPEA, followed by treatment with a base such as 2-(diethoxyphosphoryl)ethyl acetate, KOtBu, and a solvent such as THF. Hydrolysis of the ester in compound C-III by reaction with a base such as aqueous LiOH in a solvent such as THF yields the corresponding carboxylic acid (structure not shown), which can then be converted to lactam C-IV by treatment with a reagent such as 2-chloro-1-methylpyridine-1-ium iodide in the presence of a base such as DIPEA and a solvent such as DCM.

[0499] Scheme 4b

[0500] [ka] Compounds A-IIId can be prepared as shown in scheme 4b. Olefin CV can be prepared by treating aldehyde AI with phosphonate C-IV in the presence of a base such as NaH and a solvent such as THF. Lactams A-IIIc are obtained by hydrogenation of the olefins in compounds C-V by treatment with a reagent such as hydrogen, Pd / C and a solvent such as MeOH or EtOH. Alternatively, olefin CV can be treated with R in the presence of an additive such as BF3·OEt2, a catalyst such as CuBr·S(CH3)2, and a solvent such as DCM. 2aLactam A-IIIc can be obtained by reacting it with a suitable nucleophile such as M. Compound A-IIId can be prepared by treating lactam A-IIIc with a reagent such as samarium(II) iodide in a solvent such as THF. Compound A-IIId can be converted to the compound of formula I using the method described in Scheme 1 for the conversion of compound A-III to the compound of formula I.

[0501] Scheme 5

[0502] [ka] Compound A-IIIc may also be prepared as shown in Scheme 5. Compound A-IIIc is obtained by treating bromide A-II with protected lactam B-II (using a protecting group such as a toluenesulfonyl group) in the presence of a base such as LiHMDS and a solvent such as THF.

[0503] Scheme 6

[0504] [ka] Olefin CV may also be prepared as shown in Scheme 6. Olefin CV can be obtained by treating chloride A-VIII with lactam B-III in the presence of a base such as N-cyclohexyl-N-methylcyclohexaneamine, a catalyst such as Pd2(dba)3, and a solvent such as 1,4-dioxane. Lactam B-III may be prepared in a manner similar to the procedure described in J.Med.Chem.2016,59,3,914-924.

[0505] Scheme 7

[0506] [ka] Lactam DV may be prepared as shown in Scheme 7. Compound DI is obtained by treating bromide A-II with ester B-IV in the presence of a base such as LDA and a solvent such as THF. Ester DI is then subjected to ester hydrolysis by treatment with an aqueous base such as LiOH in a solvent such as MeOH to obtain the corresponding carboxylic acid (structure not shown). Compound D-II is obtained by subsequently reacting the carboxylic acid with 4-nitrobenzenesulfonamide using coupling conditions with a coupling agent such as HATU or EDCI in a solvent such as DMF, MeCN, or DCM with or without additives such as HOBt, in the presence of a base such as DIPEA or TEA. Compound D-II can be converted to amide D-III using the method described in Scheme 1 for the conversion of compound A-III to the compound of formula I. The corresponding bicyclic lactam is obtained by treating amide D-III with iodine and a base such as K2CO3 in a solvent such as ACN (structure not shown). Next, the bicyclic lactam is reacted with tributyltin hydride and AIBN in a solvent such as toluene to obtain lactam D-IV. Lactam DV is obtained by treating lactam D-IV with benzenethiol, a base such as K2CO3, an additive such as DMSO, and a solvent such as ACN.

[0507] intermediate Intermediate 1: tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0508] [ka]

[0509] Step A: tert-butyl(S)-((4,4-difluorocyclohexyl)(7-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A DCM / MeOH (5:1, 60 mL) solution of tert-butyl(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (2.17 g, 5.50 mmol) was cooled to 0°C. Then, sodium borohydride (265 mg, 6.90 mmol) was added, and the resulting mixture was stirred over 2.5 hours while being warmed to room temperature under an air atmosphere. The mixture was cooled to 0°C, and saturated NH4Cl aqueous solution (0.2 mL) was added dropwise to quench the mixture, and it was stirred over 30 minutes while being warmed to room temperature. The reaction mixture was partitioned between DCM (100 mL) and water (200 mL), and the aqueous layer was further extracted with DCM (3 × 30 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered through diatomaceous earth, and concentrated until dry. The residue was purified by silica gel chromatography (0-25% MeOH / DCM) to obtain the title compound as a white solid (yield 82%).

[0510] Step B: tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. A mixture of tert-butyl(S)-((4,4-difluorocyclohexyl)(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 dropwise at room temperature to a mixture of CBr4 (221 mg, 0.670 mmol) in dry DCM (3.3 mL). The resulting mixture was stirred at room temperature for 1 hour, 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 room temperature for 30 minutes. The reaction mixture was concentrated until dry, and the residue was purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound as a white foam (yield 79%).

[0511] Intermediate 2: 4-Cyclopropyl-1,2,5-Oxadiazole-3-carboxylic acid 2,5-Dioxopyrrolidine-1-yl

[0512] [ka]

[0513] Step A: 4-Cyclopropyl-1,2,5-Oxadiazole-3-Carbonyl Chloride. 4-Cyclopropyl-1,2,5-Oxadiazole-3-carboxylic acid (200 mg, 1.30 mmol) and DCM (2.6 mL) were charged into a flask. The solution was cooled to 0°C, then oxalyl chloride (0.224 mL, 2.60 mmol) was added dropwise, followed by the addition of one drop of DMF. The mixture was stirred for 3 hours and then warmed to room temperature. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily substance, which was dissolved in DCM to obtain a 2 M solution of 4-Cyclopropyl-1,2,5-Oxadiazole-3-Carbonyl Chloride, which was used without further purification.

[0514] Step B: 4-Cyclopropyl-1,2,5-Oxadiazole-3-carboxylic acid 2,5-Dioxopyrrolidine-1-yl. N-hydroxysuccinimide (231 mg, 1.95 mmol), DCM (3.25 mL), and DIPEA (0.336 mL, 1.95 mmol) were charged into a flask. The reaction mixture was cooled to 0°C, and then 4-Cyclopropyl-1,2,5-Oxadiazole-3-carbonyl chloride (2 M in DCM, 0.649 mL, 1.30 mmol, Step A) was added dropwise. The reaction mixture was stirred for 1 hour while being heated to room temperature. The reaction mixture was then sequentially washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The substance was purified by silica gel chromatography (0-100% (10% MeOH-containing siRNA) / hexane) to obtain the title compound as a clear oil (yield 39%).

[0515] Intermediate 3: tert-butyl 3-methyl-2-oxopiperidine-1-carboxylic acid

[0516] [ka] To a solution of 3-methylpiperidine-2-one (1.00 g, 8.84 mmol) and DMAP (108 mg, 0.880 mmol) in CH2Cl2 (18 mL), TEA (1.47 mL, 10.6 mmol) was added. Next, di-tert-butyl dicarbonate (2.44 g, 11.2 mmol) was added, and the reaction mixture was stirred at room temperature for 26 hours. Then, this mixture was diluted with CH2Cl2 and washed sequentially with 10% aqueous citric acid solution, 10% aqueous NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound used without further purification (yield 86%).

[0517] Intermediate 4: tert-butyl 2-oxoazepan-1-carboxylic acid

[0518] [ka] The title compound was prepared using ε-caprolactam instead of 3-methylpiperidine-2-one and THF instead of CH2Cl2, as described for the synthesis of intermediate 3. The residue was purified by silica gel chromatography (0-100% siRNA (containing 10% MeOH) / hexane) to obtain the title compound (yield 97%).

[0519] Intermediate 5: tert-butyl 2-oxo-6-(trifluoromethyl)piperidine-1-carboxylic acid

[0520] [ka] The title compound was prepared using 6-(trifluoromethyl)piperidine-2-one instead of 3-methylpiperidine-2-one and THF instead of CH2Cl2, as described in the synthesis of intermediate 3. The residue was purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound as a clear solid (yield 98%).

[0521] Intermediate 6: tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylic acid

[0522] [ka] The title compound was prepared by using 4-(trifluoromethyl)piperidine-2-one instead of 3-methylpiperidine-2-one and THF instead of CH2Cl2, as described in the synthesis of intermediate 3. The residue was purified by silica gel chromatography (0-100% siRNA (containing 10% MeOH) / hexane) to obtain the title compound (yield 99%).

[0523] Intermediate 7: tert-butyl 2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid

[0524] [ka] The title compound (89% yield) was prepared using 5-(trifluoromethyl)piperidine-2-one instead of 3-methylpiperidine-2-one, as described for the synthesis of intermediate 3.

[0525] Intermediate 8: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)pyrrolidine-2-one

[0526] [ka]

[0527] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid. LiHMDS (1.0 mL, 1.0 mmol, 1 M in THF) was added dropwise to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylic acid (176 mg, 0.950 mmol) in THF (0.95 mL) cooled to -78°C, and the resulting solution was stirred at -78°C for 1 hour. Next, a solution of tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (300 mg, 0.65 mmol, intermediate 1) in THF (1.5 mL) was added dropwise over 5 minutes. The resulting solution was stirred at -78°C for 30 minutes, then warmed to room temperature over 30 minutes and quenched by adding saturated NH4Cl aqueous solution. This mixture was then diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 times), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% ethyl acetate (containing 10% MeOH) / hexane) to obtain the title compound (yield 26%).

[0528] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)pyrrolidine-2-one. To a solution of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl (93 mg, 0.16 mmol, Step A) in CH2Cl2 (1.0 mL), TFA (1.0 mL) was added, and the reaction was stirred at room temperature for 1 hour. After that, the pH of the mixture was adjusted to pH > 10 by carefully adding 0.5 M aqueous NaOH solution, and then the mixture was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-10% (2.0M ammonia-containing MeOH) / DCM) to obtain the title compound (yield 80%).

[0529] Intermediate 9: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)piperidine-2-one

[0530] [ka]

[0531] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopiperidine-1-carboxylic acid. The title compound (yield 24%) was prepared by using tert-butyl 2-oxopiperidine-1-carboxylic acid instead of tert-butyl 2-oxopyrrolidine-1-carboxylic acid, as described for Step A of intermediate 8, and by cooling the reaction mixture to -45°C instead of -78°C.

[0532] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)piperidine-2-one. The title compound (yield 66%) was prepared using tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid (Step A) instead of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid (Step A), as described for Step B of the synthesis of intermediate 8.

[0533] Intermediate 10: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)azepan-2-one

[0534] [ka]

[0535] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxoazepan-1-carboxylic acid. The title compound (16% yield) was prepared by using tert-butyl 2-oxoazepan-1-carboxylic acid (intermediate 4) instead of tert-butyl 2-oxopyrrolidine-1-carboxylic acid, as described for Step A of the synthesis of intermediate 8, and by cooling the reaction mixture to -45°C instead of -78°C.

[0536] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)piperidine-2-one. The title compound (80% yield) was prepared using tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid (step A) instead of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxoazepane-1-carboxylic acid (step A), as described with respect to step B of the synthesis of intermediate 8.

[0537] Intermediate 11: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methylpiperidine-2-one

[0538] [ka]

[0539] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxopiperidine-1-carboxylic acid. The title compound (30% yield) was prepared using tert-butyl 3-methyl-2-oxopiperidine-1-carboxylic acid (intermediate 3) instead of tert-butyl 2-oxopyrrolidine-1-carboxylic acid, as described with respect to step A of the synthesis of intermediate 8.

[0540] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methylpiperidine-2-one. The title compound (100% yield) was prepared using tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxopyrrolidine-1-carboxylic acid (step A) instead of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxopiperidine-1-carboxylic acid (step A) as described for step B of the synthesis of intermediate 8.

[0541] Intermediate 12: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-6-(trifluoromethyl)piperidine-2-one

[0542] [ka]

[0543] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-6-(trifluoromethyl)piperidine-1-carboxylic acid. The title compound was prepared by using tert-butyl 2-oxo-6-(trifluoromethyl)piperidine-1-carboxylic acid (intermediate 5) instead of tert-butyl 2-oxopyrrolidine-1-carboxylic acid, as described for Step A of the synthesis of intermediate 8, and by cooling the reaction mixture to -45°C instead of -78°C. The residue was purified by silica gel chromatography (0-100% acetone / DCM) to obtain the title compound (yield 77%).

[0544] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-6-(trifluoromethyl)piperidine-2-one. The title compound (82% yield) was prepared using tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid (step A) instead of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-6-(trifluoromethyl)piperidine-1-carboxylic acid (step A) as described for step B of the synthesis of intermediate 8.

[0545] Intermediate 13: (3R * )-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)piperidine-2-one

[0546] [ka]

[0547] Intermediate 14:(3S * )-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)piperidine-2-one

[0548] [ka]

[0549] Process A: tert-butyl (3R *)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid and tert-butyl(3S * )-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid. The title compound was prepared by using tert-butyl 2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid (intermediate 7) instead of tert-butyl 2-oxopyrrolidine-1-carboxylic acid, as described for step A of the synthesis of intermediate 8, and by cooling the reaction mixture to -45°C instead of -78°C, with the title compound R being the first isomer to elute. * The isomer (28% yield) and the second isomer to elute are the S compounds of the title compound. * Isomers were obtained (14% yield).

[0550] Process B1:(3R * )-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)piperidine-2-one (intermediate 13). The title compound (yield 73%) is obtained by replacing tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid with tert-butyl(3R * Prepared using )-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid (Step A, the isomer that is first eluted).

[0551] Process B2:(3S * )-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)piperidine-2-one (intermediate 14). The title compound (yield 34%) is synthesized as described for step B of the synthesis of intermediate 8, by replacing tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxopyrrolidine-1-carboxylic acid with tert-butyl(3S * Prepared using )-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)piperidine-1-carboxylic acid (step A, second isomer to elute).

[0552] Intermediate 15: Diethyl((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonic acid

[0553] [ka]

[0554] Step A: (R)-2-(trifluoromethyl)oxirane. A mixture of 2-(trifluoromethyl)oxirane (150 g, 1.34 mol), (S,S)-(salen)Co(III)(OAc) (4.44 g, 6.69 mmol), and water (13.3 mL, 0.736 mol) was stirred at room temperature under an inert atmosphere for 48 hours. The mixture was then distilled at atmospheric pressure (fractions collected at 32°C) to obtain the title compound as a colorless oil in 35% yield.

[0555] Step B: (R)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide. A mixture of (R)-2-(trifluoromethyl)oxirane (52.2 g, 184 mmol, Step A), CHCl3 (522 mL), 4-toluenesulfonamide (79.8 g, 466 mmol), and Ti(Oi-Pr)4 (132 g, 466 mmol) was stirred overnight at room temperature. The reaction was then quenched by the addition of water (1 L), and the two-phase mixture was extracted with DCM (3 × 800 mL). The combined organic layers were washed with brine (3 × 1 L), dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (20-33% siRNA / petroleum ether) to obtain the title compound as a white solid in 50% yield.

[0556] Step C: (S)-1-Tosyl-2-(trifluoromethyl)aziridine. A mixture of (R)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide (66 g, 230 mmol, Step B) and PPh3 (67 g, 250 mmol) was dissolved in THF (660 mL), and the solution was cooled to 0°C. Then, DEAD (41 g, 230 mmol) was added over 30 minutes, and the resulting solution was stirred overnight at room temperature. The reaction mixture was quenched by adding water (1 L), and the two-phase solution was extracted with DCM (3 × 1 L). The combined organic layers were washed with brine (3 × 2 L), dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (5-10% siRNA / petroleum ether) to obtain the title compound as a white solid in 81% yield. The reaction was quenched by adding water (1 L), and the two-phase solution was extracted with DCM (3 × 1 L).

[0557] Step D: Ethyl (4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-((4-methylphenyl)sulfonamide)pentanoate. A mixture of KOt-Bu (4.23 g, 37.7 mmol) and ethyl 2-(diethoxyphosphoryl) acetate (7.48 mL, 37.7 mmol) in THF (47 mL) was heated at 40°C for 20 minutes. Then, (S)-1-tosyl-2-(trifluoromethyl)aziridine (5.00 g, 18.9 mmol, Step C) was added, and the reaction mixture was heated at 40°C for 16 hours. After this, the reaction mixture was cooled to room temperature, concentrated until dry, and purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound as a mixture of diastereomers in 69% yield.

[0558] Step E: Diethyl((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonic acid. Ethyl(4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-((4-methylphenyl)sulfonamide)pentanoate (6.38 g, 13.0 mmol, Step D) was dissolved in toluene (32.6 mL), and the mixture was cooled to 0°C. Then, a 2 M solution of AlMe3 in toluene (19.6 mL, 39.1 mmol) was added dropwise through a dropping funnel at a rate such that the reaction temperature did not exceed 6°C. After the addition was complete, the ice bath was removed, the reaction mixture was warmed to room temperature, and then heated overnight at 110°C. The reaction mixture was cooled to 0°C and slowly quenched by sequentially adding IPA (2.0 mL) and MeOH (1.1 mL) dropwise. Next, the resulting mixture was diluted with saturated NH4Cl aqueous solution (10 mL) and 0.1 M HCl aqueous solution (5 mL), filtered through a diatomaceous earth pad, and the filter cake was washed with toluene (2 × 25 mL). The layers were separated, and the aqueous layer was further extracted with toluene (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% toluene / hexane) to obtain the title compound as a colorless oil (yield 62%).

[0559] Intermediate 16: (S)-(1-(dimethyl(oxo)-λ 6 (-Sulfanylidene)-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamate tert-butyl

[0560] [ka]

[0561] Step A: 1,1,1-trifluoro-4-iodo-2,2-dimethylbutane. Triphenylphosphine (24.6 g, 93.7 mmol) and imidazole (5.53 g, 81.2 mmol) were added to a stirred solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (9.75 g, 62.5 mmol) in DCM (125 mL), and the resulting mixture was cooled to 0°C. Then, iodine (23.8 g, 93.7 mmol) was added in small amounts, and the mixture was stirred for 24 hours. At this point, it was quenched with saturated NaHCO3 aqueous solution and stirred for 15 minutes. The organic layer was removed, washed sequentially with semi-saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain the residue. Cold hexane (50 mL) was added to the residue, and the mixture was vigorously stirred for 10 minutes, at which point a white precipitate formed. The white solid was filtered through a silica pad and removed, and the solid was washed with a second volume of chilled hexane. The filtrate was concentrated to obtain the title compound as a clear, colorless oil (66% yield), which was used without further purification.

[0562] Step B: (2R, 5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine. (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.66 g, 3.59 mmol) was added to a stirred solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (7 mL) in THF (2.33 mL, 3.95 mmol, 1.7 M pentane solution) at -78°C, and the reaction mixture was stirred at -78°C. After 1 hour, a solution of 1,1,1-trifluoro-4-iodo-2,2-dimethylbutane (1.05 g, 3.95 mmol, Step A) in THF (6 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with phosphate buffer aqueous solution (50 mL, 0.1 M, pH 7) and diluted with diethyl ether. The organic layer was removed, and the aqueous layer was extracted with diethyl ether (2 × 50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to obtain oil. LC / MS of this oil revealed that the diastereomer mixture was in a ratio of approximately 1.5:1. This mixture was separated by silica gel chromatography (0-30% ethyl acetate / hexane) to obtain the first isomer that eluted as a yellow oil (50% yield), which was designated as the R,S diastereomer. The second isomer that eluted, designated as the R,R diastereomer, (2R,5R)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine, was isolated in 28% yield.

[0563] Step C: (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate methyl. (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine (1.15 g, 3.57 mmol, Step B, the first isomer eluted) was stirred in ACN (14.3 mL) at room temperature, to which aqueous HCl (14.3 mL, 1 M) was added. After stirring for 2 hours, the reaction mixture was poured into saturated aqueous NaHCO3 at 0°C and then extracted with RINKAN (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain oil, which was used without further purification.

[0564] Step D: (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoate methyl. Boc2O (1.56 g, 7.14 mmol) was added to a stirred solution of (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate methyl (811 mg, 3.57 mmol, Step C) in DCM (15.1 mL). After 24 hours, the reaction was quenched with aqueous HCl (10 mL, 1 M) and the layers were separated. The organic layer was sequentially washed with aqueous HCl (10 mL, 1 M), water, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to obtain oil, which was used in the next step without further purification.

[0565] Step E: (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid. To a stirred solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoate (Step D)) in 22.4 mL of THF at 0°C, 8.50 mL of LiOH aqueous solution (1 M) was added, and the resulting mixture was stirred at 0°C for 2 hours. The pH of the reaction mixture was then adjusted to pH 2 using HCl aqueous solution (1 M). The mixture was extracted with ELISA (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO--4, filtered, and concentrated to obtain a clear oil, which was used in the next step without further purification.

[0566] Process F: (S)-(1-(dimethyl(oxo)-λ 6(S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid (885 mg, 2.83 mmol, step E) in THF (7 mL) solution was mixed with t-BuOK solution (4.24 mL, 4.24 mmol, 1 M in THF) and the resulting solution was stirred at room temperature for 2 hours. Separately, CDI (550 mg, 3.39 mmol) was mixed with (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid (885 mg, 2.83 mmol, step E) in THF (7 mL) solution cooled to 0°C and the resulting mixture was stirred at 0°C for 2 hours. Subsequently, this mixture was added to a suspension derived from trimethylsulfoxonium using a cannula and the resulting mixture was stirred at room temperature. After 2 hours, the reaction mixture was filtered through diatomaceous earth, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate / hexane) to obtain the title compound as a white foam (56% yield).

[0567] Intermediate 17: (S)-(5,5,5-trifluoro-1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentyl)carbamate tert-butyl

[0568] [ka]

[0569] Step A: (S)-(1-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate tert-butyl. 5-chloropyridazin-3-amine (1.00 g, 7.72 mmol) and (S)-(1-(dimethyl(oxo)-λ 6(-sulfanylidene)-7,7,7-trifluoro-6,6-dimethyl-2-oxoheptan-3-yl)carbamate tert-butyl (3.29 g, 8.49 mmol, intermediate 16) was dissolved in toluene (21 mL). 4 Å molecular sieves (2.00 g), NaOTf (66.4 mg, 0.386 mmol), and chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium(II) (141 mg, 0.193 mmol) were added sequentially, and the resulting mixture was heated at 85°C for 16 hours. The reaction mixture was concentrated on diatomaceous earth and purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound in 30% yield.

[0570] Step B: (S)-(5,5,5-trifluoro-4,4-dimethyl-1-(7-vinylimidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate tert-butyl. (S)-(1-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate tert-butyl (0.960 mg, 2.28 mmol, Step A), potassium trifluoro(vinyl)borate (0.460 g, 3.43 mmol), and K3PO4 (1.46 g, 6.90 mmol) were added to a reactor containing 1,4-dioxane and water (24 mL, 5:1 v / v, sparged with N2 before use) under positive nitrogen gas pressure. The mixture was heated under reflux (85°C), and then RuPhos Pd G3 (49.7 mg, 60.0 mmol) was added. The resulting mixture was stirred at 85°C for 6 hours. The mixture was then cooled to room temperature, and then concentrated to remove most of the 1,4-dioxane. The residue was then diluted with RINKAN and water, the layers were separated, and the aqueous layer was extracted twice with RINKAN. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, concentrated to dryness, and the title compound was obtained as a brown foam, which was used without further purification.

[0571] Step C: (S)-(5,5,5-trifluoro-1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentyl)carbamate tert-butyl. A solution of NaIO4 (2.43 g, 11.4 mmol) in water (55 mL) was added to a solution of (S)-(5,5,5-trifluoro-4,4-dimethyl-1-(7-vinylimidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate tert-butyl (8.81 g, 22.5 mmol, Step B) in 1,4-dioxane (55 mL). The resulting mixture was then cooled in an ice bath to a temperature slightly above freezing point, and K2OsO4·2H2O (42.0 mg, 0.114 mmol) was added. The reaction mixture was then removed from the ice bath and stirred for 1 hour. The resulting high-viscosity suspension was diluted with water, and the solution was extracted with siRNA (four times). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated on diatomaceous earth, and purified by silica gel chromatography (0-50% acetone / hexane) to obtain the title compound in 64% yield.

[0572] Intermediate 18: (5S)-3-((2-((S)-1-amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one

[0573] [ka]

[0574] Process A: tert-butyl((S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-((S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate. To a suspension of NaH (62.4 mg, 1.56 mmol) in THF (4 mL), a solution of diethyl ((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonic acid (692 mg, 1.56 mmol, intermediate 15) in THF (4 mL) was added, and the resulting mixture was cooled to -78°C. Next, a solution of tert-butyl(S)-(5,5,5-trifluoro-1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentyl)carbamate (500 mg, 1.20 mmol, intermediate 17) in THF (4 mL) was added dropwise to the reaction mixture, and the resulting mixture was placed in an ice bath. The reaction mixture was stirred overnight while slowly warming to room temperature. After this, the reaction mixture was cooled to 0°C and quenched with water. The two-phase mixture was extracted with RINKAN (three times), the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% acetone / hexane) to obtain the title compound in 58% yield as a mixture of olefin isomers.

[0575] Step B: tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate. tert-butyl((S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-((S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (487 mg, 0.692 mmol, Step A) was dissolved in EtOH (28 mL), and the solution was sparged with N2. Next, 10% by weight of Pd / C (286 mg, 0.234 mmol) was added, the reaction mixture was evacuated, and the mixture was refilled with H2 using a balloon (3 times). The reaction mixture was stirred at room temperature for 3 hours, and then the reaction mixture was filtered through a diatomaceous earth / silica gel mixture, concentrated to dryness, and the title compound was obtained, which was used without further purification.

[0576] Step C: tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate. SmI2 (24 mL, 2.4 mmol, 0.1 M in THF) was added to a solution of tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (315 mg, 0.446 mmol). Step B) In THF (6.4 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. Afterward, an additional 4.5 mL of SmI2 (0.45 mmol, 0.1 M in THF) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 1 M aqueous HCl. The two-phase mixture was extracted with toluene (3 times), the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% toluene (containing 10% MeOH) / hexane) to obtain the title compound in >99% yield.

[0577] Step D: (5S)-3-((2-((S)-1-amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one. tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (300 mg, 0.544 mmol, Step C) was dissolved in DCM (6.97 mL), and then TFA (1.04 mL, 13.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 45 minutes, then concentrated until dry, and purified by silica gel chromatography (0-20% MeOH / DCM) to obtain the title compound in >99% yield.

[0578] Intermediate 19: tert-butyl(S)-3-methylene-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0579] [ka]

[0580] Step A: tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. S-5-(trifluoromethyl)pyrrolidine 2-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 added sequentially, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then sequentially washed with 10% aqueous citric acid solution, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-50% siRNA / hexane) to obtain the title compound in 70% yield.

[0581] Step B: tert-butyl(5S)-3-((dimethylamino)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. A solution of LiHMDS (2.0 mL, 2.0 mmol, 1 M in THF) was cooled to -78°C. Then, a solution of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (250 mg, 1.0 mmol, Step A) in THF (9.9 mL) was added dropwise to the LiHMDS solution, and the resulting solution was stirred at -78°C for 30 minutes. After this, N,N-dimethylmethyleneiminium iodide (370 mg, 2.0 mmol) was added little by little through a dropping funnel, and the resulting mixture was stirred at -78°C for another 30 minutes, then slowly warmed to room temperature and stirred at room temperature for 30 minutes. The reaction was quenched by adding water, and the two-phase mixture was extracted with RINKAN (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to obtain the title compound, which was used without further purification.

[0582] Step C: tert-butyl(S)-3-methylene-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. tert-butyl(5S)-3-((dimethylamino)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (3.06 g, 9.87 mmol, Step B) was dissolved in MeOH (9.9 mL), and then MeI (1.54 mL, 24.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then MeOH (25 mL) was added, and the resulting mixture was stirred at room temperature for a further 20 minutes. The reaction product was then concentrated to dryness and dissolved in DCM (49 mL) and saturated NaHCO3 aqueous solution (49 mL). The two-phase mixture was stirred vigorously overnight at room temperature. The layers were separated, and the aqueous layer was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-60% alkyl / hexane) to obtain the title compound in 59% yield.

[0583] Intermediate 20: tert-butyl(6S)-1-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-4-oxo-6-(trifluoromethyl)-5-azaspiro[2,4]heptan-5-carboxylic acid

[0584] [ka]

[0585] Intermediate 21: (1R * ,2R * )-2-(2-(S-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-1-((S-2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropyl)cyclopropane-1-carboxylic acid

[0586] [ka]

[0587] Step A: tert-butyl(S,E)-((4,4-difluorocyclohexyl)(7-((2-tosylhydrazineylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. tert-butyl(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (952 mg, 2.41 mmol) and 4-methylbenzenesulfonhydrazide (494 mg, 2.65 mmol) were dissolved in 1,4-dioxane (13 mL), and the reaction mixture was heated at 85°C for 1 hour. The reaction mixture was then concentrated to dryness to obtain the title compound (yield >99%), which was used without further purification.

[0588] Step B: tert-butyl(6S)-1-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-4-oxo-6-(trifluoromethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid and (1R * ,2R * )-2-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropyl)cyclopropane-1-carboxylic acid. Tert-butyl(S,E)-((4,4-difluorocyclohexyl)(7-((2-tosylhydrazineylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (250 mg, 0.44 mmol, step A) and 1,4-dioxane (2.2 mL) were added to a microwave vial. Next, tert-butyl(S)-3-methylene-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (240 mg, 0.89 mmol, intermediate 19) and K2CO3 (92 mg, 0.67 mmol) were added sequentially. The reaction mixture was sealed under an N2 atmosphere and heated at 110°C for 4 hours. The reaction mixture was cooled to room temperature and poured into water. The two-phase solution was extracted with siRNA (three times), the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was dissolved in DMF and purified by basic preparative HPLC (XBridge C18, 5 μm, 50 × 100 mm 10-100% MeCN / H2O (20 mM NH4OH)) to obtain intermediate 20 as the first elution fraction in 21% yield and intermediate 21 as the second elution fraction in 14% yield.

[0589] Intermediate 22: Diethyl((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)phosphonate

[0590] [ka]

[0591] Step A: (R)-N-(1-cyclopropyl-2-hydroxyethyl)-4-methylbenzenesulfonamide. To a solution of (R)-2-amino-2-cyclopropylethane-1-ol hydrochloride (4.0 g, 29 mmol) in DCM (100 mL), DIPEA (12 mL, 70 mmol) and 4-methylbenzenesulfonyl chloride (11 g, 58 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 12 hours. The reaction product was then diluted with water, and the two-phase mixture was extracted with DCM (3 × 50 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 (0-100% siRNA / petroleum ether) to obtain the title compound in 81% yield.

[0592] Step B: (R)-2-cyclopropyl-1-tosylaziridine. The title compound was synthesized in the same manner as in Step C, but using (R)-N-(1-cyclopropyl-2-hydroxyethyl)-4-methylbenzenesulfonamide (Step A) instead of (R)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide (32% yield).

[0593] Step C: Ethyl (4R)-4-cyclopropyl-2-(diethoxyphosphoryl)-4-((4-methylphenyl)sulfonamide)butanoate. The title compound was synthesized in the same manner as in Step D of Intermediate 15, using (R)-2-cyclopropyl-1-tosylaziridine (Step B) instead of (S)-1-tosyl-2-(trifluoromethyl)aziridine (yield 93%).

[0594] Step D: (4S)-4-cyclopropyl-2-(diethoxyphosphoryl)-4-((4-methylphenyl)sulfonamide)butanoic acid. To a solution of ethyl(4R)-4-cyclopropyl-2-(diethoxyphosphoryl)-4-((4-methylphenyl)sulfonamide)butanoate (4.5 g, 9.7 mmol, Step C) in THF (120 mL), an aqueous solution of LiOH·H2O (1.6 g, 39 mmol, 24 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated to remove the organic layer, and the aqueous layer was washed with DCM (3 × 50 mL). The pH of the aqueous layer was then adjusted to pH 4-5 by adding 1 M aqueous HCl. The aqueous layer was extracted with ELISA (4 × 100 mL), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound used without further purification (yield 88%).

[0595] Process E: Diethyl ((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)phosphonate.

[0596] To a solution of (4S)-4-cyclopropyl-2-(diethoxyphosphoryl)-4-((4-methylphenyl)sulfonamide)butanoic acid (3.7 g, 8.5 mmol, step D) in DCM (300 mL), DIPEA (4.5 mL, 26 mmol) and 2-chloro-1-methylpyridinium iodide (3.3 g, 13 mmol) were sequentially added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then washed with water (3 × 100 mL), the organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% siRNA / petroleum ether) to obtain the title compound in 61% yield.

[0597] Intermediate 23: (1S)-(7-(((5S)-5-cyclopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methaneaminium trifluoroacetate

[0598] [ka]

[0599] Step A: tert-butyl((S)-(7-((S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized in the same manner as in Step A of intermediate 18, using diethyl((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)phosphonate (intermediate 22) instead of diethyl((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonate (yield 69%).

[0600] Process B: tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound was synthesized using the same method as in step B of intermediate 18, but instead of tert-butyl((S)-(7-((S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate, using tert-butyl((S)-(7-((S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step A), and used without further purification.

[0601] Process C: tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. The title compound (49% yield) was synthesized in the same manner as in step C of intermediate 18, using tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step B) instead of tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step B) instead of tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxo-1-tosylpyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step B) instead of tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step B) instead of tert-butyl((1S)-5,5,5-trifluoro

[0602] Process D: (1S)-(7-(((5S)-5-cyclopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methaneaminium trifluoroacetate. The title compound (92% yield) was synthesized in the same manner as in step D of intermediate 18, using tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (step C) instead of tert-butyl((1S)-(7-(((5S)-5-cyclopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate, and the residue was used without further purification.

[0603] Intermediate 24:3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)piperidine-2-one.

[0604] [ka] The title compound was synthesized in the same manner as in step D of intermediate 18, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (step A of Example 4)). The residue was purified by silica gel chromatography (0-10% MeOH (containing 2.0 M ammonia) / DCM) to obtain the title compound in 74% yield.

[0605] Intermediate 25: tert-butyl3-methylene-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0606] [ka]

[0607] Step A: tert-butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound (83% yield) was synthesized in the same manner as in Step A of intermediate 19, using 4-(trifluoromethyl)pyrrolidine-2-one instead of S-5-(trifluoromethyl)pyrrolidine-2-one.

[0608] Step B: tert-butyl 3-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in Step B of intermediate 19, using tert-butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (Step A) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate, and used without further purification.

[0609] Step C: tert-butyl3-methylene-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in Step C of Intermediate 19, using tert-butyl3-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (Step B) instead of tert-butyl(5S)-3-((dimethylamino)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate, and used without further purification.

[0610] Intermediate 26: (1S)-(4,4-difluorocyclohexyl)(7-((2-oxo-4-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium trifluoroacetate

[0611] [ka]

[0612] Step A: tert-butyl3-((2-((S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methylene)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. tert-butyl N-[(S)-7-chloroimidazo[1,2-b]pyridazin-2-yl)-(4,4-difluorocyclohexyl)methyl]carbamate (100 mg, 0.249 mmol), tert-butyl 3-methylene-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid (99.3 mg, 0.374 mmol, intermediate 25), and Pd2dba3 (6.85 mg, 7.48 mmol) were added to a Schlenk tube, the tube was then evacuated, and argon was refilled. Next, 1,4-dioxane (0.5 mL), N-cyclohexyl-N-methylcyclohexamine (58.8 mL, 0.274 mmol), and tri-tert-butylphosphine (29.9 mL, 0.249 mmol, 1.0 M in THF) were added sequentially, and the reaction mixture was heated overnight at 90°C. The filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound in 50% yield.

[0613] Step B: tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in step C of intermediate 18, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (step A) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methylene)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) instead of tert-butyl((1S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (yield 72%).

[0614] Process C: Trifluoroacetic acid (1S)-(4,4-difluorocyclohexyl)(7-((2-oxo-4-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium. The title compound was synthesized in the same manner as in step D of intermediate 18, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate (step B) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (step B) (yield 92%).

[0615] Intermediate 27: 1-Isopropyl-1H-pyrazole-5-carboxylic acid 2,5-dioxopyrrolidine-1-yl

[0616] [ka]

[0617] Step A: 1-Isopropyl-1H-pyrazole-5-carbonyl chloride. A solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (1.0 g, 6.5 mmol) in DCM (13 mL) was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (1.1 mL, 13.0 mmol), followed by DMF (0.05 mL, 0.65 mmol), was added dropwise to the solution. The reaction mixture was stirred while slowly warming to room temperature. Once gas generation ceased, the reaction mixture was concentrated into a yellow oil, which was then dissolved in 12 mL of dry DCM for storage as a 2 M solution.

[0618] Step B: 1-Isopropyl-1H-pyrazole-5-carboxylic acid 2,5-dioxopyrrolidine-1-yl. A solution of N-hydroxysuccinimide (1.1 g, 9.7 mmol) and DIPEA (1.6 mL, 6.5 mmol) in DCM (25 mL) was cooled to 0°C under a nitrogen atmosphere. 1-Isopropyl-1H-pyrazole-5-carbonyl chloride solution (13 mL, 6.5 mmol, 2 M DCM solution, Step A) was added to the solution. The resulting solution was warmed to room temperature with stirring for 1 hour. The solution was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% Â(containing 10% MeOH) / hexane) to obtain the title compound in 61% yield as an off-white solid.

[0619] Intermediate 28: Diethyl((5S)-5-methyl-1-((4-nitrophenyl)sulfonyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonic acid

[0620] [ka]

[0621] Step A: (S)-2-methyl-1-((4-nitrophenyl)sulfonyl)-2-(trifluoromethyl)aziridine. A solution of (S)-2-amino-3,3,3-trifluoro-2-methylpropan-1-ol (7.69 g, 42.8 mmol) in anhydrous DCM (300 mL) was cooled to 0°C. Then, Nos-Cl (25.0 g, 113 mmol) was added all at once, followed by DIPEA (27.7 mL, 161 mmol) over 10 minutes. The resulting mixture was stirred at room temperature for 16 hours. The reaction was stopped by adding 200 mL of 2 M aqueous HCl solution, and liquid-liquid extraction was performed. The organic layer was washed with 5% aqueous Na2CO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-15% siRNA / petroleum ether) to obtain the title compound as a yellow oil (yield 43%).

[0622] Step B: Ethyl (4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-methyl-4-((4-nitrophenyl)sulfonamide)pentanoate. A mixture of 2-(diethoxyphosphoryl)ethyl acetate (1.3 mL, 6.4 mmol) and t-BuOK (6.4 mL, 6.4 mmol) in THF (13 mL) was heated at 40°C for 20 minutes. Then, (S)-2-methyl-1-((4-nitrophenyl)sulfonyl)-2-(trifluoromethyl)aziridine (1.0 g, 3.2 mmol, Step A) was added, and the resulting mixture was heated at 40°C for 3 hours. Then, water (50 mL) was added, and the mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to obtain a yellow oil. This oil was purified by silica gel chromatography (0-100% dimethyl / petroleum ether) to obtain the title compound as a colorless oil (yield 41%).

[0623] Step C: (4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-methyl-4-((4-nitrophenyl)sulfonamide)pentanoic acid. A mixture of ethyl (4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-methyl-4-((4-nitrophenyl)sulfonamide)pentanoate (4.6 g, 8.61 mmol, Step B), THF (50 mL), H2O (10 mL), and LiOH (1.81 g, 43.0 mmol) was heated at 50°C for 16 hours. The reaction mixture was then diluted with H2O (100 mL) and washed with HCl (100 mL). The pH of the aqueous layer was adjusted to pH 3 by adding 1 N HCl aqueous solution. The aqueous layer was then extracted with HCl (2 × 100 mL), the organic layers were combined, washed with brine, and dried over anhydrous Na2SO4. The mixture was filtered, concentrated to dryness, and used without further purification (yield 94%).

[0624] Step D: Diethyl((5S)-5-methyl-1-((4-nitrophenyl)sulfonyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonate. A mixture of (4S)-2-(diethoxyphosphoryl)-5,5,5-trifluoro-4-methyl-4-((4-nitrophenyl)sulfonamide)pentanoic acid (3.4 g, 6.7 mmol, Step C), 2-chloro-1-methylpyridine-1-ium iodide (2.57 g, 10.1 mmol), and DIPEA (3.51 mL, 20.1 mmol) in anhydrous DCM (250 mL) was stirred overnight at room temperature. The reaction mixture was sequentially washed with H2O (3 × 100 mL) and brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain a pale yellow oily substance. Next, this oil was subjected to silica gel chromatography (0-70% alkyl / petroleum ether) to obtain the title compound as a colorless oil (yield 29%).

[0625] Intermediate 29: tert-butyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0626] [ka] To a solution of 5-(trifluoromethyl)pyrrolidine-2-one (5.0 g, 32 mmol) and DMAP (40 mg, 0.32 mmol) in DCM (109 mL), TEA (5.5 mL, 39 mmol) was added, followed by the gradual addition of di-tert-butyl dicarbonate (8.5 g, 39 mmol). The resulting solution was stirred at room temperature for 18 hours. The solution was partitioned between DCM and a 0.5% aqueous citric acid solution. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% Â / hexane) to obtain the title compound (yield 62%).

[0627] Intermediate 30: tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0628] [ka] The title compound (60% yield) was prepared using (S)-5-(trifluoromethyl)pyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0629] Intermediate 31: tert-butyl 5-oxo-4-azaspiro[2,4]heptane-4-carboxylic acid

[0630] [ka] To a stirred solution of 4-azaspiro[2,4]heptan-5-one (250 mg, 2.3 mmol) in ACN (2.8 mL), di-tert-butyl dicarbonate (1 g, 4.6 mmol) and DMAP (274 mg, 2.3 mmol) were added. The mixture was stirred at room temperature for 3 hours, then diluted with water and extracted with siRNA (3 times). The organic layer was then washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-20% siRNA / hexane) to obtain the title compound (yield 71%).

[0631] Intermediate 32: tert-butyl 2-methyl-5-oxopiperidine-1-carboxylic acid

[0632] [ka] The title compound (48% yield) was prepared using 5-methylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0633] Intermediate 33: tert-butyl 2-ethyl-5-oxopyrrolidine-1-carboxylic acid

[0634] [ka] The title compound (38% yield) was prepared using 5-ethylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described for the synthesis of intermediate 29.

[0635] Intermediate 34: tert-butyl 2-isopropyl-5-oxopyrrolidine-1-carboxylic acid

[0636] [ka] The title compound (38% yield) was prepared using 5-isopropylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0637] Intermediate 35: tert-butyl6-oxo-2-oxa-5-azaspiro[3,4]octane-5-carboxylic acid

[0638] [ka] The title compound (54% yield) was prepared using 2-oxa-5-azaspiro[3.4]octan-6-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described for the synthesis of intermediate 29.

[0639] Intermediate 36: tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylic acid

[0640] [ka] The title compound (42% yield) was prepared using 5,5-dimethylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0641] Intermediate 37: tert-butyl 4,4-dimethyl-2-oxopyrrolidine-1-carboxylic acid

[0642] [ka] The title compound (44% yield) was prepared using 4,4-dimethylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0643] Intermediate 38: tert-butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0644] [ka] The title compound (44% yield) was prepared using 4-(trifluoromethyl)pyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0645] Intermediate 39: tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylic acid

[0646] [ka] The title compound (74% yield) was prepared using 4-methylpyrrolidine-2-one instead of 5-(trifluoromethyl)pyrrolidine-2-one, as described in the synthesis of intermediate 29.

[0647] Intermediate 40: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one

[0648] [ka]

[0649] Step A: 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-1-carboxylic acid. A solution of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (intermediate 30, 455 mg, 1.80 mmol) 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 hour. 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 the solution was then added to the reaction mixture at -78°C. The resulting mixture was stirred at -78°C for 1 hour. The reaction mixture was then warmed to room temperature over 1 hour, quenched with aqueous NH3Cl solution, and extracted with ethyl acetate (3 times). The organic layers were combined, washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% ethyl acetate / hexane) to obtain the title compound (yield 68%).

[0650] Step B: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one. 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-1-carboxylic acid (250 mg, 0.4 mmol, Step A) was dissolved in DCM (3.8 mL), and then TFA (0.6 mL, 8 mmol) was added. The resulting solution was stirred at room temperature for 1 hour, and then concentrated to dryness. The residue was dissolved in DCM, filtered through a silica gel / K2CO3 plug, and then concentrated to dryness to obtain the title compound, which was used without further purification.

[0651] Intermediate 41: tert-butyl(3R * ,5R * )-3-((R * )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0652] [ka]

[0653] Intermediate 42: tert-butyl(3R * ,5S * )-3-((R * )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0654] [ka]

[0655] Intermediate 43: tert-butyl(3S * ,5R * )-3-((R * )-(2-((S-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0656] [ka]

[0657] Intermediate 44: tert-butyl(3R * ,5R * )-3-((S * )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0658] [ka]

[0659] Intermediate 45: tert-butyl(3R * ,5S * )-3-((S * )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0660] [ka]

[0661] Intermediate 46: tert-butyl(3S * ,5S * )-3-((R * )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid

[0662] [ka] The title compound was synthesized in the same manner as in step A of intermediate 57. The diastereomers were separated by chiral SFC (stationary phase: Whilk O1 SS, 5 μm, 250 × 30 mm, mobile phase: 25% methanol:isopropanol (50:50) (containing 0.2% isopropylamine), 75% CO2). Intermediate 41 was the first isomer to be eluted (yield 19%). Intermediate 42 was the second isomer to be eluted (yield 18%). Intermediate 43 was the third isomer to be eluted (yield 9%). Intermediate 44 was the fourth isomer to be eluted (yield 3%). Intermediate 45 was the fifth isomer to be eluted (2% yield). Intermediate 46 was the sixth isomer to be eluted (yield 5%).

[0663] Intermediate 47: (1S)-5,5,5-trifluoro-1-(7-(hydroxy((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentan-1-aminium 2,2,2-trifluoroacetate.

[0664] [ka]

[0665] Step A: tert-butyl(5S)-3-((2-((S)-1-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in step A of intermediate 40, using tert-butyl(S)-(5,5,5-trifluoro-1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentyl)carbamate (intermediate 17) instead of tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (yield 56%).

[0666] Process B: (1S)-5,5,5-trifluoro-1-(7-(hydroxy((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-4,4-dimethylpentan-1-aminium 2,2,2-trifluoroacetate. The title compound was synthesized using tert-butyl(5S)-3-((2-((S)-1-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (step A) instead of tert-butyl3-((2-((S)-1-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid (step A), in the same manner as in step B of intermediate 57. The title compound was obtained by purification by silica gel chromatography (0-20% MeOH / DCM) without further purification.

[0667] Intermediate 48: (5S)-3-(1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-5-(trifluoromethyl)pyrrolidine-2-one

[0668] [ka]

[0669] tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A solution of tert-butyl(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (1.0 g, 2.5 mmol) in THF (32 mL) was cooled to 0°C. Then, a solution of 3 M methylmagnesium bromide in diethyl ether (2 mL, 6 mmol) was added dropwise over 5 minutes. The solution was stirred at 0°C for 1 hour. The reaction mixture was quenched with aqueous NH3Cl solution and extracted with SiO2 (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% alkylammonium sulfate / hexane) to obtain the title compound (yield 83%).

[0670] Step B: tert-butyl((1S)-(7-(1-bromoethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate. 100-200 mesh polymer bonds of triphenylphosphine (500 mg, 1.5 mmol), imidazole (60 mg, 0.9 mmol), and tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (300 mg, 0.731 mmol, Step A) were added in one go to a mixture in DCM (40 mL) of triphenylphosphine (500 mg, 1.5 mmol), imidazole (60 mg, 0.9 mmol), and tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (300 mg, 0.731 mmol, Step A). ​​Carbon tetrabromide (291 mg, 0.877 mmol) was added in one go, and the sides of the flask were rinsed with DCM (3 mL). The concentrated mixture was stirred overnight at room temperature, then filtered through a diatomaceous earth pad, rinsed twice with DCM, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (0-50% siRNA / hexane) to obtain the title compound (yield 36%).

[0671] Step C: tert-butyl(5S)-3-(1-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in Step A of intermediate 40, but using tert-butyl((1S)-(7-(1-bromoethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (Step B) instead of tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (23% yield).

[0672] Process D: (5S)-3-(1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-5-(trifluoromethyl)pyrrolidine-2-one. The title compound was synthesized in the same manner as in step B of intermediate 40, using tert-butyl(5S)-3-(1-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step C) instead of tert-butyl(5S)-3-(1-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)ethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step C) (yield 99%).

[0673] Intermediate 49: (1S)-(4,4-difluorocyclohexyl)(7-((5-methyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0674] [ka]

[0675] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-methyl-2-oxopyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in Step A, but using tert-butyl 2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate 32) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-50% ELISA / hexane) to obtain the title compound (yield 83%).

[0676] Process B: (1S)-(4,4-difluorocyclohexyl)(7-((5-methyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized in the same manner as in step B of intermediate 40, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-methyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-methyl-2-oxopyrrolidine-1-carboxylate. The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0677] Intermediate 50: (1S)-(4,4-difluorocyclohexyl)(7-((4-methyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0678] [ka]

[0679] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-methyl-2-oxopyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in Step A, but using tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (intermediate 39) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound (yield 50%).

[0680] Process B: (1S)-(4,4-difluorocyclohexyl)(7-((4-methyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized in the same manner as in step B of intermediate 40, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-methyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-methyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-methyl-2-oxopyrrolidine-1-carboxylate. The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0681] Intermediate 51: (1S)-(4,4-difluorocyclohexyl)(7-((5-ethyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0682] [ka]

[0683] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-ethyl-2-oxopyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in Step A, but using tert-butyl 2-ethyl-5-oxopyrrolidine-1-carboxylate (intermediate 33) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound (yield 34%).

[0684] Step B: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-ethyl-2-oxopyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in step B of intermediate 40, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-ethyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-ethyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-ethyl-2-oxopyrrolidine-1-carboxylate (step A). ​​The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0685] Intermediate 52: (1S)-(4,4-difluorocyclohexyl)(7-((5-isopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0686] [ka]

[0687] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-isopropyl-2-oxopyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in Step A, but using tert-butyl 2-isopropyl-5-oxopyrrolidine-1-carboxylate (intermediate 34) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound (yield 55%).

[0688] Process B: (1S)-(4,4-difluorocyclohexyl)(7-((5-isopropyl-2-oxopyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized in the same manner as in step B of intermediate 40, using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-isopropyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-isopropyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-isopropyl-2-oxopyrrolidine-1-carboxylate (step A). ​​The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0689] Intermediate 53: (1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0690] [ka]

[0691] Step A: A solution of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The 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-1-carboxylate (Step A of intermediate 40, 210 mg, 0.33 mmol) in THF (3 mL) was cooled to -78°C. Next, a 1 M LiHMDS solution (0.7 mL, 0.7 mmol) in THF was added dropwise, and the resulting solution was stirred at -78°C for 45 minutes. A solution of iodomethane (22.8 μL, 0.366 mmol) in THF (0.5 mL) was added dropwise, and the resulting mixture was stirred at -78°C for 30 minutes. Next, a solution of iodomethane (35 μL, 0.4316 mmol) in THF (0.4 mL) was added dropwise. The mixture was warmed to room temperature over 5 minutes, and then an additional iodomethane (62 μL, 0.99 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes, and then quenched with an aqueous NH3Cl solution. The mixture was extracted with siRNA (three times), and then the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The title compound used was obtained by purification using silica gel chromatography (0-100% alkylammonium sulfate / hexane) without further purification.

[0692] Process B: (1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized using tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) in the same manner as in step B of intermediate 40. The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0693] Intermediate 54: (1S)-(4,4-difluorocyclohexyl)(7-((6-oxo-2-oxa-5-azaspiro[3,4]octan-7-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0694] [ka]

[0695] Step A: tert-butyl 7-((2-(S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-6-oxo-2-oxa-5-azaspiro[3.4]octane-5-carboxylate. The title compound was synthesized in the same manner as in Step A, using tert-butyl 6-oxo-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (intermediate 35) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-100% acetone / hexane (containing 0.1% TEA)) to obtain the title compound in 53% yield.

[0696] Process B: (1S)-(4,4-difluorocyclohexyl)(7-((6-oxo-2-oxa-5-azaspiro[3,4]octan-7-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized using tert-butyl7-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-6-oxo-2-oxaspiro[3.4]octane-5-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-6-oxo-2-oxaspiro[3.4]octane-5-carboxylate (step A) in the same manner as in step B of intermediate 40. The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0697] Intermediate 55: (1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(methoxymethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0698] [ka]

[0699] Step A: tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(methoxymethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The title compound was synthesized using MOMCl instead of iodomethane, in the same manner as in Step A of intermediate 53. Purification by silica gel chromatography (0-100% ELISA / hexane) yielded the title compound used without further purification.

[0700] Process B: (1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(methoxymethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized in the same manner as in step B of intermediate 40, using 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-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(methoxymethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A). ​​The reaction mixture was concentrated until dry and used as the TFA salt without further purification.

[0701] Intermediate 56: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)pyrrolidine-2-one.

[0702] [ka]

[0703] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as in Step A, but using tert-butyl 2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (intermediate 38) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound (yield 30%).

[0704] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)pyrrolidine-2-one. The title compound was synthesized using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) instead of tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) in the same manner as in step B of intermediate 40. The reaction mixture was partitioned between a saturated aqueous Na2CO3 solution and 20% IPA / DCM. The aqueous layer was further extracted with 20% IPA / DCM (3 times). The combined organic layers were then dried over anhydrous Na2SO4, filtered, concentrated until dry, and used without further purification.

[0705] Intermediate 57: (1S)-(4,4-difluorocyclohexyl)(7-(hydroxy(2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0706] [ka]

[0707] Step A: tert-butyl3-((2-(S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The title compound was synthesized (yield 31%) using the same method as in step A of intermediate 40, but with tert-butyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (intermediate 29) instead of tert-butyl(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate instead of tert-butyl(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate.

[0708] Step B: (1S)-(4,4-difluorocyclohexyl)(7-(hydroxy(2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. To a solution of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (100 mg, 0.15 mmol, Step A) in DCM (0.5 mL), TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 1 hour, and then concentrated to dryness. The residue was used without further purification.

[0709] Intermediate 58: (1S)-(4,4-difluorocyclohexyl)(7-((5-oxo-4-azaspiro[2,4]heptan-6-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate

[0710] [ka]

[0711] Step A: tert-butyl 6-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate. The title compound was synthesized in the same manner as in Step A of intermediate 40, using tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (intermediate 31) instead of tert-butyl(S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The residue was used without further purification.

[0712] Process B: (1S)-(4,4-difluorocyclohexyl)(7-((5-oxo-4-azaspiro[2,4]heptan-6-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized using tert-butyl 6-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (step A) instead of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (step A) in the same manner as in step B of intermediate 57. The residue was purified by acidic reverse-phase preparative HPLC (C18 column, 5 μm, 30 × 250 mm, 0-100% ACN (containing 0.05% TFA) in H2O (containing 0.05% TFA)) to obtain the title compound in 2 steps with a yield of 13%.

[0713] Intermediate 59: (3R * ,5R * )-3-((R * )-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-5-(trifluoromethyl)pyrrolidine-2-one

[0714] [ka] In the same manner as in step B of intermediate 40, replace 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-1-carboxylate with tert-butyl(3R * ,5R * )-3-((R* The title compound was synthesized using )-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (intermediate 41) and used without further purification.

[0715] Intermediate 60: tert-butyl(5S)-3-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate

[0716] [ka] A solution of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(hydroxy)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A of intermediate 57, 500 mg, 0.77 mmol) in DCM (7.7 mL) was cooled to 0°C, and then DMP (491 mg, 1.2 mmol) was added little by little. The solution was stirred at room temperature for 15 minutes, and then quenched by adding saturated NaS2O3 aqueous solution. The layers were separated, and the organic layers were sequentially washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% siRNA (containing 10% MeOH) / hexane) to obtain the title compound (yield 74%).

[0717] Intermediate 61: (3R,5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)carbonyl)-3-methyl-5-(trifluoromethyl)pyrrolidine-2-one

[0718] [ka]

[0719] Step A: tert-butyl(3R,5S)-3-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. tert-butyl(5S)-3-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (334 mg, 0.52 mmol, intermediate 60) and K2CO3 (170 mg, 1.2 mmol) were dissolved in DMF (2 mL), and the mixture was stirred at room temperature for 5 minutes. Next, MeI (0.32 mL, 5.2 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over anhydrous sodium 2SO4. The organic layers were filtered, concentrated until dry, and purified by silica gel chromatography (0-100% ethyl acetate / hexane) to obtain a 3:1 mixture of the title compound and its diastereomer (tert-butyl(3S,5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate). The title compound was obtained in 53% yield, and its absolute stereochemistry was determined by 2D NMR.

[0720] Step B: (3R,5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)carbonyl)-3-methyl-5-(trifluoromethyl)pyrrolidine-2-one. To a DCM solution (1.6 mL) of tert-butyl(3R,5S)-3-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-carbonyl)-3-methyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (65 mg, 0.1 mmol, Step A), TFA (0.4 mL, 5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was purified by silica gel chromatography (0-10% MeOH (containing 2M NH3) / DCM) to obtain the title compound in 63% yield.

[0721] Intermediate 62: (1S)-(7-(((5S)-3-(cyanomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methaneaminium 2,2,2-trifluoroacetate

[0722] [ka]

[0723] Step A: tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(cyanomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. The title compound was synthesized in the same manner as in Step A of intermediate 53, using bromoacetonitrile instead of iodomethane. The residue was purified by silica gel chromatography (0-100% ethyl acetate / hexane) to obtain the title compound (yield 56%).

[0724] Process B: (1S)-(7-(((5S)-3-(cyanomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methaneaminium 2,2,2-trifluoroacetate. The title compound was synthesized using tert-butyl(5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(cyanomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) instead of tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(cyanomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) in the same manner as in step B of intermediate 57. The residue was purified by silica gel chromatography (0-30% MeOH / DCM) to obtain the title compound (yield 79%).

[0725] Intermediate 63: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one.

[0726] [ka]

[0727] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid. The title compound was synthesized in the same manner as intermediate 40, but using tert-butyl 2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (intermediate 29) instead of tert-butyl(S)2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (intermediate 30), and used without further purification.

[0728] Process B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one. The title compound was synthesized using tert-butyl3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (step A) instead 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-1-carboxylate (step A) in the same manner as step B of intermediate 40, and was used without further purification.

[0729] Example 1: 4-Cyclopropyl-N-((S)-(7-(((R * )-5,5-difluoro-2-oxopiperidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide

[0730] [ka]

[0731] Example 2: 4-Cyclopropyl-N-((S)-(7-(((S * )-5,5-difluoro-2-oxopiperidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide

[0732] [ka]

[0733] Step A: tert-butyl 3-((2-((S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluoro-2-oxopiperidine-1-carboxylate. A solution of 1,1-dimethylethyl 5,5-difluoro-2-oxo-1-piperidinecarboxylic acid (467 mg, 1.99 mmol) in THF (16.4 mL) was cooled to -78°C, and then LiHMDS (2.13 mL, 2.13 mmol, 1 M in THF) was added. The resulting mixture was stirred at -78°C for 1 hour. Next, tert-butyl S-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (754 mg, 1.64 mmol, intermediate 1) was dissolved in THF (3.3 mL), and the resulting solution was added dropwise to the reaction mixture over 10 minutes. The resulting mixture was stirred at -78°C for 20 minutes, and then warmed to room temperature over 1 hour. The mixture was extracted with ethyl acetate (3 times), the organic layers were combined, washed with brine, dehydrated with anhydrous sodium 2SO4, filtered, concentrated, and dried. The residue was purified by silica gel chromatography (0-50% ethyl acetate / hexane) to obtain the title compound (yield 20%).

[0734] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluoropiperidine-2-one. To a mixture of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluoro-2-oxopiperidine-1-carboxylate (230 mg, 0.37 mmol, Step A) in DCM (4.8 mL), TFA (0.72 mL, 9.4 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to remove the TFA, then filtered through silica gel and a K2CO3 plug, and concentrated to dryness to obtain the title compound (100% yield).

[0735] Process C: 4-Cyclopropyl-N-((S-(7-(((R * )-5,5-difluoro-2-oxopiperidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-((S-(7-(((S *)-5,5-difluoro-2-oxopiperidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide. To a solution of 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-difluoropiperidine-2-one (154 mg, 0.37 mmol, step B) in ACN (3 mL), DIPEA (0.26 mL, 1.5 mmol) was added, and the resulting solution was stirred at room temperature under N2 for 5 minutes. Next, a solution of 2,5-dioxopyrrolidine-1-yl-4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate (143 mg, 0.57 mmol, intermediate 2) in ACN (1 mL) was added to the reaction mixture. The resulting mixture was stirred under N2 at room temperature for 2 hours. The reaction product was concentrated to dryness, dissolved in DCM, and purified by silica gel chromatography (0-100% acetone / hexane (containing 0.1% TEA)) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Chiralpak IB N, 5 μm, 250 × 21 mm, 30% methanol, 70% CO2). The first isomer to elute (yield 19%) was (R * ) The isomer (Example 1) is designated as (S * )Isomer (Example 2) was specified. Example 1: 1H NMR(500MHz,DMSO-d6)δ 9.47(d,J=9.0Hz,1H),8.44(d,J=2.0Hz,1H),8.19(s,1H),7.91(d,J=1.5Hz,1H),7.89-7.86(m, 1H),5.18(t,J=8.5Hz,1H),3.58-3.44(m,2H),3.24-3.06(m,1H),2.97-2.88(m,1H),2.82(dd,J =8.0,14.0Hz,1H),2.32-2.23(m,2H),2.21-2.13(m,2H),2.13-1.95(m,3H),1.92-1.87(m,1H), 1.84-1.71(m,2H),1.66-1.59(m,1H),1.44-1.24(m,2H),1.18-1.06(m,2H),1.01-0.91(m,2H). MS(ESI)m / z:[M+H] + Measured value: 550.3. Example 2: 1 H NMR(400MHz,DMSO-d6)δ 9.47(d,J=9.0Hz,1H),8.44(d,J=2.0Hz,1H),8.19(s,1H),7.91(s,1H),7.90-7.86(m,1H),5.19(t,J=8.5Hz,1H),3.58-3.47(m, 2H),3.19-3.13(m,1H),2.99-2.89(m,1H),2.87-2.79(m,1H),2.31-2.23(m,2H),2.21-1.96(m,4H),1.95-1.71(m,3H),1.63(br d,J=13.6Hz,1H),1.45-1.23(m,2H),1.18-1.08(m,2H),1.02-0.93(m,2H). MS(ESI)m / z:[M+H] + Actual measured value: 550.3.

[0736] Example 3: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S * ,4R * )-2-oxo-4-(trifluoromethyl)-3-piperidyl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0737] [ka]

[0738] Example 4: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * ,4S * )-2-oxo-4-(trifluoromethyl)-3-piperidyl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0739] [ka]

[0740] Step A: tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)piperidine-1-carboxylic acid. The title compound was prepared by using tert-butyl 2-oxo-4-(trifluoromethyl)piperidine-1-carboxylic acid (intermediate 6) instead of 1,1-dimethylethyl 5,5-difluoro-2-oxo-1-piperidinecarboxylic acid, as described for the synthesis of Step A in Examples 1 and 2, and by cooling the reaction to -45°C instead of -78°C. The residue was purified by silica gel chromatography (0-100% (10% MeOH-containing ELISA) / hexane) to obtain the title compound (yield 55%).

[0741] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)piperidine-2-one. To a mixture of tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-4-(trifluoromethyl)piperidine-1-carboxylate (390 mg, 0.600 mmol, Step A) in DCM (2 mL), TFA (2.0 mL, 26 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and then dissolved in DCM, and 0.5 M NaOH aqueous solution was slowly added. The mixture was separated, and the aqueous layer was further extracted with DCM. 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 (0-10% MeOH (containing 2M NH3) / DCM) to obtain the title compound (yield 94%).

[0742] Step C: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S * ,4R * )-2-oxo-4-(trifluoromethyl)-3-piperidyl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * ,4S *)-2-oxo-4-(trifluoromethyl)-3-piperidyl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide. A solution of 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (108 mg, 0.7 mmol) and T3P (0.41 mL, 0.69 mmol, 50% in ethyl acetate) in ethyl acetate (2.5 mL) was mixed with DIPEA (0.19 mL, 1.1 mmol), and the resulting mixture was stirred at room temperature for 2 minutes. Next, a solution of 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)piperidine-2-one (154 mg, 0.350 mmol, step B) in DCM (2.5 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 18 hours. A solution of 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (85 mg, 0.55 mmol), T3P (0.33 mL, 0.55 mmol, 50% in ethyl acetate), and DIPEA (0.19 mL, 1.1 mmol) in ethyl acetate (0.8 mL) was stirred at room temperature for 10 minutes, then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 4 hours. The reaction products were then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (once). 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% siRNA (containing 10% MeOH) / hexane) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Whelk O1 SS, 5 μm, 250 × 21 mm, 25% methanol, 75% CO2). The first isomer to elute (32% yield) was (3S * ,4R * ) The isomer (Example 3) is designated as (3R), and the second isomer to elute (yield 29%) is designated as (3R * ,4S * )Isomer (Example 4) was specified. Example 3: 1H NMR(500MHz,DMSO-d6)δ 9.48(d,J=9.1Hz,1H),8.38(d,J=2.0Hz,1H),8.20(s,1H),7.92(br s,1H),7.85(d,J=1.6Hz,1H),5.19(t,J=8.6Hz,1H),3.25-3.03(m,4H),2.80-2.70(m,2H),2.27(tt,J=5.0,8.4Hz,1H),2.21-2.14(m,1H) ),2.09-1.97(m,3H),1.93-1.87(m,1H),1.87-1.71(m,3H),1.66-1.59(m,1H),1.44-1.23(m,2H),1.16-1.06(m,2H),1.01-0.91(m,2H). MS(ESI)m / z:[M+H] + Measured value: 582.2. Example 4: 1 H NMR(500MHz,DMSO-d6)δ 9.47(d,J=9.1Hz,1H),8.39-8.37(m,1H),8.21-8.19(m,1H),7.93-7.91(m,1H),7.87-7.85(m, 1H),5.19(t,J=8.5Hz,1H),3.24-3.19(m,1H),3.17-3.11(m,2H),3.09-3.03(m,1H),2.81-2.70 (m,2H),2.28(tt,J=5.0,8.4Hz,1H),2.22-2.13(m,1H),2.09-1.97(m,3H),1.92-1.87(m,1H), 1.86-1.71(m,3H),1.66-1.60(m,1H),1.44-1.23(m,2H),1.17-1.06(m,2H),1.01-0.93(m,2H). MS(ESI)m / z:[M+H] + Actual measured value: 582.2.

[0743] Example 5: 4-Methoxy-N-[(1S)-5,5,5-trifluoro-4,4-dimethyl-1-[7-[[(3R * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazine-2-yl]pentyl]-1,2,5-oxadiazole-3-carboxamide

[0744] [ka]

[0745] Example 6: 4-Methoxy-N-[(1S)-5,5,5-trifluoro-4,4-dimethyl-1-[7-[[(3S * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazine-2-yl]pentyl]-1,2,5-oxadiazole-3-carboxamide

[0746] [ka] A solution of (5S)-3-((2-((S)-1-amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one (138 mg, 0.31 mmol, intermediate 18), 4-methoxy-1,2,5-oxadiazole-3-carboxylic acid (66 mg, 0.46 mmol), and DIPEA (0.26 mL, 1.53 mmol) in DCM (3.1 mL) was stirred at room temperature for 10 minutes, then T3P (0.36 mL, 0.61 mmol, 50% in ethyl) was added, and the resulting mixture was stirred at room temperature for 60 minutes. The reaction mixture was concentrated to dryness and purified by preparative basic HPLC (X-Bridge Prep C18 5μm column, 50×250mm, 5-100% acetonitrile / water (containing 20mM NH4OH)) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Chiralpak IF, 5μm, 250×21mm, 20% ACN / methanol 1 / 1, 80% CO2). The first isomer to elute (yield 2%) was (R * )Isomer (Example 5) is designated, and the sixth isomer to elute is (S * The isomer (Example 2) was designated. The second isomer that eluted was re-purified by silica gel chromatography (0-100% acetone / hexane) to obtain Example 6 in a yield of 6%. Example 5: 1H NMR(500MHz,DMSO-d6)δ 9.39-9.35(m,1H),8.71-8.68(m,1H),8.48-8.45(m,1H),8.13-8.11(m,1H),7.97-7.9 5(m,1H),5.20-5.15(m,1H),4.25-4.20(m,1H),4.11-4.09(m,3H),3.12-3.06(m,1H), 2.95-2.87(m,1H),2.76-2.69(m,1H),2.19-2.13(m,1H),2.12-2.04(m,2H),1.99-1.9 0(m,1H),1.68-1.60(m,1H),1.55-1.48(m,1H),1.29-1.24(m,1H),1.10-1.08(m,6H). MS(ESI)m / z:[M+H] + Measured value: 578.2. Example 6: 1 H NMR(500MHz,DMSO-d6)δ 9.36(d,J=8.6Hz,1H),8.65(s,1H),8.45(d,J=2.0Hz,1H),8.12(s,1H),7.96-7.94(m,1 H),5.18(dt,J=5.3,8.6Hz,1H),4.36-4.18(m,1H),4.10(s,3H),3.10(dd,J=4.9,14.3H z,1H),2.99-2.83(m,1H),2.75(dd,J=9.2,14.3Hz,1H),2.46-2.39(m,1H),2.16-2.04( m, 1H), 1.95 (td, J=8.6, 12.8Hz, 1H), 1.71-1.59 (m, 2H), 1.55-1.48 (m, 1H), 1.08 (s, 6H). MS(ESI)m / z:[M+H] + Actual measured value: 578.2.

[0747] Example 7: N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazine-2-yl]methyl]-4-methoxy-1,2,5-oxadiazole-3-carboxamide

[0748] [ka]

[0749] Example 8: N-((S)-(4,4-difluorocyclohexyl)(7-(((3S * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-methoxy-1,2,5-oxadiazole-3-carboxamide

[0750] [ka] 4-methoxy-1,2,5-oxadiazole-3-carboxylic acid (63 mg, 0.44 mmol) and T3P (0.30 mL, 0.51 mmol, 50% in ethyl acetate) in ethyl acetate (0.77 mL) were mixed with DIPEA (0.12 mL, 0.70 mmol), and the resulting mixture was stirred at room temperature for 10 minutes. Next, a solution of (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one (100 mg, 0.230 mmol, intermediate 40) in DCM (2.3 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction product was concentrated to dryness, dissolved in DMF, and purified by preparative basic HPLC to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Chiralpak IB N3, 5 μm, 250 × 21 mm, 30% methanol / isopropanol 1 / 1, 70% CO2). The first isomer to elute (yield 21%) was (R * ) The isomer (Example 7) is designated as (S * )Isomer (Example 2) was specified. Example 7: 1H NMR(500MHz,DMSO-d6)δ 9.28(d,J=9.1Hz,1H),8.65(s,1H),8.45(d,J=2.0Hz,1H),8.16(s,1H),7.95-7.93(m,1H),5.15(s,1H),4.29-4.22(m,1H) ),4.08(s,3H),3.10(dd,J=4.9,14.4Hz,1H),2.94-2.86(m,1H),2.73(dd,J=9.4,14.4Hz,1H),2.49-2.37(m,1H),2.15(br d,J=8.4Hz,1H),2.11-1.94(m,2H),1.88-1.79(m,2H),1.78-1.71(m,1H),1 .71-1.64(m,1H),1.63-1.56(m,1H),1.41-1.33(m,1H),1.31-1.23(m,1H). MS(ESI)m / z:[M+H] + Measured value: 558.0. Example 8: 1 H NMR(500MHz,DMSO-d6)δ 9.32-9.28(m,1H),8.70-8.68(m,1H),8.47-8.45(m,1H),8.17-8.16(m,1H),7.96-7.9 4(m,1H),5.18-5.13(m,1H),4.25-4.20(m,1H),4.10-4.09(m,3H),3.11-3.06(m,1H), 2.94-2.87(m,1H),2.75-2.69(m,1H),2.21-2.10(m,3H),2.07-1.97(m,2H),1.89-1.8 0(m,2H),1.80-1.72(m,1H),1.65-1.59(m,1H),1.43-1.34(m,1H),1.31-1.24(m,1H). MS(ESI)m / z:[M+H] + Actual measured value: 558.2.

[0751] Example 9: N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide

[0752] [ka]

[0753] Example 10: N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * ,5S * )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide

[0754] [ka] In 6.2 mL of ACN, a solution of (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5-(trifluoromethyl)pyrrolidine-2-one (100 mg, 0.230 mmol, intermediate 40) was sequentially mixed with DIPEA (0.20 mL, 1.2 mmol) and 2,5-dioxopyrrolidine-1-yl4-methyl-1,2,5-oxadiazole-3-carboxylate (97 mg, 0.43 mmol). The resulting mixture was stirred at room temperature for 10 minutes and then concentrated to dryness. The residue was purified by basic preparative HPLC (×-Bridge Prep C18 5μm column, 50×250mm, 5-100% acetonitrile / water (containing 20mM NH4OH)) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Chiralpak IB N3, 5μm, 250×21mm, 25% methanol, 75% CO2). The first isomer to elute (yield 16%) was (S * ) The isomer (Example 9) is designated as (R * )Isomer (Example 2) was specified. Example 9: 1H NMR(500MHz,DMSO-d6)δ 9.45-9.39(m,1H),8.65(s,1H),8.45(d,J=2.0Hz,1H),8.20(s,1H),7.96-7.93(m,1 H),5.19-5.15(m,1H),4.31-4.24(m,1H),3.13-3.08(m,1H),2.97-2.89(m,1H),2.7 7-2.71(m,1H),2.48-2.47(m,3H),2.45-2.36(m,1H),2.23-2.15(m,1H),2.11-1.95 (m,2H),1.95-1.88(m,1H),1.86-1.60(m,4H),1.44-1.35(m,1H),1.34-1.23(m,1H). MS(ESI)m / z:[M+H] + Measured value: 542.2. Example 10: 1 H NMR(500MHz,DMSO-d6)δ 9.33(d,J=9.0Hz,1H),8.62(s,1H),8.38(d,J=2.0Hz,1H),8.13(s,1H),7.87(d,J=1.5Hz,1H),5.09(s,1H),4.16(br s,1H),3.04-2.98(m,1H),2.88-2.79(m,1H),2.68-2.61(m,1H),2.41-2.39(m,3H),2.15-1.91(m,5 H),1.86-1.79(m,1H),1.79-1.63(m,2H),1.59-1.51(m,1H),1.37-1.27(m,1H),1.26-1.16(m,1H). MS(ESI)m / z:[M+H] + Actual measured value: 542.2.

[0755] Example 11: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(1R * ,5R * )-7-oxo-6-azabicyclo[3.2.1]octan-1-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0756] [ka]

[0757] Example 12: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(1S * ,5S * )-7-oxo-6-azabicyclo[3.2.1]octan-1-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0758] [ka]

[0759] Step A: 1-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclohexa-3-ene-1-carboxylate methyl. To a mixture of methylcyclohexa-3-ene-1-carboxylate (0.51 mL, 3.6 mmol) in THF (30 mL) at -70°C, LDA (9.41 mL, 9.41 mmol, 1 M in THF) was added dropwise over 10 minutes, and the resulting mixture was stirred at -70°C for 30 minutes. Next, a solution of tert-butyl(S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (1.5 g, 3.26 mmol, intermediate 1) in THF (8 mL) was added to the reaction mixture over 5 minutes. The resulting mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched with a solution of HOAc (0.5 mL) in THF (25 mL), and the mixture was stirred at -70°C for 5 minutes. The cooling bath was then removed, and the reaction mixture was warmed to room temperature. The mixture was partitioned between water (40 mL) and ethyl acetate (50 mL), and the aqueous layer was further extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-30% Â / petroleum ether) to obtain the title compound as a white solid (yield 53%).

[0760] Step B: 1-((2-S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclohexa-3-ene-1-carboxylic acid. A mixture of methyl 1-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclohexa-3-ene-1-carboxylate (1.03 g, 1.99 mmol, Step A) and LiOH·H2O (833 mg, 19.9 mmol) in H2O (10 mL) and MeOH (30 mL) was heated overnight at 35°C. The reaction mixture was concentrated to remove MeOH, diluted with water (10 mL), and extracted with DCM (20 mL). Next, the pH of the aqueous layer was adjusted to pH 3 by adding a 1 N HCl aqueous solution, and then the aqueous layer was extracted with siRNA (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated until dry to obtain the title compound (100% yield) as a yellow oily substance, which was used without further purification.

[0761] Process C: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclohexa-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A mixture of 1-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclohexa-3-en-1-carboxylic acid (1.00 g, 1.98 mmol, step B), EDCI (379 mg, 1.98 mmol), HOBt (267 mg, 1.98 mmol), and DIPEA (0.86 mL, 4.9 mmol) in DCM (30 mL) was stirred at room temperature for 30 minutes, then 4-nitrobenzenesulfonamide (400 mg, 1.98 mmol) was added all at once, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (3 × 100 mL). The organic layers were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to obtain the title compound as a yellow oily substance (yield 47%).

[0762] Step D: 1-((2-((S)-amino4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-N-((4-nitrophenyl)sulfonyl)cyclohexa-3-en-1-carboxamide. A mixture of tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclohexa-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (437 mg, 0.63 mmol, Step C), 1,4-dioxane, 4 M HCl (4 mL, 16 mmol), and 1,4-dioxane (4 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (15 mL), and the pH of the solution was adjusted to pH 8 by adding saturated NaHCO3 aqueous solution. The mixture was extracted with toluene (four times with 15 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (100% yield) as a white oily substance, which was used without further purification.

[0763] Step E: 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclohexa-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. A mixture of 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (195 mg, 1.27 mmol), 1-hydroxypyrrolidine-2,5-dione (146 mg, 1.27 mmol), and EDCI (304 mg, 1.58 mmol) in DCM (10 mL) was stirred at room temperature for 30 minutes. Next, 1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-N-((4-nitrophenyl)sulfonyl)cyclohexa-3-en-1-carboxamide (396 mg, 0.63 mmol, step D) and DIPEA (0.55 mL, 3.2 mmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was subjected directly to silica gel chromatography (0-10% MeOH / DCM) to obtain the title compound as an off-white solid (yield 69%).

[0764] Process F: 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((4-iodo-6-((4-nitrophenyl)sulfonyl)-7-oxo-6-azabicyclo[3.2.1]octan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. A mixture of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclohexa-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (370 mg, 0.51 mmol, step E) and K2CO3 (430 mg, 3.06 mmol) in ACN (5 mL) was cooled to 0°C. Then, I2 (518 mg, 2.04 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to obtain the title compound as an oily substance (yield 65%).

[0765] Process G: 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((6-((4-nitrophenyl)sulfonyl)-7-oxo-6-azabicyclo[3.2.1]octan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((4-iodo-6-((4-nitrophenyl)sulfonyl)-7-oxo-6-azabicyclo[3.2.1]octan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (160 mg, 0.19 mmol, step F), n-Bu3SnH (59 μL, 0.23 mmol), and AIBN 10 mg, 0.056 mmol) were added to a flask, which was then evacuated and packed three times with N2. The resulting mixture was heated at 110°C for 2 hours. The reaction mixture was cooled to room temperature and poured into 1 M KF aqueous solution (5 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with toluene (3 × 15 mL), and the organic layers were combined. The organic extracts were washed with brine (15 mL), dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to obtain the title compound as a yellow oil (yield 37%).

[0766] Process H: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(1R * ,5R * )-7-oxo-6-azabicyclo[3.2.1]octan-1-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(1S * ,5S *)-7-oxo-6-azabicyclo[3.2.1]octan-1-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide. A mixture of benzenethiol (10 mg, 0.09 mmol) and K2CO3 (38 mg, 0.28 mmol) in ACN (0.5 mL) was mixed with a solution of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((6-((4-nitrophenyl)sulfonyl)-7-oxo-6-azabicyclo[3.2.1]octan-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide (50 mg, 0.069 mmol, step G) in ACN (2.5 mL) and added dropwise over 2 minutes. Then, DMSO (0.1 mL) was added, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was stopped by adding 1 N NaOH aqueous solution (10 mL), and the mixture was extracted with ELISA (twice with 150 mL). The organic layers were combined, washed with brine (15 mL), and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% Â / petroleum ether) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Phenomenex-Cellulose-2, 10 μm, 250 × 30 mm, 50% methanol (containing 0.1% NH4OH), 50% CO2). The first isomer to elute (30% yield) was (1R * ,5R * ) The isomer (Example 11) is designated as (1S) and the second isomer to elute (yield 47%) is designated as (1S) * ,5S * ) isomer (Example 12) was specified. Example 11: 1H NMR(400MHz,DMSO-d6)δ 9.49(d,J=9.2Hz,1H),8.35(d,J=2.0Hz,1H),8.19(s,1H),7.84-7.82(m,1H),7.68(s,1H) ,5.21-5.13(m,1H),3.55-3.50(m,1H),2.86-2.79(m,1H),2.75-2.68(m,1H),2.31-2.23( m,1H),2.23-2.14(m,1H),2.10-1.94(m,2H),1.93-1.86(m,2H),1.84-1.68(m,2H),1.67- 1.57(m,2H),1.55-1.44(m,3H),1.42-1.25(m,5H),1.15-1.09(m,2H),0.98-0.93(m,2H). MS(ESI)m / z:[M+H] + Measured value: 540.3. Example 12: 1 H NMR(400MHz,DMSO-d6)δ 9.49(d,J=9.2Hz,1H),8.35(d,J=2.0Hz,1H),8.18(s,1H),7.83(d,J=1.6Hz,1H),7.67(s, 1H),5.17(t,J=8.4Hz,1H),3.52(s,1H),2.86-2.79(m,1H),2.74-2.68(m,1H),2.31-2.23 (m,1H),2.22-2.11(m,1H),2.10-1.94(m,2H),1.92-1.86(m,2H),1.84-1.68(m,2H),1.67 -1.58(m,2H),1.57-1.44(m,3H),1.41-1.22(m,5H),1.17-1.06(m,2H),1.01-0.91(m,2H). MS(ESI)m / z:[M+H] + Actual measured value: 540.3.

[0767] Example 13: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * )-5,5-dimethyl-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0768] [ka]

[0769] Example 14: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S)-5,5-dimethyl-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0770] [ka]

[0771] Step A: tert-butyl 4-((2-(S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate. The title compound was prepared using tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylic acid (intermediate 36) instead of 1,1-dimethylethyl 5,5-difluoro-2-oxo-1-piperidinecarboxylic acid, as described for the synthesis of Step A in Examples 1 and 2. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound in 7% yield.

[0772] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-dimethylpyrrolidine-2-one. To a mixture of tert-butyl 4-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (33 mg, 0.056 mmol, Step A) in DCM (1 mL), TFA (0.2 mL, 2.6 mmol) was added, and the resulting mixture was stirred at room temperature for 40 minutes. The mixture was concentrated and then partitioned between 20% IPA / DCM (10 mL) and saturated Na2CO3 aqueous solution. The aqueous layer was further extracted with 20% IPA / DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated until dry to obtain the title compound used without further purification (100% yield).

[0773] Step C: 4-Cyclopropyl-N-[(S-(4,4-difluorocyclohexyl)-[7-[[(3R * )-5,5-dimethyl-2-oxo-pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-[(S-(4,4-difluorocyclohexyl)-[7-[[(3S *)-5,5-dimethyl-2-oxo-pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide. 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (20 mg, 0.13 mmol) and T3P (0.10 mL, 0.17 mmol, 50% in ethyl acetate) were dissolved in ethyl acetate (0.27 mL), to which DIPEA (28 μL, 0.16 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Next, a solution of 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5-dimethylpyrrolidine-2-one (21 mg, 0.054 mmol, step B) in DCM (0.6 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (0-100% acetone / hexane (containing 0.1% TEA)) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Whelk O1 SS, 5 μm, 250 × 21 mm, 30% methanol, 70% CO2). The first isomer to elute (yield 19%) was (3R * )Isomer (Example 13) is designated, and the 14th isomer to elute (yield 17%) is (3S * )Isomer (Example 2) was specified. Example 13: 1H NMR(500MHz,DMSO-d6)δ 9.48-9.45(m,1H),8.45-8.43(m,1H),8.19-8.17(m,1H),7.93-7.91(m,1H),7.83-7.80(m,1H),5.21-5.1 6(m,1H),3.12-3.07(m,1H),2.99-2.90(m,1H),2.66-2.60(m,2H),2.31-2.24(m,1H),2.23-2.14(m,1H), 2.10-2.01(m,1H),2.01-1.95(m,1H),1.93-1.88(m,1H),1.84-1.74(m,1H),1.66-1.59(m,1H),1.56-1.4 9(m,1H),1.44-1.34(m,1H),1.33-1.21(m,2H),1.17-1.14(m,3H),1.14-1.10(m,5H),0.98-0.94(m,2H). MS(ESI)m / z:[M+H] + The measured value is 528.3. Example 14: 1 H NMR(500MHz,DMSO-d6)δ 9.47-9.44(m,1H),8.44-8.43(m,1H),8.18-8.16(m,1H),7.92-7.90(m,1H),7.82-7.80(m,1H),5.20-5.1 5(m,1H),3.28-3.28(m,1H),3.11-3.06(m,1H),2.96-2.89(m,1H),2.64-2.62(m,1H),2.30-2.24(m,1H), 2.20-2.14(m,1H),2.08-1.95(m,2H),1.93-1.86(m,2H),1.85-1.71(m,2H),1.66-1.58(m,1H),1.56-1.4 9(m,1H),1.42-1.34(m,1H),1.34-1.21(m,2H),1.16-1.13(m,3H),1.12-1.11(m,3H),0.97-0.94(m,2H). MS(ESI)m / z:[M+H] + The measured value is 528.3.

[0774] Example 15: 4-シクロプロピル-N-[(S)-(4,4-ジフルオロシクロヘキシル)-[7-[[(3R *)-4,4-dimethyl-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0775] [ka]

[0776] Example 16: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S)-4,4-dimethyl-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0777] [ka]

[0778] Step A: tert-butyl 3-((2-(S)-(tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4,4-dimethyl-2-oxopyrrolidine-1-carboxylate. The title compound was prepared using tert-butyl 4,4-dimethyl-2-oxopyrrolidine-1-carboxylic acid (intermediate 37) instead of 1,1-dimethylethyl 5,5-difluoro-2-oxo-1-piperidinecarboxylic acid, as described for the synthesis of Step A in Examples 1 and 2. The residue was purified by silica gel chromatography (0-100% ELISA / hexane) to obtain the title compound in 23% yield.

[0779] Step B: 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4,4-dimethylpyrrolidine-2-one. The title compound (99% yield) was prepared using tert-butyl 3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4,4-dimethyl-2-oxopyrrolidine-1-carboxylate (step A) instead of tert-butyl 4-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4,4-dimethyl-5-oxopyrrolidine-1-carboxylate, as described for the synthesis of step B in Example 13 and Example 14.

[0780] Step C: 4-Cyclopropyl-N-[(S-(4,4-difluorocyclohexyl)-[7-[[(3R * )-4,4-dimethyl-2-oxo-pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-[(S-(4,4-difluorocyclohexyl)-[7-[[(3S *)-4,4-dimethyl-2-oxo-pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide. 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (47 mg, 0.31 mmol) and T3P (0.24 mL, 0.41 mmol, 50% in ethylethanol) were dissolved in ethylethanol (1 mL), to which DIPEA (110 μL, 0.61 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Next, a solution of 3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4,4-dimethylpyrrolidine-2-one (80 mg, 0.2 mmol, step B) in DCM (2 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 2.5 hours. A solution of 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (25 mg, 0.16 mmol), T3P (0.1 mL, 0.17 mmol, 50% in ethyl acetate), and DIPEA (50 μL, 0.28 mmol) was sonicated at room temperature for 5 minutes, then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated until dry and purified by silica gel chromatography (0-100% acetone / hexane (containing 0.1% TEA)) to obtain a mixture of diastereomers. The diastereomers were separated by chiral SFC (Whelk O1 SS, 5 μm, 250 × 30 mm, 35% methanol, 65% CO2). The first isomer to elute (yield 9%) was (3R * )The isomer (Example 15) is designated as (3S) and the 16th isomer to elute (yield 9%) is designated as (3S) * )Isomer (Example 2) was specified. Example 15: 1H NMR(500MHz,DMSO-d6)δ 9.50(d,J=9.0Hz,1H),8.60(d,J=1.8Hz,1H),8.24(s,1H),8.03(s,1H),7.65(s,1H),5.20(t,J=8.5Hz,2H), 2.97(d,J=9.5Hz,1H),2.91-2.84(m,2H),2.76-2.70(m,1H),2.59-2.54(m,1H),2.31-2.26(m,1H),2.19(br s,1H),2.09-1.96(m,2H),1.94-1.88(m,1H),1.86-1.72(m,2H),1.68-1.61(m,1 H),1.44-1.24(m,2H),1.15-1.10(m,2H),1.02-0.99(m,6H),0.98-0.95(m,2H). MS(ESI)m / z:[M+H] + Measured value: 528.3. Example 16: 1 H NMR(500MHz,DMSO-d6)δ 9.49-9.44(m,1H),8.54-8.52(m,1H),8.18-8.17(m,1H),7.98-7.96(m,1H),7.65-7.63(m,1H),5.20 -5.16(m,1H),2.98-2.94(m,1H),2.90-2.84(m,2H),2.72-2.66(m,1H),2.57-2.53(m,1H),2.30-2.2 4(m,1H),2.22-2.13(m,1H),2.09-1.93(m,2H),1.92-1.86(m,1H),1.85-1.71(m,2H),1.66-1.60(m, 1H),1.44-1.22(m,2H),1.14-1.09(m,2H),1.00-0.99(m,3H),0.98-0.97(m,3H),0.96-0.94(m,2H). MS(ESI)m / z:[M+H] + Actual measured value: 528.3.

[0781] Example 17: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)-(7-(((1R * ,4R * )-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide

[0782] [ka]

[0783] Example 18: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)-(7-(((1S, * 4S * )-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide **

[0784] [ka]

[0785] Step A: Methyl(S)-1-((2-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-ene-1-carboxylate. The title compound (yield 55%) was prepared using methylcyclopenta-3-ene-1-carboxylate instead of methylcyclohexa-3-ene-1-carboxylate, as described for the synthesis of Step A in Examples 11 and 12.

[0786] Process B: (S)-1-((2-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-en-1-carboxylic acid. The title compound (92% yield) was prepared using methyl(S)-1-((2-(((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-en-1-carboxylate (step A) instead of methyl 1-((2-(((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-en-1-carboxylate, as described for the synthesis of step B in Example 11 and Example 12.

[0787] Process C: tert-butyl(S)-((4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclopenta-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound (yield 73%) was prepared using (S)-1-((2-(((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-en-1-carboxylic acid (step B) instead of 1-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)cyclopenta-3-en-1-carboxylic acid (step B) as described for the synthesis of step C in Example 11 and Example 12.

[0788] Process D: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((6-iodo-2-((4-nitrophenyl)sulfonyl)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was prepared using tert-butyl(S)-((4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclopenta-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (step C) instead of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclopenta-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (step C) instead of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclopenta-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (step C) as described for the synthesis in step F of Example 11 and Example 12. The reaction mixture was stirred overnight instead of at room temperature for 2 hours, and further purified by silica gel chromatography (0-80% RINKAN / petroleum ether) to obtain the title compound as a yellow oily substance (55% yield).

[0789] Process E: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((6-iodo-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. The title compound was prepared using tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((6-iodo-2-((4-nitrophenyl)sulfonyl)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (step D) instead of 4-cyclopropyl-N--1,2,5-oxadiazole-3-carboxamide. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) followed by preparative TLC (5% MeOH / DCM) to obtain the title compound as a yellow oily substance (yield 31%).

[0790] Process F: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A flask containing a mixture of tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((6-iodo-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (30 mg, 0.049 mmol, step E), wet Pd / C (50 mg, 10% Pd, 50% water), and TEA (0.034 mL, 0.24 mmol) in 5 mL of MeOH) was purged and refilled three times with H2. The resulting mixture was stirred at room temperature under H2 (15 psi) for 5 minutes and then filtered. The filtrate cake was washed with MeOH (20 mL), and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (0-0.8% MeOH / DCM) to obtain the title compound as a pale yellow solid.

[0791] Process G: 4-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one hydrochloride. The title compound was prepared using tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-((3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (step F) instead of 4-cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-((1-(((4-nitrophenyl)sulfonyl)carbamoyl)cyclohexa-3-en-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. The reaction mixture was concentrated to obtain the title compound as a yellow oil (yield 84%).

[0792] Process H: 4-Cyclopropyl-N-((S)-4,4-Difluorocyclohexyl)(7-(((1R * ,4R * )-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-((S)-4,4-difluorocyclohexyl)(7-(((1S * ,4S * )-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. The title compound was prepared using 4-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one hydrochloride (step G) instead of 1-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-N-((4-nitrophenyl)sulfonyl)cyclohexa-3-en-1-carboxamide, as described for the synthesis in step E of Example 11 and Example 12. The residue was purified by preparative TLC (5% MeOH / DCM). Next, the diastereomers were separated by chiral SFC (DAICEL CHIRALCEL OD-H, 5 μm, 250 × 30 mm, 25% ethanol (containing 0.1% NH4OH), 75% CO2). The first isomer to elute (yield 30%) was (1R * ,4R * ) The isomer (Example 17) is designated as (1S), and the second isomer to elute (yield 25%) is designated as (1S * ,4S * )Isomer (Example 18) was specified. Example 17: 11H NMR (400MHz, CDCl3)δ 8.61-8.52(m,1H),8.39-8.27(m,1H),7.99-7.87(m,2H),5.69-5.55(m,1H), 5.33-5.23(m,1H),3.93-3.83(m,1H),3.41-3.30(m,1H),3.04-2.92(m,1H), 2.59-2.48(m,1H),2.24-2.20(m,1H),2.00-1.94(m,2H),1.79-1.71(m,4H), 1.67-1.60(m,3H),1.56-1.46(m,2H),1.42-1.30(m,3H),1.18-1.06(m,4H). MS(ESI)m / z:[M+H] + Measured value: 526.3. Example 18: 1 H NMR(400MHz,CDCl3)δ 8.56-8.43(m,1H),8.18-7.97(m,1H),7.92-7.79(m,2H),5.62-5.49(m,1H),5.32 -5.22(m,1H),3.93-3.82(m,1H),3.42-3.28(m,1H),3.03-2.89(m,1H),2.61-2.4 7(m,1H),2.34-2.25(m,1H),2.10-2.04(m,2H),2.00-1.91(m,2H),1.68-1.61(m, 4H), 1.55-1.52(m, 1H), 1.49-1.42(m, 2H), 1.41-1.30(m, 3H), 1.20-1.08(m, 4H). MS(ESI)m / z:[M+H] + Actual measured value: 526.3.

[0793] Example 19: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-((R * )-1-((3R * ,5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide

[0794] [ka]

[0795] Example 20: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-((R * )-1-((3S * ,5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide

[0796] [ka]

[0797] Step A: tert-butyl((S)-(4,4-difluorocyclohexyl)(7-((E)-((S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A suspension of NaH (76.5 mg, 1.91 mmol, 60% in mineral oil) in THF (4 mL) was mixed with a solution of diethyl((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)phosphonic acid (848 mg, 1.91 mmol, intermediate 15) in THF (4 mL), and the resulting mixture was cooled to -78°C. Next, a mixture of tert-butyl S-(4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl) carbamate (580 mg, 1.47 mmol) in THF (4 mL) was added dropwise to the phosphonate mixture. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0°C and quenched with water. The two-phase mixture was extracted with ethyl acetate (three times), the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (0-100% ethyl acetate / hexane) to obtain the title compound in 78% yield as a mixture of olefin isomers (75:25 E:Z).

[0798] Step B: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-((5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. In an oven-dried Schlenk tube, copper(I) bromide-dimethyl sulfide complex (6.95 mg, 0.034 mmol) and (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene (25.97 mg, 0.041 mmol) were dissolved in dichloromethane (0.25 mL) and stirred at room temperature under a nitrogen atmosphere for 20 minutes. Next, a solution of tert-butyl((S)-(4,4-difluorocyclohexyl)(7-((E)-((S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-ylidene)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (231 mg, 0.34 mmol, Step A) in dichloromethane (1.25 mL) was added all at once. After stirring at room temperature for 5 minutes, the reaction mixture was cooled to -78 °C, and then boron trifluoride diethyl etherate (84 μL, 0.68 mmol) was added. After stirring at -78 °C for 20 minutes, ethyl magnesium bromide solution (0.23 mL, 3.0 M in diethyl ether, 0.68 mmol) was added dropwise over 5 minutes. After stirring at -78°C for 2 hours, the reaction mixture was quenched with MeOH, followed by the addition of saturated NH4Cl aqueous solution, and the mixture was warmed to room temperature. The reaction mixture was extracted with dichloromethane (3 × 10 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated until dry. The resulting residue was purified by silica gel chromatography (0-100% siRNA / hexane) to obtain the title compound in 81% yield as a mixture of diastereomers (55:45 dr).

[0799] Step C: tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate. A solution of samarium(II) iodide (13.7 mL, 0.1 M in THF, 1.37 mmol) was added to a solution of tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-(5S)-2-oxo-1-tosyl-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (196 mg, 0.28 mmol, Step B) in a solution of dry THF (2 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours, then 5 mL of 1 M aqueous HCl was added, and the mixture was extracted three times (10 mL each time) with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% alkyl / hexane, then 0-40% MeOH / alkyl) to obtain the title compound as a mixture of diastereomers (55:45 dr) in 58% yield.

[0800] Step D: (5S)-3-(1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)propyl)-5-(trifluoromethyl)pyrrolidine-2-one. A solution of tert-butyl((1S)-(4,4-difluorocyclohexyl)(7-(1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (90 mg, 0.16 mmol, Step C) in 1.6 mL of dichloromethane) was cooled to 0°C, and trifluoroacetic acid (0.7 mL, 0.22 M) was added dropwise. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated, and the solvent was removed by azeotropic distillation with toluene (2 × 5 mL). To the obtained residue, HCl (2 mL) and saturated NaHCO3 aqueous solution (2 mL) were added. The pH of the resulting mixture was adjusted to pH=10 by adding 3 M NaOH aqueous solution. The layers were separated, and the aqueous layer was further extracted with HCl (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The obtained residue was dried under high vacuum to obtain the title compound as a mixture of diastereomers (55:45 dr) in 91% yield.

[0801] Step E: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-((R * )-1-((3R * ,5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide and 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-((R * )-1-((3S *,5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5-oxadiazole-3-carboxamide. To a solution of 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (26 mg, 0.16 mmol) in 1 mL of ethylacetate, N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) and 1-propanephosphonic anhydride (0.13 mL, 0.22 mmol, 50 wt. in ethylacetate) were added. The reaction mixture was stirred at room temperature for 20 minutes. Next, a solution of (5S)-3-(1-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)propyl)-5-(trifluoromethyl)pyrrolidine-2-one (50 mg, 0.11 mmol, step D) in dichloromethane (0.3 mL) was added dropwise at room temperature, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (5 mL), and the organic layer was extracted with HCl (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0-100% HCl / hexane, then 0-20% MeOH / HCl) to obtain the title compound as a mixture of diastereomers (55:45 dr) in 64% yield. Diastereomers were separated by chiral SFC (stationary phase: Chiralpak IE, 5 μm, 250 × 30 mm, mobile phase: 30% methanol, 70% CO2). The first isomer to elute (yield 13%) was (R * ) The isomer (Example 19) is designated as (S * )Isomer (Example 2) was specified. Example 19: 1H NMR(500MHz,MeOH-d4)δ 8.41(d,J=2.1Hz,1H),8.11(s,1H),7.84(d,J=2.0Hz,1H),5.27(d,J=8.6Hz,1H),4.21-4.10(m,1H),3. 23(dt,J=9.5,5.6Hz,1H),3.08(td,J=9.7,5.4Hz,1H),2.52-2.42(m,1H),2.40-2.35(m,1H),2.29-2.1 9(m,1H),2.13-1.94(m,4H),1.94-1.85(m,2H),1.81-1.70(m,2H),1.65(dd,J=13.1,3.5Hz,1H),1.52( td,J=12.6,3.9Hz,1H),1.54-1.37(m,1H),1.17-1.09(m,2H),1.05-0.98(m,2H),0.93(t,J=7.3Hz,3H). MS(ESI)m / z:[M+H] + Measured value: 596.2. Example 20: 1 H NMR(500MHz,MeOH-d4)δ 8.41(d,J=2.1Hz,1H),8.10(s,1H),7.81(d,J=2.0Hz,1H),5.26(d,J=8.6Hz,1H), 4.15-4.08(m,1H),3.02-2.96(m,2H),2.44-2.31(m,3H),2.29-2.18(m,1H),2.19- 2.07(m,1H),2.05-1.99(m,2H),1.98-1.91(m,1H),1.89(s,1H),1.87-1.60(m,3H ),1.20-1.09(m,2H),1.54-1.38(m,2H),1.06-0.97(m,2H),0.84(t,J=7.3Hz,3H). MS(ESI)m / z:[M+H] + Actual measured value: 596.2.

[0802] Example 21: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3R * )-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazine-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide

[0803] [ka]

[0804] Example 22: 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(3S * )-2-oxopyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazine-2-yl]methyl]-1,2,5-oxadiazole-3-carboxamide ...

Claims

1. Formula I: 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, R １ａ and R １ｂ are each independently H, -C （１～３） alkyl, -C （３～５） cycloalkyl, -C （１～３） alkyl -O-C （１～３） alkyl, or -C （１～３） alkyl -N(C （１～３） alkyl) ２ wherein the -C （１～３） alkyl is unsubstituted or substituted with 1 to 6 R １ａａ groups, or R １ａ and R １ｂ together with the carbon atom to which they are attached form spiro C （３～５） cycloalkyl, or 【Chemistry 2】 A spiroheterocylyl is formed by selecting from R, where ・ is R １ａ and R １ｂ This indicates the carbon atom to which R is bonded, or １ａ and R １ｃ But together C （１～２） Forming alkylenyl crosslinks, R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （３～５） Cycloalkyl, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｄ However, each instance is independent of -OH, halo, and -C. （１～３） Alkyl, -C （３～５） Cycloalkyl, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N-(C （１～３） Alkyl) ２ And in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ａａ However, each appearance is independent and is a halo. R ２ However, H, -OH, -C （１～３） Alkyl, -C （３～５） Cycloalkyl, -C （１～３） Alkyl-O-C （１～３） Alkyl, -C （１～３） Alkyl-O-C （３～５） A cycloalkyl or a 4-6 membered heterocycline, wherein the -C in the formula （１～３） Alkyl, the above-C （３～５） Cycloalkyl, the above-C （１～３） Alkyl-O-C （１～３） Alkyl, and the aforementioned -C （１～３） Alkyl-O-C （３～５） The cycloalkyl group is either unsubstituted or has 1 to 6 R groups. ２ａａ Substituted with or R ２ａ and R １ｃ However, together with the carbon atoms to which they are bonded, C （３～５） Forming a cycloalkyl or 4-6 membered heterocycline, R ２ａａ However, each instance is independently a halo, -OH, or -CN. R ２ｂ However, H or -C （１～３） Alkyl, or R ２ａ and R ２ｂ However, together with the carbon atoms to which they are bonded, they form C=O. R ３ However, -C （１～１０） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （３～５） Cycloalkyl, -C （１～６） Alkyl-O-C （３～５） Cycloalkyl-C （１～３） It is an alkyl group, each of which is either unsubstituted or substituted with 1 to 6 halo atoms. R ４ However, it is either unsubstituted or has 1-2 R ４ａ It is a five-membered heteroaryl substituted with a group, R ４ａ is halo, -C （１～６） alkyl, -O-C （１～６） alkyl, -C （１～６） alkyl-O-C （１～６） alkyl, or -C （０～２） alkyl-C （３～６） cycloalkyl, wherein the -C （１～６） alkyl, the -O-C （１～６） alkyl, the -C （１～６） alkyl-O-C （１～６） alkyl, and the -C （０～２） alkyl-C （３～６） cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halo, -CH ３ , -CH ２ F, -CHF ２ , and -CF ３ ; n is 1, 2, or 3, and A compound or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

2. The compound has formula Ig-1: 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the formula.

3. R １ａ and R １ｂ are each independently H, -C （１～３） alkyl, or -C （３～５） cycloalkyl, wherein the -C （１～３） alkyl is unsubstituted or substituted with 1 to 6 R １ａａ groups, or R １ａ and R １ｂ together with the carbon atom to which they are attached form spiro C （３～５） cycloalkyl, or 【Chemistry 4】 A spiroheterocylyl is formed by selecting from R, where ・ is R １ａ and R １ｂ This indicates the carbon atom to which R is bonded, or １ａ and R １ｃ But together C （１～２） Forming alkylenyl crosslinks, R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｄ Each instance is independently represented by Halo, -C. （１～３） Alkyl, or -C （３～５） It is a cycloalkyl, in which -C （１～３） Alkyl groups are either unsubstituted or have 1 to 6 R groups. １ａａ It is substituted with the base, R １ａａ However, each instance is independently fluorine, R ２ａ However, H, -OH, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. ２ａａ Substituted with or R ２ａ and R １ｃ However, together with the carbon atoms to which they are bonded, C （３～５） Forming a cycloalkyl or 4-6 membered heterocycle, R ２ａａ However, each instance is independently fluorine, -OH, or -CN. R ２ｂ However, H or -C （１～３） Alkyl, or R ２ａ and R ２ｂ However, together with the carbon atoms to which they are bonded, they form C=O. R ３ However, -C （１～１０） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （３～５） Cycloalkyl, -C （１～６） Alkyl-O-C （３～５） Cycloalkyl-C （１～３） Alkyl, or -C （３～６） It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R ４ However, it is either unsubstituted or has 1-2 R ４ａ It is a five-membered heteroaryl substituted with a group, R ４ａ But, hello, -C （１～６） Alkyl, -O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （０～２） Alkyl-C （３～６） It is a cycloalkyl, in which -C （１～６） Alkyl, the -O-C （１～６） Alkyl, the above-C （１～６） Alkyl-O-C （１～６） Alkyl, and the aforementioned -C （０～２） Alkyl-C （３～６） The cycloalkyl group is either unsubstituted or contains fluorine, -CH ３ ien-CH ２ F, -CHF ２ , and -CF ３ It is substituted with 1 to 6 substituents independently selected from the above, n is 1, 2, or 3, and The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

4. R １ａ However, H, -C （１～３） Alkyl, or -C （３～５） It is a cycloalkyl, in which -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ Substituted with or R １ａ and R １ｃ But together C （１～２） Forming alkylenyl crosslinks, R １ｂ However, H, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ Substituted with or R １ａ and R １ｂ However, together with the carbon atoms to which they are bonded, spiro C （３～５） Cycloalkyl, or 【Transformation 5】 A spiroheterocylyl is formed by selecting from R, where ・ is R １ａ and R １ｂ This indicates the carbon atom to which it is bonded. R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｄ However, each appearance is independent of either a halo or -C. （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ａａ However, each instance is independently fluorine, R ２ａ However, H, -OH, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. ２ａａ Substituted with or R ２ａ and R １ｃ However, together with the carbon atoms to which they are bonded, C （３～５） Forming a cycloalkyl or 4-6 membered heterocycle, R ２ａａ However, each instance is independently either fluorine or -OH. R ２ｂ However, H or -C （１～３） Alkyl, or R ２ａ and R ２ｂ However, together with the carbon atoms to which they are bonded, they form C=O. R ３ However, -C （１～１０） Alkyl or -C （３～６） It is a cycloalkyl group, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R ４ However, it is either unsubstituted or has 1-2 R ４ａ It is a five-membered heteroaryl substituted with a group, R ４ａ However, -C （１～６） Alkyl, -O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （０～２） Alkyl-C （３～６） It is a cycloalkyl, n is 1, 2, or 3, and A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

5. R １ａ However, H, -C （１～３） Alkyl, or -C （３～５） It is a cycloalkyl, in which -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｂ However, H, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｄ However, each appearance is independent of either a halo or -C. （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ａａ However, each instance is independently fluorine, R ２ａ However, H, -OH, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. ２ａａ It is substituted with the base, R ２ａａ However, each instance is independently fluorine, R ２ｂ However, H or -C （１～３） Alkyl, or R ２ａ and R ２ｂ However, together with the carbon atoms to which they are bonded, they form C=O. R ３ However, -C （４～１０） They are alkyl or cyclohexyl, each of which is either unsubstituted or substituted with 1 to 6 fluorine atoms. R ４ However, it is either unsubstituted or has 1-2 R ４ａ It is a five-membered heteroaryl substituted with a group, R ４ａ However, -C （１～６） Alkyl, -O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （３～６） It is a cycloalkyl, n is 1, 2, or 3, and A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

6. R １ａ However, H, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｂ However, H, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And, R １ｄ However, each appearance is independent of either a halo or -C. （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 6 R groups. １ａａ It is substituted with the base, R １ａａ However, each instance is independently fluorine, R ２ａ However, H, -OH, or -C （１～３） It is alkyl, R ２ｂ However, H or -C （１～３） It is alkyl, R ３ However, -C （４～１０） They are alkyl or cyclohexyl, each substituted with 1 to 6 fluorine atoms. R ４ However, it is either unsubstituted or has 1-2 R ４ａ It is a five-membered heteroaryl substituted with a group, R ４ａ However, -C （１～６） Alkyl, -O-C （１～６） Alkyl, -C （１～６） Alkyl-O-C （１～６） Alkyl, or -C （３～６） It is a cycloalkyl, n is 1 or 2, and A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

7. R １ａ However, -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 3 R groups. １ａａ It is substituted with the base, R １ｂ However, H, or -C （１～３） It is alkyl, and in the formula, -C （１～３） The alkyl group is either unsubstituted or has 1 to 3 R groups. １ａａ It is substituted with the base, R １ｃ However, H, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ And, R １ａａ However, each instance is independently fluorine, R ２ａ However, it is H or -OH, R ２ｂ However, it is H, R ３ However, -C substituted with 1 to 3 fluorine atoms （４～８） Alkyl, or 【Transformation 6】 And, R ４ but, 【Transformation 7】 And, R ４ａ However, -C （１～６） Alkyl, -O-C （１～６） Alkyl, or -C （３～６） It is a cycloalkyl, n is 1, and A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein m is 0.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 1.

9. Formulas Ib-1 to Ib-7: 【Transformation 8】 A compound according to claim 8 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.

10. Formulas Ib-1a to Ib-7a: 【Chemistry 9】 A compound according to claim 8 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.

11. Formula Ib-8: 【Chemistry 10】 A compound according to claim 8 or a pharmaceutically acceptable salt thereof having the formula.

12. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 2.

13. Formulas Ic-1 to Ic-7: 【Chemistry 11】 A compound according to claim 12 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.

14. Formulas Ic-1a to Ic-7a: 【Chemistry 12】 A compound according to claim 12 or a pharmaceutically acceptable salt thereof having a formula selected from the group consisting of the following.

15. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 3.

16. Formulas Id-1 to Id-2: 【Chemistry 13】 A compound according to claim 15 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of the following.

17. Formulas Id-1a to Id-2a: 【Chemistry 14】 A compound according to claim 15 or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of the following.

18. R １ａ However, H, -C （１～３） Alkyl, or -C （３～５） It is a cycloalkyl, and the -C （１～３） The alkyl group is either unsubstituted or substituted with 1 to 6 fluorine atoms, and R １ｂ However, H or -C （１～３） It is alkyl, and in the formula, -C （１～３） The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein the alkyl group is unsubstituted or substituted with 1 to 6 fluorine atoms.

19. R １ａ However, H, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ , or cyclopropyl, and R １ｂ However, H, -CH ３ , or -CF ３ The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. R １ａ However, H or -C （１～３） Alkyl, and the aforementioned -C （１～３） The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein the alkyl group is unsubstituted or substituted with one to three fluorine atoms.

21. R １ａ However, H, -CH ３ , or -CF ３ The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

22. R １ｂ However, H or -CH ３ The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

23. R １ｃ However, halo, -OH, -C （１～３） Alkyl, -C （１～３） Alkyl-CN, -C （１～３） Alkyl-O-C （１～３） Alkyl, or -C （１～３） Alkyl-N(C) （１～３） Alkyl) ２ The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

24. R １ｃ However, H, -C （１～３） Alkyl-CN, or -C （１～３） Alkyl-O-C （１～３） A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is alkyl.

25. R １ｃ However, H, fluorine, -OH, -CH ３ ien-CH ２ CN, -CH ２ OCH ３ , or -CH ２ N(CH ３ ) ２ The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

26. R １ｄ However, each appearance is independent of either a halo or -C. （１～３） It is alkyl, and in the formula, -C （１～３） The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein the alkyl group is unsubstituted or substituted with one to three fluorine atoms.

27. R １ｄ However, each appearance is independent of F, -CH ３ , or -CF ３ The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

28. Formula Ie-1: 【Chemistry 15】 The formula is as follows: In the formula, R １ but, 【Chemistry 16】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

29. R １ but, 【Chemistry 17】 A compound according to claim 28 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

30. R １ but, [Chemistry 18] A compound according to claim 8 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

31. Formula Ie-2: 【Chemistry 19】 The formula is as follows: In the formula, R １ but, 【Chemistry 20】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

32. R1 is 【Chemistry 21】 A compound according to claim 31 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

33. R1 is 【Chemistry 22】 A compound according to claim 31 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

34. R ２ａ However, H, -OH, or -C （１～３） It is alkyl, and R ２ｂ However, H or -C （１～３） Alkyl, or R ２ａ and R ２ｂ However, the compounds according to any one of claims 1 to 5 and 8 to 33, or pharmaceutically acceptable salts thereof, wherein they combine with the carbon atoms to which they are bonded to form C=O.

35. R ２ａ H and R ２ｂ H is, R ２ａ is -OH and R ２ｂ H is, R ２ａ ga-CH ３ And R ２ｂ H is, R ２ａ ga-CH ２ CH ３ And R ２ｂ H is, R ２ａ is -OH and R ２ｂ ga-CH ３ is, or R ２ａ and R ２ｂ However, the compounds according to any one of claims 1 to 5 and 8 to 33, or pharmaceutically acceptable salts thereof, wherein they combine with the carbon atoms to which they are bonded to form C=O.

36. R ２ａ However, it is H or -OH, and R ２ｂ A compound according to any one of claims 1 to 6 and 8 to 33, or a pharmaceutically acceptable salt thereof, wherein H is present.

37. R ３ However, -C （１～１０） Alkyl or -C （３～６） A compound according to any one of claims 1 to 3 and 8 to 36, or a pharmaceutically acceptable salt thereof, wherein each cycloalkyl group is either unsubstituted or substituted with one to six fluorine atoms.

38. R ３ However, -C （４～８） A compound according to any one of claims 1 to 6 or 8 to 36, or a pharmaceutically acceptable salt thereof, wherein each alkyl or cyclohexyl compound is substituted with 1 to 6 fluorine atoms.

39. R ３ but, 【Chemistry 23】 The compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

40. R ３ but, 【Chemistry 24】 The compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

41. R ３ but, 【Chemistry 25】 The compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

42. R ４ However, it is a five-membered heteroaryl compound containing one to three heteroatoms selected from O and N, and the heteroaryl compound is either unsubstituted or contains one to two R atoms. ４ａ A compound according to any one of claims 1 to 6 or 8 to 41, or a pharmaceutically acceptable salt thereof, which is substituted with a group.

43. R ４ However, it is a five-membered heteroaryl compound containing one to three heteroatoms selected from O and N, and the heteroaryl compound contains one R ４ａ A compound according to any one of claims 1 to 6 or 8 to 41, or a pharmaceutically acceptable salt thereof, which is substituted with a group.

44. R ４ However, one R ４ａ A compound according to any one of claims 1 to 6 or 8 to 41, or a pharmaceutically acceptable salt thereof, which is pyrazolyl or oxadiazolyl substituted with a group.

45. R ４ but, 【Chemistry 26】 The compound according to any one of claims 1 to 6 or 8 to 41, or a pharmaceutically acceptable salt thereof.

46. R ４ａ However, -C （１～６） Alkyl, -O-C （１～６） Alkyl, or -C （３～６） A compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

47. R ４ａ However, -CH ３ , -CH(CH ３ ) ２ , -OCH ３ The compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, which is cyclopropyl.

48. R ４ but, 【Chemistry 27】 A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

49. R ４ but, 【Chemistry 28】 The compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof.

50. Formula Ik: 【Chemistry 29】 A compound according to any one of claims 1 to 7 having the formula, or a pharmaceutically acceptable salt thereof.

51. Equation Ij-2: 【Transformation 30】 A compound according to any one of claims 1 to 7 having the formula, or a pharmaceutically acceptable salt thereof.

52. Formula Im: 【Chemistry 31】 A compound according to any one of claims 1 to 7 having the formula, or a pharmaceutically acceptable salt thereof.

53. Equation Im-2: 【Chemistry 32】 A compound according to any one of claims 1 to 7 having the formula, or a pharmaceutically acceptable salt thereof.

54. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds in Table 1. 【Request Item 55】 【Chemistry 33】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

56. The following formula: 【Transformation 34】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

57. The following formula: 【Chemistry 35】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

58. The following formula: 【Transformation 36】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

59. The following formula: 【Chemistry 37】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

60. The following formula: 【Transformation 38】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

61. The following formula: 【Chemistry 39】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

62. The following formula: 【Chemistry 40】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

63. The following formula: 【Chemistry 41】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

64. The following formula: 【Chemistry 42】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

65. The following formula: 【Chemistry 43】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

66. The following formula: 【Chemistry 44】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

67. The following formula: 【Chemistry 45】 A compound according to claim 55 or a pharmaceutically acceptable salt thereof having the above.

68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

69. A pharmaceutical composition prepared by combining a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

70. A pharmaceutical composition according to claim 68 or 69, or a pharmaceutically acceptable salt thereof, administered orally.

71. A pharmaceutical composition according to claim 70, or a pharmaceutically acceptable salt thereof, administered as a tablet or capsule.

72. A process for preparing a pharmaceutical composition, comprising combining a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

73. A method for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment and / or improvement.

74. The method according to claim 73, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A 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 disease, multiple myeloma, and systemic lupus erythematosus.

75. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriasis.

76. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriatic arthritis.

77. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is rheumatoid arthritis.

78. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is ankylosing spondylitis.

79. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is hidradenitis suppurativa.

80. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is bullous pemphigoid.

81. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is atopic dermatitis.

82. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is vitiligo.

83. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

84. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is systemic lupus erythematosus.

85. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is asthma.

86. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is uveitis.

87. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is chronic obstructive pulmonary disease.

88. The method according to claim 74, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple myeloma.

89. The method according to any one of claims 73 to 88, wherein the compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt thereof is administered orally.

90. The method according to any one of claims 73 to 89, wherein the compound according to any one of claims 1 to 58 or a pharmaceutically acceptable salt thereof is administered as a tablet or capsule.

91. Compounds as described herein.

92. The methods described herein.

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