Imidazopyridazine il-17 inhibitor compounds

Abstract

Disclosed herein are compounds having the following formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 and m are defined in the specification, as well as methods of making the compounds disclosed herein and methods of using the compounds disclosed herein to treat or ameliorate IL-17 mediated syndromes, conditions, and / or diseases.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 570,318, filed March 27, 2024, the entire disclosure of which, except for any definitions, disclaimers, denials and inconsistencies, is incorporated herein by reference. Background Technology

[0003] Interleukin-17 (“IL-17”), also known as IL-17A and CTLA-8, is primarily produced by CD4+ Th17 cells and also by other immune cells such as CD8+ T cells, γδ T cells, NK cells, NKT cells, and innate lymphocytes (ILCs). IL-17A exists as a homodimer (A / A) or as a heterodimer (A / F) alongside IL-17F and signals by binding to the dimer receptor complexes IL-17RA and IL-17RC. IL-17RA is universally expressed at particularly high levels in hematopoietic cell types, while IL-17RC is preferentially expressed in 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 nascent gene transcription by triggering the NF-κB, C / EBP, and MAPK pathways via the ACT1–TRAF6–TRAF4 complex. It also stabilizes target mRNA transcripts 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 and activate lymphocytes to sites of injury or inflammation and maintain a pro-inflammatory state.

[0004] Preclinical and clinical data have demonstrated the significant pathological role of IL-17A in a variety of autoimmune and inflammatory diseases. Animal and human studies have shown that IL-17A plays a crucial role in the pathogenesis of the various diseases and / or conditions discussed in this article. The significance of targeting IL-17A has been demonstrated by the conversion efficacy of injectable IL-17A neutralizing antibodies in patients.

[0005] Despite progress in injectable IL-17A antagonist antibodies, there has long been a need to develop oral small-molecule IL-17A inhibitors, as they could broaden treatment options for many patients who do not have access to biologics. Furthermore, safe and effective small-molecule IL-17A inhibitors could offer patients significant benefits over injectable IL-17A neutralizing antibodies, such as convenient dosing regimens and cost savings, which in turn could provide effective long-term disease management.

[0006] However, the development of oral small molecule therapies remains challenging, and no oral small molecule IL-17A inhibitors have entered late-stage clinical trials. Therefore, there is a need for novel small molecule IL-17A modulators (e.g., inhibitors). This disclosure aims to overcome this need and other problems encountered in the art. Summary of the Invention

[0007] This application discloses a compound of formula (I):

[0008]

[0009] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 4 And m are as defined in this article.

[0010] This application also discloses a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] This application also discloses a method for treating and / or improving IL-17A-mediated inflammatory syndromes, conditions, or diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the IL-17A-mediated inflammatory syndrome, condition, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus. Detailed Implementation

[0012] definition

[0013] Discussions of documents, laws, materials, devices, articles, or the like included in this specification are for background purposes only. Such discussions are not an admission that any or all of these matters constitute part of the prior art with respect to any disclosed or claimed compound or method.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Otherwise, certain terms used herein have the meanings set forth in this specification.

[0015] It should be noted that, unless the context clearly indicates otherwise, the singular forms “a” and “the” as used herein and in the appended claims include plural references.

[0016] To assist the reader of this application, the specification has been divided into paragraphs or sections, or relating to various embodiments of this application. These divisions should not be construed as separating the main content of a paragraph or section or embodiment from the main content of another paragraph or section or embodiment. Rather, those skilled in the art will understand that this specification has broad application and covers all conceivable combinations of sections, paragraphs, and sentences. The discussion of any embodiment is intended to be exemplary only and is not intended to indicate that the scope of this disclosure (including the claims) is limited to these examples.

[0017] For the purposes of this disclosure, the term "application" means a method of therapeutically or prophylactically preventing, treating, or improving a syndrome, symptom, or disease as described herein by using a compound of this disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. Such methods include, but are not limited to, administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof at different times during a treatment process, or administering it concurrently or sequentially as a combination therapy.

[0018] The term "subject" refers to a patient, which may be an animal, preferably a mammal, and most preferably a human, who will be treated or has been treated by the method according to the embodiments of this application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) (such as monkeys or apes), humans, etc., more preferably including humans.

[0019] The term “therapeutic effective amount” or “effective amount” means the amount of an active compound or agent that elicits a biological or medical response in an tissue system, animal or human that is sought by a researcher, veterinarian, physician or other clinician, including but not limited to the prevention, treatment or improvement of symptoms of a syndrome, condition or disease being treated.

[0020] The term "pharmaceutically acceptable" means approved or permitted by a federal or state regulatory agency or by an appropriate agency in a country outside the United States, or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, especially humans.

[0021] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of the compound disclosed herein that is non-toxic, biologically tolerable, or in other words, biologically suitable for administration to a subject. Generally, see G.S. Paulekuhn et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665–72; S.M. Berge et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, edited by Stahl and Wermuth, 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 undue toxicity, irritation, or allergic reactions. The compounds disclosed herein may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, thereby being able to react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0022] 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 a group of immune cells in response to stimulation of that group of immune cells. An exemplary amino acid sequence of human IL-17 is represented in GenBank accession number NP_002181.1, and it can be encoded by nucleic acid sequences such as those in GenBank accession number NM_002190.3.

[0023] As used herein, the term "modifier" refers to any reagent or molecule capable of binding to IL-17, including small molecule compounds.

[0024] As used herein, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, and any product obtained directly or indirectly by combining a specified amount of the specified ingredient.

[0025] As used herein, in one embodiment, the term "treatment" for any disease, symptom, syndrome, or condition means improving the disease, symptom, syndrome, or condition (i.e., slowing or halting or mitigating the development of at least one of the disease or its clinical symptoms). In another embodiment, "treatment" means alleviating or improving at least one physiological or biochemical parameter associated with or causing the disease, symptom, syndrome, or condition, including parameters that the patient may not be able to discern. In yet another embodiment, "treatment" means regulating the disease, symptom, syndrome, or condition physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing bodily parameters), or both.

[0026] As used herein, the term "prevention" means that if it has not yet occurred, the condition or disease has not progressed, or if it has already occurred, the condition or disease has not progressed further. The ability to prevent some or all of the symptoms associated with the condition or disease is also considered. In one implementation, "prevention" means preventing or delaying the onset, development, or progression of a disease, symptom, syndrome, or illness.

[0027] As used in this article, the term "QD" means once a day.

[0028] As used in this article, the term "BID" means twice a day.

[0029] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., (C1-C2)). 12 Alkyl groups are alkyl groups or have 1 to 6 carbon atoms (i.e., (C1-C6)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (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 (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), hepyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10CH3) and dodecyl (-(CH2)) 11 CH3). Any alkyl group may be unsubstituted or substituted.

[0030] Term "C" (a-b) "(where a and b are integers, referring to the specified number of carbon atoms) refers to alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl, or the alkyl portion of a group, where alkyl appears as a prefix and contains a to b (inclusive) carbon atoms. For example, C (1-4) This indicates a group containing 1, 2, 3, or 4 carbon atoms.

[0031] The term "alkylene" refers to a compound derived from an alkylene group having 1 to 12 carbon atoms (i.e., C1-C1). 12 Alkyl groups are straight-chain or branched saturated divalent hydrocarbon moieties of alkanes 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, alkylene refers to C1-C6 alkylene. (1-4) Alkylene. In another embodiment, alkylene refers to C... (1-2) Alkylene.

[0032] The term "cycloalkyl" refers to a compound having 3 to 8 carbon atoms (i.e., C360, C460, C560, C6 ... (3-8) cycloalkyl groups, such as, but not limited to, 3 to 6 carbon atoms (i.e., C64 ... (3-6) A cycloalkyl group is a saturated or partially unsaturated all-carbon cyclic system, wherein the cycloalkyl cyclic system has a single or multiple rings in the form of a spirocyclic or bicyclic ring. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified in this specification, the cycloalkyl group may be unsubstituted or substituted. Some cycloalkyl groups may exist as spirocycloalkyl groups, wherein the two cycloalkyl rings are fused by a single carbon atom; for example, but not limited to, an example of spiropentyl is... Examples of spirohexyl include, but are not limited to, those of spirohexyl. , and Examples of cycloheptyl groups include, but are not limited to, those of cycloheptyl groups. , , and Examples of cyclooctyl include, but are not limited to, those of cyclooctyl. , , , , and Unless otherwise specified in this specification, the spirocyclic alkyl group may be unsubstituted or substituted. Bicyclic cycloalkyl systems also include... or .

[0033] The term "heterocyclic group" refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members and containing a carbon atom and at least one atom other than carbon, wherein the atom is selected from the group consisting of N, O, and S. The terms "heterocyclic group" and "heterocyclic alkyl group" include, but are not limited to, cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Exemplary heterocycles include, but are not limited to, oxobutyryl, aziridinyl, aziroxybutyryl, pyrrolyl, pyrrolidone, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise specified, the heterocyclic group is attached to its side group at any heteroatom or carbon atom that produces a stable structure. In one embodiment, a heterocyclic group refers to a 3- to 10-membered heterocyclic group. In another embodiment, a heterocyclic group refers to a 3- to 8-membered heterocyclic group. In yet another embodiment, a heterocyclic group refers to a 3- to 6-membered heterocyclic group.

[0034] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than a carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes, but is not limited to, a single aromatic ring 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, pyridazinyl, pyrimidinyl, and pyrazolyl. azole group, diazole group, iso Azolyl, triazolyl, imidazole, tetrazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, or furanyl.

[0035] The term "halogen" or "halogenated" refers to bromo (-Br), chlorine (-Cl), fluorine (-F), or iodine (-I).

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

[0037] A “diastereomer” is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0038] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "non-racemic" mixture of enantiomers is a mixture of enantiomers in a non-1:1 ratio.

[0039] If the method used to prepare compounds according to this disclosure produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. These compounds can be prepared in racemic form, as racemic mixtures, or as individual enantiomers by enantiomer-specific synthesis or by resolution. For example, these compounds can be resolved into their component enantiomers by standard techniques, such as forming diastereomeric pairs with optically active acids (such as (-)-ditolyl-D-tartaric acid and / or (+)-ditolyl-L-tartaric acid), followed by fractional crystallization and regeneration of the free base. The compound can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliaries. Alternatively, these compounds can be resolved using a chiral column via HPLC or SFC. In some cases, rotational isomers of the compound may be present, which can be separated by... 1 H NMR observation, thus leading to 1 Complex multiplets and peak integrals in H NMR spectra.

[0040] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. The chiral center of the absolute configuration is known to be marked with prefixes R and S by the standard ordering rule procedure, and, where necessary, by the appropriate positional priority (Pure & Appl. Chem. 45, 1976, 11–30).

[0041] In any method used to prepare the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups in the relevant molecule. This can be achieved with conventional protecting groups, such as in “Protective Groups in Organic Chemistry,” edited by J.F.W. McOmie, Plenum Press, 1973; and in T.W. Greene and P.G. W. M. Uts, “Protective Groups in Organic Synthesis,” John Wiley & Sons, 1991. Protecting groups can be removed at convenient subsequent stages using methods known in the art.

[0042] Furthermore, within the scope of this disclosure, any element, particularly when mentioned in connection with a compound of this disclosure or its pharmaceutically acceptable salt, is intended to include all or a mixture of isotopes (naturally occurring or synthetically produced) of the element in its natural abundance or in its isotopically enriched form. For example, a mention of hydrogen within its scope includes... 1 H, 2 H (i.e., deuterium or D) and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (deuterium) isotopes. For example, it represents -C. (1-6) Alkyl groups include not only -CH3, but also -CD3; not only -CH2CH3, but also -CD2CD3, and so on. Similarly, references to carbon and oxygen within their scope include, respectively, […]. 12 C 13 C and 14 C, and 15 O and 16 O and 17 O and 18 O. Isotopes may be radioactive or non-radioactive. The radiolabeled compounds disclosed herein may include, but are not limited to, those selected from, [list of compounds]. 3 H, 11 C 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br、 76 Br、 77 Br and 82 Radioactive isotopes of the Br group. In some embodiments, the radioactive isotopes are selected from... 3 H, 11 C and 18 Group F.

[0043] compound

[0044] This application discloses a compound having the formula (I), (I-1), or (I-2):

[0045] , or ,

[0046] Or its pharmaceutically acceptable salt.

[0047] in:

[0048] Each R 1 Independently for those not replaced or by one to six R1a -C substituent (1-3) alkyl;

[0049] Each R 1a Independently halogenated;

[0050] R 2 for or ;

[0051] R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-8) cycloalkyl;

[0052] R 4 It is either not replaced or replaced by one or two Rs. 4a Five-membered heteroaryl groups substituted with functional groups;

[0053] Each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms;

[0054] R 5 H, -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 5a Group substitution;

[0055] Each R 5a Independently halogenated;

[0056] R 6 H or -C (1-3) alkyl;

[0057] R 7 H or -C (1-3) alkyl;

[0058] R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5)Cycloalkyl groups are unsubstituted or have one to six R groups. 8a Group substitution;

[0059] Each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl;

[0060] Each m is independently 0, 1, or 2; and

[0061] Each n is independently 0 or 1.

[0062] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I).

[0063]

[0064] Or its pharmaceutically acceptable salt.

[0065] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-1).

[0066]

[0067] Or its pharmaceutically acceptable salt.

[0068] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-2).

[0069]

[0070] Or its pharmaceutically acceptable salt.

[0071] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently for those not replaced or by one to three Rs 1a -C substituent (1) Alkyl group. In some embodiments, each R 1 Independently for the unreplaced -C (1) Alkyl group. In some embodiments, each R 1 Independently for one to six R 1a -C substituent (1) Alkyl group. In some embodiments, each R 1 Independently for a R 1a -C substituent (1)Alkyl group. In some embodiments, each R 1 Independently for two R 1a -C substituent (1) Alkyl group. In some embodiments, each R 1 Independently for the three R 1a -C substituent (1) alkyl.

[0072] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently for one to three R 1a -C substituent (1) Alkyl groups, and each R 1a Independently, it is halogenated. In some embodiments, the halogenation is brominated (-Br), chlorinated (-Cl), fluorinated (-F), or iodinated (-I). In some embodiments, the halogenation is brominated (-Br). In some embodiments, the halogenation is chlorinated (-Cl). In some embodiments, the halogenation is fluorinated (-F). In some embodiments, the halogenation is iodinated (-I).

[0073] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0074] R 2 for or .

[0075] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0076] R 2 for .

[0077] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0078] R 2 for And n is 0.

[0079] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0080] R 2 for And n is 1.

[0081] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0082] R2 for And R 5 H, -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 5a Group substitution;

[0083] Each R 5a It is an independent halogen.

[0084] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0085] R 2 for And R 5 For H.

[0086] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0087] R 2 for And R 5 For those not replaced or replaced by one to six R 5a -C substituent (1-3) alkyl.

[0088] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0089] R 2 for And R 5 For those not replaced or replaced by one to three Rs 5a -C substituent (1) alkyl.

[0090] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0091] R 2 for And R 5 For those not replaced or replaced by one to five Rs 5a -C substituent (2) alkyl.

[0092] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0093] R 2 for And R5 For those not replaced or replaced by one to six R 5a -C substituent (3) alkyl.

[0094] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0095] R 2 for And R 5 For those not replaced or replaced by one to six R 5a -C substituent (3-5) Cycloalkyl.

[0096] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0097] R 2 for And R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (3) Cycloalkyl.

[0098] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0099] R 2 for And R 5 For those not replaced or replaced by one to six R 5a -C substituent (4) Cycloalkyl.

[0100] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0101] R 2 for And R 5 For those not replaced or replaced by one to six R 5a -C substituent (5) Cycloalkyl.

[0102] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Not replaced. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 By an R 5a Group substitution. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 By two R5a Group substitution. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 By three Rs 5a Group substitution. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 by four R 5a Group substitution. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 by five R 5a Group substitution. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 By six R 5a Group substitution.

[0103] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 5a Independently, it is halogenated. In some embodiments, the halogenation is brominated (-Br), chlorinated (-Cl), fluorinated (-F), or iodinated (-I). In some embodiments, the halogenation is brominated (-Br). In some embodiments, the halogenation is chlorinated (-Cl). In some embodiments, the halogenation is fluorinated (-F). In some embodiments, the halogenation is iodinated (-I).

[0104] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0105] R 2 for And R 6 H or -C (1-3) alkyl.

[0106] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0107] R 2 for And R 6 For H.

[0108] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0109] R 2 for And R 6 -C (1-3) alkyl.

[0110] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0111] R 2 for And R 6 -C (1) alkyl.

[0112] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0113] R 2 for And R 6 -C (2) alkyl.

[0114] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0115] R 2 for And R 6 -C (3) alkyl.

[0116] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0117] R 2 yes .

[0118] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0119] R 2 for And n is 0.

[0120] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0121] R 2 for And n is 1.

[0122] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0123] R 2 for And R 7 H or -C (1-3) alkyl.

[0124] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0125] R 2 for And R 7 For H.

[0126] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0127] R 2 for And R 7 -C (1-3) alkyl.

[0128] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0129] R 2 for And R 7 -C (1) alkyl.

[0130] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0131] R 2 for And R 7 -C (2) alkyl.

[0132] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0133] R 2 for And R 7 -C (3) alkyl.

[0134] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0135] R 2 for And R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 8a Group substitution;

[0136] Each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0137] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0138] R 2 for And R 8 It is NH2.

[0139] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0140] R 2 for And R 8 -C (1-3) alkyl.

[0141] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0142] R 2 for And R 8 -C (1) alkyl.

[0143] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0144] R 2 for And R 8 -C (2) alkyl.

[0145] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0146] R 2 for And R 8 -C (3) alkyl.

[0147] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0148] R 2 for And R 8 -C (3-5) Cycloalkyl.

[0149] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0150] R 2 for And R 8 -C (3) Cycloalkyl.

[0151] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0152] R 2 for and -C (4) Cycloalkyl.

[0153] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0154] R 2 for And R 8 -C (5) Cycloalkyl.

[0155] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0156] R 2 for And R 8 -OC (1-3) alkyl.

[0157] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0158] R 2 for And R 8 -OC (1) alkyl.

[0159] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0160] R 2 for And R 8 -OC (2) alkyl.

[0161] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0162] R 2 for And R 8 -OC (3) alkyl.

[0163] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0164] R 2 for And R 8 -OC (3-5) Cycloalkyl.

[0165] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0166] R 2 for And R 8 -OC (3) Cycloalkyl.

[0167] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0168] R 2 for And R 8 -OC (4) Cycloalkyl.

[0169] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0170] R 2 for And R 8 -OC (5) Cycloalkyl.

[0171] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0172] R 2 for And R 8 For those not replaced or replaced by one to six R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0173] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0174] R 2 for And R 8 -C that has not been replaced (1-3) Alkyl or -C (3-5) Cycloalkyl.

[0175] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0176] R 2 for And R 8 For one to six R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0177] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0178] R 2 for And R 8 For being an R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0179] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0180] R 2 for And R 8 For being two R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0181] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0182] R 2 for And R 8 For being three R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0183] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0184] R 2 for And R 8 For being four R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0185] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0186] R 2 for And R 8 For being five R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0187] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0188] R 2 for And R 8 For being six R 8a -C substituent (1-3) Alkyl or -C (3-5) Cycloalkyl, and each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0189] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl. In some embodiments, R 8a Independently, it is halogenated. In some embodiments, the halogenation is brominated (-Br), chlorinated (-Cl), fluorinated (-F), or iodinated (-I). In some embodiments, the halogenation is brominated (-Br). In some embodiments, the halogenation is chlorinated (-Cl). In some embodiments, the halogenation is fluorinated (-F). In some embodiments, the halogenation is iodinated (-I). In some embodiments, R 8a Independently for -OC (1-3) Alkyl group. In some embodiments, R 8a Independently for -OC (3-5) Cycloalkyl.

[0190] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C (3-5) Cycloalkyl. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C (3) Cycloalkyl. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C (4) Cycloalkyl. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C (5) Cycloalkyl. In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-5) Cycloalkyl. In some embodiments, R 3 It has not been replaced. In some implementations, R 3 It is replaced by a halogen atom. In some implementations, R 3 It is replaced by two halogen atoms. In some implementations, R 3 It is replaced by three halogen atoms. In some implementations, R 3 It is replaced by four halogen atoms. In some implementations, R 3 It is replaced by five halogen atoms. In some implementations, R 3 It was replaced by six halogen atoms.

[0191] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4For those not replaced or replaced by one or two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms. In some embodiments, the halogenation is brominated (-Br), chlorinated (-Cl), fluorinated (-F), or iodinated (-I). In some embodiments, the halogenation is brominated (-Br). In some embodiments, the halogenation is chlorinated (-Cl). In some embodiments, the halogenation is fluorinated (-F). In some embodiments, the halogenation is iodinated (-I).

[0192] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 It is an unsubstituted 5-membered heteroaryl group.

[0193] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0194] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group-substituted 5-membered heteroaryl groups; R 4a -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0195] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0196] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0197] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently, -OC is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0198] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a Group-substituted 5-membered heteroaryl groups; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (0-2) Alkyl-C (3-6) Cycloalkyl.

[0199] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For those not replaced or replaced by one or two R 4a Group substitution diazole; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C(0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0200] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For those that have not been replaced diazole.

[0201] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a Group substitution diazole; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0202] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group substitution diazole; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0203] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group substitution diazole; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0204] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group substitution diazole; each R 4a Independently, -OC is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0205] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group substitution diazole; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (0-2) Alkyl-C (3-6) Cycloalkyl.

[0206] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being two R 4a Group substitution diazole; each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein -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 one to six halogen atoms.

[0207] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being two R 4a Group substitution diazole; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0208] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being two R 4a Group substitution diazole; each R 4a Independently, -OC is either unsubstituted or substituted with one to six halogen atoms. (1-6) alkyl.

[0209] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being two R 4a Group substitution diazole; each R 4a Independently, -C is either unsubstituted or substituted with one to six halogen atoms. (0-2) Alkyl-C (3-6) Cycloalkyl.

[0210] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0211] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0212] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0213] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0214] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0215] In some embodiments, this document discloses compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0216] R 1 Each time it appears, it is independently either unreplaced or replaced by one to four Rs. 1a -C substituent (1-2) alkyl;

[0217] R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-6) cycloalkyl;

[0218] R 4 For not being replaced or by an R 4a A five-membered heteroaryl group with one to four heteroatoms selected from N, O, and S, substituted with a functional group; and

[0219] Each R 4a Independently for -C (1-3) Alkyl, -OC (1-3) Alkyl or -C (3-6) cycloalkyl, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl and -C(3-6) The cycloalkyl group is either unsubstituted or substituted with one to four halogen atoms.

[0220] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0221] Each R 1 Independently for those not replaced or by one to three Rs 1a -C substituent (1) alkyl;

[0222] R 3 -C is either unsubstituted or substituted with one to four halogen atoms. (5-6) cycloalkyl;

[0223] R 4 For being an R 4a A five-membered heteroaryl group substituted with one to three heteroatoms selected from N and O; and

[0224] Each R 4a Independently for -C (1-2) Alkyl, -OC (1-2) Alkyl or -C (3-4) cycloalkyl, wherein -C (1-2) Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed herein, wherein the compound of formula (I) is a compound having formula (Ia), formula (Ia-a), or formula (Ia-b):

[0225] , or .

[0226] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia).

[0227] .

[0228] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-a).

[0229] .

[0230] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-b).

[0231] .

[0232] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ib), formula (Ib-1), or formula (Ib-2).

[0233] , or .

[0234] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib).

[0235] .

[0236] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib-1).

[0237] .

[0238] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib-2).

[0239] .

[0240] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ic), formula (Ic-1), or formula (Ic-2):

[0241] , or .

[0242] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic).

[0243] .

[0244] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic-1).

[0245] .

[0246] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic-2).

[0247] .

[0248] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 For those not replaced or replaced by one to three Rs 1a -CH3 with a substituent group.

[0249] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 -C(R) 1a 3.

[0250] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-1).

[0251] .

[0252] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-2).

[0253] .

[0254] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-3).

[0255] .

[0256] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-4).

[0257] .

[0258] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 for .

[0259] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 for And n is 0.

[0260] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0261] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0262] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one to six R 5a -C substituent (1-3) Alkyl, and R 6 H or -C (1-2) alkyl.

[0263] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (1-2) Alkyl, and R 6 H or -C (1-2) alkyl.

[0264] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For -CH3 and R 6 H or -C (1-2) alkyl.

[0265] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For -CH3 and R 6 It is -CH2CH3.

[0266] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For -CH3 and R 6 For H.

[0267] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For -CH3 and R 6 It is -CH3.

[0268] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CH2CHF2.

[0269] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CH2CHF2 and R 6 -C (1-3) alkyl.

[0270] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 It is -CH2CHF2 and R 6 For H.

[0271] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (3-5) Cycloalkyl.

[0272] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (3-4) Cycloalkyl.

[0273] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one or two R 5a -C substituent (3) Cycloalkyl.

[0274] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For those not replaced or replaced by one or two R 5a -C substituent (3) cycloalkyl and R 6 For H.

[0275] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 For H.

[0276] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 for .

[0277] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 for And n is 0.

[0278] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 -C (1-3) alkyl.

[0279] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 It is -CH3.

[0280] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 For H.

[0281] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0282] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0283] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein -C (1-3) Alkyl and -C (3-5) The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0284] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C is either unsubstituted or substituted with one to six halogen atoms. (1-3) alkyl.

[0285] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (1-3) alkyl.

[0286] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C is either unsubstituted or substituted with one to four fluorine atoms. (1-3) alkyl.

[0287] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 It can be -CH3, -CHF2 or -C(CH3)F2.

[0288] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (3-5) Cycloalkyl.

[0289] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (3-4) Cycloalkyl.

[0290] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 It is an unsubstituted or substituted cyclopropyl group with one or two halogen atoms.

[0291] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 It is a cyclopropyl group substituted with a halogen atom.

[0292] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 8 -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0293] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-6) Cycloalkyl.

[0294] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C is either unsubstituted or substituted with one to four halogen atoms. (4-6) Cycloalkyl.

[0295] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 -C is either unsubstituted or substituted by one or two halogen atoms. (5-6) Cycloalkyl.

[0296] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 It is an unsubstituted or substituted cyclohexyl group.

[0297] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 It is an unsubstituted or substituted cyclohexyl group.

[0298] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 for

[0299] .

[0300] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For one or two R 4a A five-membered heteroaryl group with one to three heteroatoms selected from N and O, substituted with a functional group;

[0301] Each R 4a Independently for -C (1-2) Alkyl, -OC (1-2) Alkyl or -C (3-4) cycloalkyl, wherein -C (1-2) Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0302] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0303] Each R 4a Independently for -C (1-2)Alkyl, -OC (1-2) Alkyl or -C- (3-4) cycloalkyl, wherein -C (1-2) Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0304] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0305] Each R 4a Independently for -C (1-2) Alkyl, -OC (1) Alkyl or -C (3) cycloalkyl, wherein -C (1-2) Alkyl and -C (3) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0306] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0307] Each R 4a It can be independently -CH3, -C(CH3)F2, -OCH3 or -cyclopropyl.

[0308] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 For being an R 4a Group substitution Diazole group.

[0309] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0310] .

[0311] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 4a Independently for -C (1-2) alkyl.

[0312] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4aIt is - CH3.

[0313] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 4a Independently -CF3, -CHF2, or -CF2(CH3).

[0314] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 4a Independently for -OC (1-2) alkyl.

[0315] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4a is -O-CH3.

[0316] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 4a Independently, -C is either unsubstituted or substituted with one to three halogen atoms. (3-5) Cycloalkyl.

[0317] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 4a Independently, -C is either unsubstituted or substituted with one to three halogen atoms. (3-4) Cycloalkyl.

[0318] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4a for .

[0319] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0320] , , or .

[0321] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0322] .

[0323] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0324] .

[0325] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0326] .

[0327] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0328] .

[0329] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0330]

[0331]

[0332] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0333]

[0334] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0335]

[0336] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0337]

[0338] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0339]

[0340] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0341] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0342] .

[0343] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0344] .

[0345] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0346] .

[0347] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0348] .

[0349] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0350] .

[0351] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0352] .

[0353] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0354] .

[0355] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0356] .

[0357] In some embodiments, this document discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is

[0358] .

[0359] In some embodiments, this document discloses a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, this document discloses a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient.

[0361] In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., tablets or capsules).

[0362] In some embodiments, this document discloses a pharmaceutical composition prepared by means of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0363] In some embodiments, this document discloses a method for preparing a pharmaceutical composition comprising a mixture of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0364] Therapeutic uses

[0365] Preclinical and clinical data have demonstrated the significant pathological role of IL-17A in a variety of autoimmune and inflammatory diseases.

[0366] For psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesion skin and blood of patients with psoriasis and are correlated with disease severity. IL-17A directly synergizes with other cytokines on keratinocytes, such as TNFα, IFNγ, or IL-22, triggering an autoproliferative inflammatory response in the skin and leading to the formation of psoriatic plaques. Blocking IL-17A with antibodies against IL-17A or IL-23 resulted in a complete reversal of molecular and clinical disease characteristics in most patients with psoriasis, demonstrating the significant role of IL-17A and IL-17-producing T cells in the immunopathogenesis of psoriasis. (Hawkes et al., “Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies”, J Allergy Clin Immunol., 2017, 140(3): 645–653). The development and approval of IL-17 monoclonal antibodies (such as secukinumab, ixekizumab, and brodalumab) and their conversion efficacy in psoriasis have demonstrated that IL-17A is 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).

[0367] For psoriatic arthritis (PsA): IL-17A is mechanistically associated with PsA via NFκB activation, which triggers the transcription of several PsA-related genes, including receptor activators of nuclear factor κB ligand (RANKL). RANKL triggers the differentiation of osteoclast precursor cells into activated osteoclasts, leading to bone resorption in PsA and subsequent joint deformities (Adamopoulos I. and Mellins E., Nature reviews Rheumatology 2015; 11:189-94). PsA joints are enriched with IL-17+CD8+ T cells, and the level of this T cell subset is associated with disease activity (Menon B. et al., Arthritis & Rheumatology 2014; 66: 1272-81). Compared to osteoarthritis patients, synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression and secrete increased IL-6, CXCL8, and MMP3 in vitro. Both secukinumab and ixekizumab are FDA-approved PsA drugs. In matched-adjusted indirect comparative analyses, secukinumab was associated with a higher ACR 20 / 50 / 70 response rate in patients with active PsA compared to anti-TNF antibodies (Mease P. et al., Eur. J. Rheumatol. 2019 July 1, 6(3):113-121; Strand V. et al., J. Comp. Eff. Res. 2019, 8(7):497-510; Nash P. et al., Rheumatol. Ther. 2018, 5(1):99-122). In a recent head-to-head study, ixekizumab outperformed adalimumab in achieving simultaneous improvement in both joint and skin disease (ACR50 and PASI100) in patients with PsA who had an inadequate response to conventionally synthesized disease-mitigating antirheumatic drugs (Mease, P. et al., Ann Rheum Diss 2020; 79:123-131). Given that small molecules typically have better tissue penetration, small molecule inhibitors of IL-17A can exert similar or better efficacy than biologics by targeting the same target.

[0368] For rheumatoid arthritis (RA): IL-17A has been recognized as crucial for the progression of RA. "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. CellBiol. 2004, 82(1): 1-9. Furthermore, in RA, IL-17A acts locally on synovial cells and osteoclasts, leading to synovitis and joint destruction. Robert and Miossec have proposed using synovial biopsy tissue and / or biomarkers to precisely identify patients responding to IL-17A inhibition. Their work concludes that IL-17 inhibitors should now be considered in the development of precision medicine for RA. (Robert M. and Miossec P., Front. Med., 2019, 5:364).

[0369] For ankylosing spondylitis (AS): Various studies have reported elevated levels of IL-17A and Th17, as well as other IL-17-producing cells, in blood samples from AS patients (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). April 2015; 54(4): 728–735). In situ analysis of the AS spine revealed an increase in IL-17A-producing cells in the small (articular) joint bones (Appel H et al., Arthritis Res. Ther. 2011; 13(3):R95). Two advanced IL-17A neutralizing antibodies, secukinumab and ixekizumab, both FDA-approved for AS, have demonstrated superior efficacy compared to placebo, even in responders with insufficient anti-TNF activity. Conversely, anti-IL-23 p40 and p19 biologics have 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 a fundamental mechanism of differentiation along the IL-23 / IL-17 pathway in AS and providing strong evidence to support continued development of IL-17A inhibitors.

[0370] For hidradenitis suppurativa (HS): It has been reported that IL-17 and IL-17-producing T helper cells are increased in the 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). Of the nine patients with moderate to severe HS, seven (78%) achieved HiSCR in an open-label pilot trial using secukinumab (Prussick L. et al., British J. Dermatol. Sep 2019; 181(3):609-611), and more clinical trials on anti-IL-17 mAb in HS are underway.

[0371] For bullous pemphigoid (BP): IL-17 is elevated in the vesicular fluid and perivesicular skin of BP patients. (LeJan S. et al., J. Invest. Dermatol. 2014; 134 (12):2908-2917.; Chakievska L. JAutoimmun. 2019, 96:104-112.) Exome sequencing of BP patients revealed mutations in twelve IL-17-related genes in one-third of the patients, providing a genetic link between the IL-17 pathway and BP (Chakievska L. JAutoimmun. 2019, 96:104-112). In mouse BP, IL-17A- / - mice were protected, and anti-IL-17A treatment significantly reduced skin lesions in wild-type mice (Chakievska L. J Autoimmun. 2019, 96:104-112). Phase 2 trials of ixekizumab in treatment-naïve and refractory BP patients are underway (NCT03099538).

[0372] For atopic dermatitis (AD): IL-17 was found to be elevated in the peripheral blood and lesions of AD patients, and Th17 cell infiltration was more pronounced in acute lesions than in chronic lesions, suggesting a role in the acute phase of AD (Koga C. et al., J. Invest. Dermatol. 2008, 128, 2625–2630). Molecular profiling analysis from ustekinumab phase II suggests that the IL-23 / Th17 / IL-17 pathway may play a role in AD (Khattri S. et al., Exp. Dermatol. Jan. 2017; 26(1):28–35).

[0373] For vitiligo: Numerous studies in vitiligo patients have demonstrated a positive correlation between increased Th17 cell frequency in both the circulation and lesions, as well as elevated IL-17 levels, and disease duration, severity, and activity (Singh R. et al., Autoimmun.Rev, April 2016, 15(4):397-404). Mouse studies have shown that depigmentation is associated with increased IL-17 expression / secretion, which regulates vitiligo development (Eby J. et al., Pigment Cell & Melanoma Res. November 2014, 27(6):1075-85).

[0374] For multiple sclerosis (MS): IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF), and brain lesions and cells from MS patients (Lock, C. et al., Nat. Med. 2002, 8: 500–508; Matusevicius, D. et al., Mult. Scler. 1999, 5: 101–104; Tzartos, J. et al., Am. J. Pathol. 2008, 172: 146–155). IL-17-producing T cells are rich 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 are elevated in the CSF of patients with relapsing-remitting MS (RRMS) and correlated with the CSF / serum albumin quotient (a measure of blood-brain barrier (BBB) ​​dysfunction) and in vitro data. In vitro data showed that IL-17A combined with IL-6 reduced the expression of tight junction-related genes and disrupted the monolayer integrity in BBB cell lines, highlighting the potential importance of targeting IL-17A to maintain BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol. 2019, 332:147-154). Secukinumab has achieved promising results for the first time in a proof-of-concept study in MS patients (Havrdová, E. et al., J. Neurol. 2016, 263: 1287–1295.

[0375] For 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 the airways of asthma 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 model of asthma (Camargo LdN. et al., Front Immunol. 2018; 8:1835; dos Santos T. et al., Front. Physiol. 2018, 9:1183).

[0376] For chronic obstructive pulmonary disease (COPD): Increased Th17 cells were observed in patients with COPD compared to current smokers and healthy subjects without COPD, and a negative correlation was found between Th17 cells and lung function (Vargas-Rojas M. et al., Respir. Med. 2011 Nov; 105(11):1648–54). In three recent human COPD studies, gene expression profiles in bronchial epithelium showed that higher IL-17 signature expression was associated with a lack of response to inhaled corticosteroids, suggesting the existence of a COPD subgroup that may benefit from IL-17 inhibitor therapy (Christenson S. et al., J. Clin. Invest. 2019; 129(1):169–181).

[0377] For uveitis: IL-17 promotes the release of inflammatory mediators from the retinal pigment epithelium cell line, disrupting the retinal pigment epithelium barrier function (Chen Y. et al., PLoS One. 2011; 6:e18139). IL-17 levels are 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., Inflammation 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 in rats and significantly inhibited the development of experimental autoimmune uveitis (Zhang R. et al., Curr. Eye Res. 2009 Apr; 34(4):297-303). Analysis of secondary efficacy data from a phase 3 subcutaneous (sc) secukinumab trial for uveitis showed that secukinumab had a beneficial effect in reducing the use of concomitant immunosuppressive drugs (Dick A. et al., Ophthalmology 2013, 120(4):777-87). Subsequent studies of intravenous secukinumab for uveitis demonstrated that intravenous secukinumab was more effective than sc administration, suggesting that optimal exposure is required to obtain efficacy and confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015, 122(5), 939-948). It was also reported that uteroclosab, which blocks the IL-23 / IL-17 pathway, successfully treated patients with severe non-infectious uveitis with psoriasis and PsA who could not respond to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep; 30(5); e12527.).

[0378] For multiple myeloma (MM): Serum IL-17A levels were significantly elevated in MM patients compared with healthy subjects, and also significantly elevated in advanced patients (Lemancewicz D. et al., Med. Sci. Monit. 2012; 18(1): BR54–BR59). After the tumor was first detected in mice, weekly administration of secukinumab for up to 4 weeks in the SCIDhu model of human myeloma resulted in significant inhibition of tumor growth and reduced bone damage compared with isotype control mice (Prabhala R. et al., Leukemia. Feb. 2016, 30(2): 379–389).

[0379] For systemic lupus erythematosus (SLE): Elevated serum or plasma IL-17 levels, expansion of IL-17-producing T cells in peripheral blood, and Th17 cell infiltration 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. Jan. 2010; 37(1):81-5; Chen X. et al., J. Clin. Immunol., Mar. 2010; 30(2):221-5; Xing Q. et al., Rheumatol. Int., Apr. 2012; 32(4):949-58). An imbalance between Th17 cells and regulatory T (Treg) cells has been observed in SLE patients, including those in quiescent phase (Ma J. et al., Clin. Rheumatol. 2010; 29(11):1251–1258; Dolff S. et al., Clin. Immunol., 2011, 141(2):197–204). Adenovirus overexpression of IL-17A enhanced the severity of lupus nephritis, while blocking IL-17A with neutralizing antibodies reduced the severity of lupus nephritis (Wen, Z. et al., PLoSOne. 2013, 8: e58161). In a phase 2 study, uterotumab (an anti-IL-12 / 23 p40 monoclonal antibody blocking the IL-23 / IL-17 pathway) has been shown to be effective in SLE patients (van Vollenhoven R. et al., Lancet 2018; 392:1330–39). Human expression studies, animal models, and clinical trials suggest that IL-17 blockade may be a promising treatment strategy for SLE (Koga T. et al., Expert Rev. Clin. Immunol., 2019, 15(6) 629-637).

[0380] Therefore, this application also relates to a method for treating and / or improving IL-17-mediated inflammatory syndromes, symptoms, or diseases, the method comprising administering to a subject in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a combination thereof, or a medicament thereof.

[0381] In some implementations, this document discloses methods for treating or improving IL-17A-mediated inflammatory syndromes, symptoms, or diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndromes, conditions, or diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[0383] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is psoriasis.

[0384] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is psoriatic arthritis.

[0385] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is rheumatoid arthritis.

[0386] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is ankylosing spondylitis.

[0387] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is hidradenitis suppurativa.

[0388] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is bullous pemphigoid.

[0389] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is atopic dermatitis.

[0390] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is vitiligo.

[0391] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is multiple sclerosis.

[0392] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is systemic lupus erythematosus.

[0393] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is asthma.

[0394] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is uveitis.

[0395] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is chronic obstructive pulmonary disease.

[0396] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is multiple myeloma.

[0397] In some embodiments, this document discloses a method for treating and / or improving IL-17A-mediated inflammatory syndromes, conditions, or diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0398] In some embodiments, this document discloses the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and / or improvement of IL-17A-mediated inflammatory syndromes, conditions, or diseases 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.

[0399] In some embodiments, this document discloses the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, 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.

[0400] In some embodiments, this document discloses methods for treating and / or improving IL-17-mediated inflammatory syndromes, symptoms, or diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a combination thereof, or a medicament thereof.

[0401] In some implementations, this document discloses methods for treating and / or improving IL-17-mediated inflammatory syndromes, conditions, or diseases selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, hormone-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a combination thereof, or a drug thereof.

[0402] In some embodiments, this document discloses methods for treating or improving IL-17-mediated inflammatory syndromes, conditions, or diseases selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis, wherein the method comprises administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a combination thereof, or a drug thereof.

[0403] In some embodiments, this document discloses a method for modulating 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.

[0404] This article also discloses a method for inhibiting the production of interleukin-17, which involves administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0405] combination therapy

[0406] The compounds of formula (I) or their pharmaceutically acceptable salts, their compositions or their pharmaceutical preparations may also be used in combination with one or more additional therapeutic agents.

[0407] In some implementations, the one or more additional therapeutic agents are selected from the group consisting of: anti-inflammatory agents, immunomodulators, and immunosuppressants.

[0408] In some embodiments, this document discloses a method for treating and / or improving IL-17-mediated inflammatory syndrome, condition, or disease in a subject with such need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a combination thereof, or a drug thereof, in combination with one or more other therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, condition, or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis, or hidradenitis suppurativa. In some embodiments, the IL-17-mediated inflammatory syndrome, condition, or disease is psoriasis. In some embodiments, the IL-17-mediated inflammatory syndrome, condition, or disease is psoriatic arthritis. In some embodiments, the IL-17-mediated inflammatory syndrome, condition, or disease is ankylosing spondylitis. In some embodiments, the IL-17-mediated inflammatory syndrome, condition, or disease is hidradenitis suppurativa.

[0409] Dosage regimen

[0410] The dosage applied will be affected by factors such as the route of administration, the recipient's health status, weight and age, treatment frequency, and the presence of concurrent and unrelated treatments.

[0411] It will also be apparent to those skilled in the art that the therapeutically effective dose of the compounds or pharmaceutical compositions thereof disclosed herein will vary depending on the desired effect. Therefore, the appropriate dose to be administered can 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 formulation, and the progression of the disease condition. Furthermore, factors relevant to the specific subject receiving treatment, including the subject's age, weight, diet, and time of administration, will necessitate adjustments to the dose to an appropriate therapeutic level. Therefore, the above doses are examples of general cases. Of course, there may be individual cases where a higher or lower dose range should be used, and such cases are also within the scope of this disclosure.

[0412] Pharmaceutical Composition

[0413] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carrier. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antimicrobial and antifungal agents, and isotonic agents. Exemplary excipients that may also be formulation components include, but are not limited to, fillers, binders, disintegrants, and lubricants.

[0414] The pharmaceutical compositions disclosed herein may be administered in any manner that achieves their intended purpose. Examples include, but are not limited to, administration via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, local, oral, or ocular routes. Alternatively or concurrently, they may be administered orally.

[0415] This document also discloses a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, this application includes, but is not limited to, pharmaceutical compositions prepared by mixing a pharmaceutically acceptable carrier with any one of the compounds disclosed herein.

[0416] While embodiments of the invention have been described in conjunction with certain specific embodiments for illustrative purposes, the invention is not limited thereto. Therefore, various modifications, adaptations, and combinations of various features of the described embodiments can be practiced without departing from the scope of the invention as set forth in the claims. Furthermore, the following examples are illustrative and not restrictive of the compounds, compositions, and methods described herein. Other suitable modifications and adjustments known to those skilled in the art are within the scope of the following embodiments. Any and all journal articles, patent applications, granted patents, or other cited references are incorporated herein by reference in their entirety.

[0417] In some implementation schemes, the following non-limiting implementation schemes are provided:

[0418] 1. A compound having the formula (I), (I-1), or (I-2):

[0419] , or Or its pharmaceutically acceptable salt,

[0420] in:

[0421] Each R 1 Independently for those not replaced or by one to six R 1a -C substituent (1-3) alkyl;

[0422] Each R 1a Independently halogenated;

[0423] R 2 for or ;

[0424] R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-8) cycloalkyl;

[0425] R 4 It is either not replaced or replaced by one or two Rs. 4a Five-membered heteroaryl groups substituted with functional groups;

[0426] Each R 4a Independently for -C(1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein the -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 one to six halogen atoms;

[0427] R 5 H, -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 5a Group substitution;

[0428] Each R 5a Independently halogenated;

[0429] R 6 H or -C (1-3) alkyl;

[0430] R 7 H or -C (1-3) alkyl;

[0431] R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 8a Group substitution;

[0432] Each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl;

[0433] Each m is independently 0, 1, or 2; and

[0434] Each n is independently 0 or 1.

[0435] 2. The compound or a pharmaceutically acceptable salt thereof according to embodiment 1, wherein...

[0436] R 1 Each time it appears, it is independently either unreplaced or replaced by one to four Rs. 1a -C substituent (1-2) alkyl;

[0437] R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-6) cycloalkyl;

[0438] R 4 For not being replaced or by an R 4a A five-membered heteroaryl group with one to four heteroatoms selected from N, O, and S, substituted with a functional group; and

[0439] Each R 4a Independently for -C (1-3) Alkyl, -OC (1-3) Alkyl or -C (3-6) cycloalkyl, wherein the -C (1-3) Alkyl, -OC (1-3) Alkyl and -C (3-6) The cycloalkyl group is either unsubstituted or substituted with one to four halogen atoms.

[0440] 3. The compound or a pharmaceutically acceptable salt thereof according to embodiment 1, wherein...

[0441] Each R 1 Independently for those not replaced or by one to three Rs 1a -C substituent (1) alkyl;

[0442] R 3 -C is either unsubstituted or substituted with one to four halogen atoms. (5-6) cycloalkyl;

[0443] R 4 For being an R 4a A five-membered heteroaryl group substituted with one to three heteroatoms selected from N and O; and

[0444] Each R 4a Independently for -C (1-2) Alkyl, -OC (1-2) Alkyl or -C (3-4) cycloalkyl, wherein the -C (1-2) Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0445] 4. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ia), formula (Ia-a), or formula (Ia-b):

[0446] , or .

[0447] 5. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ib), formula (Ib-1), or formula (Ib-2).

[0448] , or .

[0449] 6. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ic), formula (Ic-1), or formula (Ic-2):

[0450] , or .

[0451] 7. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 6, wherein R 1 For those not replaced or replaced by one to three Rs 1a -CH3 with a substituent group.

[0452] 8. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 7, wherein R 1 -C(R) 1a 3.

[0453] 9. A compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-1).

[0454] .

[0455] 10. A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-2).

[0456] .

[0457] 11. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 10, wherein the compound of formula (I) is a compound of formula (Ia-3).

[0458] .

[0459] 12. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, wherein R 2 for .

[0460] 13. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 12, wherein R 2 for And n is 0.

[0461] 14. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 13, wherein n is 0.

[0462] 15. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 12, wherein n is 1.

[0463] 16. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15, wherein R 5 For those not replaced or replaced by one to six R 5a -C substituent (1-3) Alkyl, and R 6 H or -C (1-2) alkyl.

[0464] 17. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 16, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (1-2) Alkyl, and R 6 H or -C (1-2) alkyl.

[0465] 18. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 17, wherein R 5 For -CH3 and R 6 H or -C (1-2) alkyl.

[0466] 19. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 18, wherein R 5 For -CH3 and R 6 It is -CH2CH3.

[0467] 20. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 18, wherein R 5 For -CH3 and R 6 For H.

[0468] 21. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 18, wherein R 5 For -CH3 and R 6 It is -CH3.

[0469] 22. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 18, wherein R 5 It is -CH2CHF2.

[0470] 23. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 17 and 22, wherein R 5 It is -CH2CHF2 and R 6 -C (1-3) alkyl.

[0471] 24. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 17 and 22, wherein R 5 It is -CH2CHF2 and R 6 For H.

[0472] 25. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (3-5) Cycloalkyl.

[0473] 26. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15 and 25, wherein R 5 For those not replaced or replaced by one to four Rs 5a -C substituent (3-4) Cycloalkyl.

[0474] 27. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15, 25 and 26, wherein R 5 For those not replaced or replaced by one or two R 5a -C substituent (3) Cycloalkyl.

[0475] 28. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15 and 25 to 27, wherein R 5 For those not replaced or replaced by one or two R 5a -C substituent (3) Cycloalkyl, and R 6 For H.

[0476] 29. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15, wherein R 5 For H.

[0477] 30. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14 and 15, wherein R 2 for .

[0478] 31. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14 and 30, wherein R 2 for And n is 0.

[0479] 32. The compound or a pharmaceutically acceptable salt thereof according to any one of 1 to 11, 14, 15, 30 and 31, wherein R 7 -C (1-3) alkyl.

[0480] 33. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 32, wherein R 7 It is -CH3.

[0481] 34. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, and 15, wherein R 7 For H.

[0482] 35. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 34, wherein R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0483] 36. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 35, wherein R 8 -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0484] 37. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 36, wherein R 8 -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5)The cycloalkyl group is either unsubstituted or substituted with one to six halogen atoms.

[0485] 38. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 37, wherein R 8 -C is either unsubstituted or substituted with one to six halogen atoms. (1-3) alkyl.

[0486] 39. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 38, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (1-3) alkyl.

[0487] 40. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-1 to 11, 14, 15 and 30 to 39, wherein R 8 -C is either unsubstituted or substituted with one to four fluorine atoms. (1-3) alkyl.

[0488] 41. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 40, wherein R 8 It can be -CH3, -CHF2 or -C(CH3)F2.

[0489] 42. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 37, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (3-5) Cycloalkyl.

[0490] 43. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15, 30 to 37 and 42, wherein R 8 -C is either unsubstituted or substituted with one to four halogen atoms. (3-4) Cycloalkyl.

[0491] 44. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15, 30 to 37, 42 and 43, wherein R 8 It is an unsubstituted or substituted cyclopropyl group with one or two halogen atoms.

[0492] 45. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15, 30 to 37 and 42 to 44, wherein R 8 It is a cyclopropyl group substituted with a halogen atom.

[0493] 46. ​​A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 11, 14, 15 and 30 to 36, wherein R 8 -OC (1-3) Alkyl or -OC (3-5) Cycloalkyl.

[0494] 47. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 46, wherein R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-6) Cycloalkyl.

[0495] 48. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 47, wherein R 3 -C is either unsubstituted or substituted with one to four halogen atoms. (4-6) Cycloalkyl.

[0496] 49. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 48, wherein R 3 -C is either unsubstituted or substituted by one or two halogen atoms. (5-6) Cycloalkyl.

[0497] 50. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 49, wherein R 3 It is an unsubstituted or substituted cyclohexyl group.

[0498] 51. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 50, wherein R 3 It is an unsubstituted or substituted cyclohexyl group.

[0499] 52. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 51, wherein R 3 for

[0500] .

[0501] 53. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 52, wherein R 4 For one or two R 4a A five-membered heteroaryl group with one to three heteroatoms selected from N and O, substituted with a functional group;

[0502] Each R 4a Independently for -C (1-2) Alkyl, -OC (1-2) Alkyl or -C (3-4) cycloalkyl, wherein the -C (1-2)Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0503] 54. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 53, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0504] Each R 4a Independently for -C (1-2) Alkyl, -OC (1-2) Alkyl or -C- (3-4) cycloalkyl, wherein the -C (1-2) Alkyl, -OC (1-2) Alkyl and -C (3-4) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0505] 55. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 54, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0506] Each R 4a Independently for -C (1-2) Alkyl, -OC (1) Alkyl or -C (3) cycloalkyl, wherein the -C (1-2) Alkyl and -C (3) The cycloalkyl group is either unsubstituted or substituted with one to three halogen atoms.

[0507] 56. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, wherein R 4 For being an R 4a A five-membered heteroaryl group with three heteroatoms selected from N and O that are substituted with a group;

[0508] Each R 4a It can be independently -CH3, -C(CH3)F2, -OCH3 or -cyclopropyl.

[0509] 57. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 56, wherein R 4 For being an R 4a Group substitution Diazole group.

[0510] 58. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 57, wherein R 4 for

[0511] .

[0512] 59. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58, wherein each R 4a Independently for -C (1-2) alkyl.

[0513] 60. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 59, wherein R 4a It is - CH3.

[0514] 61. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57 or 58, wherein each R 4a Independently -CF3, -CHF2, or -CF2(CH3).

[0515] 62. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57 or 58, wherein each R 4a Independently for -OC (1-2) alkyl.

[0516] 63. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57, 58 or 62, wherein R 4a is -O-CH3.

[0517] 64. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57 or 58, wherein each R 4a Independently, -C is either unsubstituted or substituted with one to three halogen atoms. (3-5) Cycloalkyl.

[0518] 65. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57, 58 or 64, wherein each R 4a Independently, -C is either unsubstituted or substituted with one to three halogen atoms. (3-4) Cycloalkyl.

[0519] 66. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-1 to 55, 57, 58, 64 or 65, wherein R 4a for .

[0520] 67. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57 or 58, wherein R 4 for

[0521] , , or .

[0522] 68. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58 or 64 to 67, wherein R 4 for

[0523] .

[0524] 69. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58 or 61 to 63, wherein R 4 for

[0525] .

[0526] 70. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 55, 57, 58, 61 or 67, wherein R 4 for

[0527] .

[0528] 71. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58, 61 or 67, wherein R 4 for

[0529] .

[0530] 72. A compound, said compound being selected from the group consisting of:

[0531]

[0532]

[0533] Or its pharmaceutically acceptable salt.

[0534] 73. The compound according to embodiment 72, wherein the compound is selected from the group consisting of:

[0535]

[0536] Or its pharmaceutically acceptable salt.

[0537] 74. The compound according to embodiment 73, wherein the compound is selected from the group consisting of:

[0538]

[0539] Or its pharmaceutically acceptable salt.

[0540] 75. The compound according to embodiment 72, wherein the compound is selected from the group consisting of:

[0541]

[0542] Or its pharmaceutically acceptable salt.

[0543] 76. The compound according to embodiment 72, wherein the compound is selected from the group consisting of:

[0544]

[0545] Or its pharmaceutically acceptable salt.

[0546] 77. A compound, said compound being selected from the group consisting of:

[0547]

[0548] Or its pharmaceutically acceptable salt.

[0549] 78. The compound according to embodiment 77, having the following formula

[0550]

[0551] Or its pharmaceutically acceptable salt.

[0552] 79. The compound according to embodiment 77, having the following formula

[0553]

[0554] Or its pharmaceutically acceptable salt.

[0555] 80. The compound according to embodiment 77, having the following formula

[0556]

[0557] Or its pharmaceutically acceptable salt.

[0558] 81. The compound according to embodiment 77, having the following formula

[0559]

[0560] Or its pharmaceutically acceptable salt.

[0561] 82. The compound according to embodiment 77 has the following formula:

[0562]

[0563] Or its pharmaceutically acceptable salt.

[0564] 83. The compound according to embodiment 77, having the following formula

[0565]

[0566] Or its pharmaceutically acceptable salt.

[0567] 84. The compound according to embodiment 77, having the following formula

[0568]

[0569] Or its pharmaceutically acceptable salt.

[0570] 85. The compound according to embodiment 77, having the following formula

[0571]

[0572] Or its pharmaceutically acceptable salt.

[0573] 86. The compound according to embodiment 77, having the following formula

[0574]

[0575] Or its pharmaceutically acceptable salt.

[0576] 87. A pharmaceutical composition comprising at least one compound according to embodiments 1 to 86 or a pharmaceutically acceptable salt thereof.

[0577] 88. A pharmaceutical composition comprising at least one compound according to embodiments 1 to 86 or a pharmaceutically acceptable salt thereof and an excipient.

[0578] 89. A method for treating and / or improving IL-17A-mediated inflammatory syndrome, condition, or disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 86.

[0579] 90. The method according to embodiment 89, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[0580] 91. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is psoriasis.

[0581] 92. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is psoriatic arthritis.

[0582] 93. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is rheumatoid arthritis.

[0583] 94. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is ankylosing spondylitis.

[0584] 95. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is hidradenitis suppurativa.

[0585] 96. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is bullous pemphigoid.

[0586] 97. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is atopic dermatitis.

[0587] 98. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is vitiligo.

[0588] 99. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is multiple sclerosis.

[0589] 100. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is systemic lupus erythematosus.

[0590] 101. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is asthma.

[0591] 102. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition or disease is uveitis.

[0592] 103. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is chronic obstructive pulmonary disease.

[0593] 104. The method according to embodiment 90, wherein the IL-17A-mediated inflammatory syndrome, condition, or disease is multiple myeloma.

[0594] 105. The method according to any one of embodiments 90, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58 is administered orally.

[0595] 106. The method according to embodiment 90, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 58 is administered as a tablet or capsule.

[0596] Example

[0597] Example

[0598] abbreviation

[0599] The following abbreviations may be used in this document and throughout the application.

[0600]

[0601] NMR spectra were recorded in DMSO-d6 at 300 K on a Bruker 600MHz instrument equipped with a 5mm BBO probe or a 500MHz instrument with a 5mm BBFO probe. For 1 The 1H NMR signal assignment and relative stereochemistry were determined using standard pulse sequences available in TopSpin 4.1 (Bruker Inc.) to obtain 1D 1H, 1D 13C, and 2D correlation spectra (COSY). 1 H- 13 The spectra of heteronuclear single quantum correlation (HSQC), heteronuclear multibond correlation (HMBC), nuclear Overhouse effect spectroscopy (NOESY), and 1H-19F heteronuclear Overhouse effect spectroscopy (HOESY).

[0602] Intermediate 1: (S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl) tert-butyl carbamate

[0603]

[0604] Step A: (S)-((4,4-difluorocyclohexyl)(7-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)tert-butyl carbamate. A solution of (S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)tert-butyl carbamate (2.17 g, 5.50 mmol) in DCM / MeOH (5:1, 60 mL) was cooled to 0 °C. Then, sodium borohydride (265 mg, 6.90 mmol) was added, and the resulting mixture was stirred in air while being warmed to room temperature for 2.5 hours. The mixture was cooled to 0 °C, quenched by dropwise addition of a saturated aqueous solution of NH4Cl (0.2 mL), and stirred for 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 to dryness. The residue was purified by silica gel chromatography (0–25% MeOH / DCM) to give the title compound as a white solid (82% yield). MS (ESI) m / z: [M+H] + The measured value is 397.2.

[0605] Step B: (S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate. At room temperature, a mixture of CBr4 (221 mg, 0.670 mmol) in anhydrous DCM (3.3 mL) was added dropwise to a solution of (S)-((4,4-difluorocyclohexyl)(7-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)tert-butyl carbamate (132 mg, 0.330 mmol, Step A), PPh3 (105 mg, 0.400 mmol), and imidazole (46 mg, 0.67 mmol) in anhydrous DCM (10 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 to dryness, and the residue was purified by silica gel chromatography (0-100% EtOAc / hexane) to give the title compound as a white foam (79% yield). MS (ESI) m / z: [M+H] + The measured value is 461.1.

[0606] Intermediate 2: (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0607]

[0608] S-5-(trifluoromethyl)pyrrolidone-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 mixture was then washed sequentially with 10% citric acid aqueous solution, water, and brine, dried over a MgSO4-free environment, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-50% EtOAc / hexane) to give the title compound (70% yield). MS (ESI) m / z: [2M+Na] + The measured value is 529.3.

[0609] Intermediate 3: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazolium [1,2-b]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0610]

[0611] A solution of (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (455 mg, 1.80 mmol, intermediate 2) in THF (14 mL) was cooled to -78 °C. Then, a 1.5 M solution of LiHMDS in THF (1.4 mL, 2.0 mmol) was added dropwise, and the resulting solution was stirred at -78 °C for 1 hour. A solution of (S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate tert-butyl ester (642 mg, 1.40 mmol, intermediate 1) was dissolved in THF (2 mL), and this solution was added to the mixture of intermediate 2 in THF 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 NH4Cl solution, and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc / hexane) to give the title compound (68% yield). MS (ESI) m / z: [M+H] + The measured value is 632.3.

[0612] Intermediate 4: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazolium [1,2-b]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester

[0613]

[0614] Under N2 conditions, a solution of (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 (500 mg, 0.792 mmol, intermediate 3) in anhydrous THF (7 mL) was cooled to -78 °C in a dry ice / acetone bath. After stirring at -78 °C for 3 min, LiHMDS (1.8 mL, 1.80 mmol, 1 M THF solution) was added dropwise, and the resulting mixture was stirred at -78 °C for 1.5 h. Then, a solution of ethyl chloroformate (98.4 mL, 1.03 mmol) in THF (2 mL) was added dropwise to the reaction mixture at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. The reaction was then warmed to 0°C using an ice / water bath and stirred at 0°C for 30 minutes. The mixture was then quenched at 0°C with 7.9 mL of a 9:1 EtOAc:AcOH solution. Water (4 mL) was added to the opaque solution, and the mixture was extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over anhydrous Mg2SO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 704.3.

[0615] Intermediate 5: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7- Ethyl 2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate

[0616]

[0617] TFA (1.08 mL, 14.1 mmol) was added dropwise to a solution of (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester (1.1 g, 1.56 mmol, intermediate 4) in DCM (1 mL), and the resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated to dryness and purified by basic preparative HPLC (XBridge C18, 5 mm, 50 × 100 mm, 10% to 100% MeCN / H2O (20 mM NH4OH)) to give the title compound (31% yield, in two steps). MS (ESI) m / z: [M+H] + The measured value is 504.1.

[0618] Intermediate 6: (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- diazole-3-carboxamido)(4,4-difluorocyclohexane) (hexyl)methyl)imidazo[1,2-b]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid

[0619]

[0620] Step A: (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Diazol-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid ethyl ester.

[0621] Add 4-cyclopropyl-1,2,5- 2,5-dioxopyrrolidine-1-yl diazon-3-carboxylic acid (159 mg, 0.633 mmol, intermediate 9) and DIPEA (0.335 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was purified directly by silica gel chromatography (0% to 100% EtOAc / hexane) to give the title compound (92% yield). MS (ESI) m / z: [M+H] + The measured value is 640.9.

[0622] Step B: (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Diazol-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid. (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-) Diazol-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (325 mg, 0.508 mmol, step A) was reacted with LiOH (48.7 mg, 2.03 mmol) in 4.5 mL of THF:H2O (8:1). The reaction was stirred at room temperature for 30 min. The mixture was concentrated and then azeotropically reacted with ACN (3x) to give a residue, which was purified by basic preparative HPLC (XBridge C18, 5 mm, 50 × 100 mm, 10% to 100% MeCN / H2O (20 mM NH4OH)) to give the title compound (84% yield). MS (ESI) m / z: [M+H] + The measured value is 612.3.

[0623] Intermediate 7: (5S)-2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)methyl tert-butyl 5-(trifluoromethyl)pyrrolidine-1-carboxylate

[0624]

[0625] A solution of (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (1.0 g, 3.95 mmol, intermediate 2) in THF (15 mL) was added dropwise to a solution of LiHMDS in THF (7.9 mL, 1.0 M, 7.9 mmol) at -78 °C via a feeding funnel, and the resulting mixture was stirred at -78 °C for 30 min. Then, a solution of (bromomethyl)borate pinacol ester (2.6 g, 11.85 mmol) in THF (8 mL) was added, and the resulting mixture was warmed to room temperature over 1 hour. The reaction mixture was then quenched by dropwise addition of water (20 mL) at 0 °C. The organic layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0% to 50% EtOAc / hexane (containing 0.1% NEt3)) to give the title compound (82% yield).

[0626] Intermediate 8: 4-(1,1-difluoroethyl)-1,2,5- Diazol-3-carboxylic acid

[0627]

[0628] 4-(1,1-difluoroethyl)-1,2,5- A mixture of ethyl diazole-3-carboxylate (10.0 g, 48.5 mmol) and LiOH•H₂O (6.11 g, 146 mmol) in EtOH / water (120 mL, 2:1) was stirred at room temperature for 3 hours. The mixture was concentrated to remove EtOH. Then, water (50 mL) was added and the mixture was extracted with EtOAc (2 × 100 mL). The pH of the aqueous layer was adjusted to pH < 3 by adding 1 N HCl aqueous solution, and then the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a yellow oil. The oil was diluted with ACN and water, frozen, and lyophilized to give the title compound as a yellow solid (6.8% yield). MS (ESI) m / z: [MH] + The measured value is 177.0.

[0629] Intermediate 9: 4-Cyclopropyl-1,2,5- 2,5-Dioxopyrrolidone-1-yl diazol-3-carboxylic acid ester

[0630]

[0631] Step: 4-Cyclopropyl-1,2,5- Diazole-3-carbonyl chloride. 4-Cyclopropyl-1,2,5- A solution of diazon-3-carboxylic acid (200 mg, 1.30 mmol) in DCM (2.6 mL) was cooled to 0 °C, and then oxalyl chloride (0.224 mL, 2.60 mmol) was added dropwise, followed by 1 drop of DMF. The mixture was stirred for 3 hours while being heated to room temperature. The reaction mixture was concentrated under reduced pressure to a yellow oil and dissolved in DCM to give 2 M 4-cyclopropyl-1,2,5- The diazole-3-carbonyl chloride solution can be used without further purification.

[0632] Step B: 4-Cyclopropyl-1,2,5- 2,5-Dioxopyrrolidone-1-yl diazon-3-carboxylic acid. N-hydroxysuccinimide (231 mg, 1.95 mmol), DCM (3.25 mL), and DIPEA (0.336 mL, 1.95 mmol) were added to a flask. The reaction mixture was cooled to 0 °C, and then 4-cyclopropyl-1,2,5- Diazole-3-carbonyl chloride (2M DCM solution, 0.649 mL, 1.30 mmol, step A). ​​The reaction mixture was stirred for 1 hour while being heated to room temperature. The reaction mixture was then washed successively with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The substance was purified by silica gel chromatography (0-100% (EtOAc containing 10% MeOH) / hexane) to give the title compound as a clear oil (39% yield). MS (ESI) m / z: [M+H] + The measured value is 252.2.

[0633] Intermediate 10: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine- 7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidine-2-one hydrochloride

[0634]

[0635] Step A: (5S)-3-azido-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. Evacuate the flask containing a solution of (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 tert-butyl ester (250 mg, 0.4 mmol, intermediate 3) in THF (8 mL) and refill three times with N2. The mixture was cooled to -78°C, and then a 1M LiHMDS solution in THF (2.0 mL, 2.0 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred at -78°C for 30 minutes. Then, a solution of TsN3 (390 mg, 1.98 mmol) in THF (1 mL) was added, followed by a solution of acetic acid (0.21 mL, 3.6 mmol) in THF (1 mL) after 2 minutes. The resulting mixture was stirred at -78°C for 30 minutes. The mixture was partitioned between a saturated aqueous solution of NH4Cl (30 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a yellow oil. The oil was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to give the title compound as a yellow solid (17% yield). MS (ESI) m / z:[M+H) + The measured value is 673.1.

[0636] Step B: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidine-2-one hydrochloride. The mixture of (5S)-3-azido-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 0.13 mmol, Step A) in DCM (3 mL) was cooled to 0°C in an ice-water bath, and then HCl (3.0 mL, 12 mmol, 4 M) was added dropwise over 2 minutes. (Alkane solution). The resulting mixture was stirred at room temperature for 12 hours, then concentrated to dryness to give the title compound as a white solid (88% yield). MS (ESI) m / z: [M+H] + The measured value is 473.4.

[0637] Intermediate 11: N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl (4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- diazole-3-carboxamide

[0638]

[0639] Step A: N-((1S)-(7-(((5S)-3-azido-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- Diazole-3-carboxamide. 4-Cyclopropyl-1,2,5- The mixture of diazon-3-carboxylic acid (50 mg, 0.32 mmol), EDCI (141 mg, 0.74 mmol), HOBt (65 mg, 0.48 mmol), and NMM (135 mL, 1.23 mmol) in DCM (3 mL) was stirred until homogeneous and then cooled to 0 °C in an ice-water bath. Then, a solution of (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidine-2-one hydrochloride (125 mg, 0.25 mmol, intermediate 10) in DCM (2 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0% to 80% EtOAc / petroleum ether) to give the title compound as a yellow solid (60% yield). MS (ESI) m / z: [M+H] + The measured value is 609.2.

[0640] Step B: N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- Diazole-3-carboxamide. Containing N-((1S)-(7-(((5S)-3-azido-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- The flask containing a mixture of diazole-3-carboxamide (90 mg, 0.15 mmol, step A) and 10 wt% Pd / C (45 mg, 0.042 mmol) in EtOAc (5 mL) was evacuated and refilled three times with H2. The resulting mixture was stirred at room temperature for 1 hour in H2 (approximately 3 atm). The reaction mixture was then filtered under vacuum, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (0–80% EtOAc / petroleum ether) to give the title compound as a white solid (81% yield). MS (ESI) m / z: [M+H] + The measured value is 583.3.

[0641] Intermediate 12: N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl (4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- diazole-3-carboxamide

[0642]

[0643] As described for the synthesis of intermediate 11, 4-methoxy-1,2,5- Diazol-3-carboxylic acid replaces 4-cyclopropyl-1,2,5- The title compound was prepared using diazon-3-carboxylic acid. MS (ESI) m / z: [M+H] + The measured value is 573.1.

[0644] Intermediate 13: N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl (4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- diazole-3-carboxamide

[0645]

[0646] As described for the synthesis of intermediate 11, 4-methyl-1,2,5- Diazol-3-carboxylic acid replaces 4-cyclopropyl-1,2,5- The title compound was prepared using diazon-3-carboxylic acid. MS (ESI) m / z: [M+H] + The measured value is 557.1.

[0647] Intermediate 14: N-((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridyl (azine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)-2-methoxyacetamide

[0648]

[0649] Step A: (5S)-3-amino-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. As described for the synthesis of intermediate 11, step B, (5S)-3-azido-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 10, step A) is used instead of N-((S)-(7-(((5S)-3-azido-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- The title compound was prepared using diazole-3-carboxamide (96% yield). MS (ESI) m / z: [M+H] + The measured value is 647.3.

[0650] Step B: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(2-methoxyacetamyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. As described in the synthesis for Example 6, (5S)-3-amino-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (step A) was used instead of N-((S)-(7-((((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- The title compound was prepared from diazole-3-carboxamide using 2-methoxyacetyl chloride instead of 1-fluorocyclopropane-1-carbonyl chloride. The residue was purified by silica gel chromatography (0-40% EtOAc / petroleum ether) to give the title compound as a white solid (74% yield). MS (ESI) m / z: [M+H] + The measured value is 719.2.

[0651] Step C: N-((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)-2-methoxyacetamide.

[0652] As described in step B of intermediate 1002, the title compound was prepared using (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(2-methoxyacetamido)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (step B) instead of (5S)-3-azido-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. The residue was purified by preparative HPLC (XBridge OBD C18, 5 μm, 150 × 30 mm, 14% to 41% ACN / H2O (containing 10 mM NH4HCO3 + 0.05% NH3)) to give the title compound as a single diastereomer, which was named the (3S) diastereomer as a white solid (59% yield). MS (ESI) m / z: [M+H] + The measured value is 519.2.

[0653] Intermediate 15: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine- methyl 7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate

[0654]

[0655] Step A: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl ester was prepared as described for the synthesis of intermediate 5, using methyl chloroformate instead of ethyl chloroformate. The residue was purified by silica gel chromatography (50% to 60% EtOAc / petroleum ether) to give the title compound as a brown solid (74% yield). MS (ESI) m / z: [M+H] + The measured value is 690.4.

[0656] Step B: Methyl (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. As described for the synthesis of intermediate 10, step B, the title compound (94% yield) was prepared using (5S)-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid tert-butyl ester (step A) instead of (5S)-3-azido-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester). MS (ESI) m / z: [M+H + The measured value is 490.2.

[0657] Intermediate 16: 2-Cyclopropoxyacetyl chloride

[0658]

[0659] The mixture of 2-cyclopropoxyacetic acid (50 mg, 0.43 mmol) in DCM (2 mL) was stirred until homogeneous and then cooled to 0 °C in an ice-water bath. Next, a solution of DMF (0.0033 mL, 0.043 mmol) in DCM (1 mL) was added, followed by a solution of (COCl)₂ (0.036 mL, 0.43 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour and used as the DCM solution in the next reaction.

[0660] Intermediate 17: N-((S)-(7-(((5S)-3-(aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl) (Methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- diazole-3-methyl amide

[0661]

[0662] Step A: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. A solution of (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 tert-butyl ester (500 mg, 0.79 mmol, intermediate 3) in THF (10 mL) was cooled to -78 °C, and then LiHMDS (4.0 mL, 4.0 mmol, 1 M THF solution) was added dropwise over 1 minute. The resulting mixture was stirred at -78 °C for 30 minutes, and then a solution of 2-(bromomethyl)isoindoline-1,3-dione (950 mg, 3.96 mmol) in THF (2 mL) was added. The reaction mixture was stirred at -78 °C for 30 minutes, and then a saturated NH4Cl aqueous solution (50 mL) was added dropwise over 10 minutes. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a colorless oil. The oil was purified by silica gel chromatography (0–30% EtOAc / petroleum ether) to provide the title compound as a white solid (70% yield). MS (ESI) m / z: [M+H] + The measured value is 791.3.

[0663] Step B: 2-(((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)isoindoline-1,3-dione hydrochloride. As described for the synthesis of intermediate 10, step B, the title compound (97% yield) was prepared using (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (step A) instead of (3R,5S)-3-azido-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. MS (ESI) m / z: [M+H] + The measured value is 591.3.

[0664] Step C: 4-Cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazol-3-carboxamide. 2-(((5S)-3-((2-(((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)isoindoline-1,3-dione hydrochloride (283 mg, 0.450 mmol, step B), 4-cyclopropyl-1,2,5- A mixture of lithium diazole-3-carboxylate (93 mg, 0.58 mmol), EDCI (277 mg, 1.44 mmol), HOBt (131 mg, 0.970 mmol), and NMM (0.26 mL, 2.4 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a yellow oil. The oil was purified by silica gel chromatography (60% to 70% EtOAc / petroleum ether) to give the title compound as a brown solid (58% yield). MS (ESI) m / z: [M+H] + The measured value is 727.2.

[0665] Step D: N-((S)-(7-(((5S)-3-(aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- Diazol-3-carboxamide. 4-Cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-((1,3-dioxoisoindololin-2-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- A mixture of diazole-3-carboxamide (550 mg, 0.76 mmol, step C) and N₂H₄•H₂O (187 mg, 3.66 mmol) in MeOH (15 mL) was stirred at room temperature for 30 min, then heated at 70 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a white solid. The solid was purified by silica gel chromatography (0% to 10% MeOH / DCM) to give the title compound as a white solid (49% yield). MS (ESI) m / z: [M+H] + The measured value is 597.2.

[0666] Intermediate 18: 2-((5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- diazole-3-carboxamido)(4,4-di- (Fluorocyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetic acid

[0667]

[0668] Step A: (5S)-3-((2-((S)-((tert-butyloxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(2-methoxy-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. The title compound was prepared using methyl bromoacetate instead of ethyl chloroformate, as described for the synthesis of intermediate 4. The residue was purified by silica gel chromatography (0% to 100% EtOAc (containing 10% MeOH) / hexane) followed by preparative HPLC on basic conditions (loaded with minimal DMF, XBridge C18, 5 mm, 50 × 250 mm, 10% to 100% MeCN / H2O (20 mMNH4OH)) to give the title compound as a brown solid (34% yield). MS (ESI) m / z: [M+H] + The measured value is 718.2.

[0669] Step B: Methyl 2-((5S)-3-((2-(((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetate. A solution of (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-(2-methoxy-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (434 mg, 0.62 mmol, Step A) in DCM (3 mL) was cooled to 0 °C in an ice-water bath, and then TFA (0.94 mL, 12.3 mmol) was added dropwise. The resulting solution was stirred at 0°C for 2 minutes, then the ice bath was removed, and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and then diluted with a 4:1 DCM:IPA and saturated NaHCO3 aqueous solution. The pH of the mixture was adjusted to approximately pH 11 by adding 1 M NaOH aqueous solution. The layers were then separated, and the aqueous layer was further extracted with 4:1 DCM:IPA (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound as an oil, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 518.2.

[0670] Step C: 2-((5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Methyl 2-((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetate was added to a solution of methyl 2-((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetate (310 mg, 0.62 mmol, step B) in ACN (1.7 mL). 2,5-dioxopyrrolidone-1-yl diazon-3-carboxylic acid (201 mg, 0.8 mmol, intermediate 9) and DIPEA (320 mL, 1.85 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. The residue was purified by silica gel chromatography (0% to 100% EtOAc (containing 10% MeOH) / hexane) to give the title compound (100% yield) as a pale yellow oil. MS (ESI) m / z: [M+H] +The measured value is 654.2.

[0671] Step D: 2-((5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Diazol-3-carbamate)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetic acid. To 2-((5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Methyl diazol-3-carbamate(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetate (330 mg, 0.52 mmol, step C) was reacted with LiOH (31 mg, 1.3 mmol) in 2.5 mL of THF:H₂O (4:1). The reaction was heated at 45 °C for 1 h, then another 25 mg, 1.03 mmol of LiOH was added, and the mixture was heated at 45 °C for 21 h. Then, 0.62 mL of 4 M HCl was added, and the mixture was concentrated and then azeotropically treated with THF to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 626.3.

[0672] Intermediate 19: (5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester

[0673]

[0674] A solution of (S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (2.0 g, 7.9 mmol, intermediate 2) in THF (30 mL) was added dropwise to a LiHMDS solution (15.8 mL, 1 M THF solution, 15.8 mmol) at -78 °C, and the resulting mixture was stirred at -78 °C for 1 h. Then, a solution of ethyl chloroformate (0.83 mL, 8.7 mmol) in THF (15 mL) was added dropwise to the reaction mixture at -78 °C. The mixture was heated to room temperature and maintained at room temperature for 1 h. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 60% EtOAc / hexane) to give the title compound (98% yield). MS (ESI) m / z: [(M-100)+H] + The measured value is 226.1.

[0675] Example

[0676] Example 1: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3S,5S)-3-((2,2-Difluoroethyl) (3-yl)carbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl (base)-1,2,5- diazole-3-carboxamide

[0677]

[0678] (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Diazol-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid (75 mg, 0.123 mmol, intermediate 6) was added to a solution of 2,2-difluoroethylamine (17.8 mL, 0.245 mmol), HATU (65.3 mg, 0.172 mmol), and DIPEA (84.5 mL, 0.491 mmol) in DMF (1.2 mL). After stirring at room temperature for 2 hours, additional 2,2-difluoroethylamine (14.3 mL, 0.196 mmol), HATU (60.6 mg, 0.159 mmol), and DIPEA (63.4 mL, 0.368 mmol) were added, and the reaction mixture was stirred at room temperature for another 30 minutes. The reaction mixture was filtered and directly purified by basic preparative HPLC (XBridge C18, 5 mm, 50 × 100 mm, 10% to 100% MeCN / H2O (20 mM NH4OH)) to give a mixture of diastereomers. The diastereomers were separated by chiral SFC (stationary phase: Whelk O1 SS, 5 mm, 250 × 21 mm, mobile phase: 20% methanol, 80% CO2). The first eluted isomer was the (3R) isomer, 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((3R,5S)-3-((2,2-difluoroethyl)carbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazole-3-carboxamide. A second eluting isomer was obtained in 36% yield, which was the major isomer, namely the (3S) isomer: 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-((2,2-difluoroethyl)carbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazole-3-carboxamide. 1H NMR (500MHz, DMSO-d6) δ 8.14 - 8.12 (m, 1H), 7.92 - 7.89 (m, 1H), 7.77 - 7.72 (m, 1H), 7.71 -7.69 (m, 1H), 7.52 (t, J = 6.0Hz, 1H), 6.10 - 6.02 (m, 1H), 6.01 - 5.96 (m,1H), 5.90 - 5.85 (m, 1H), 5.79 - 5.74 (m, 1H), 5.31 (dd, J = 8.0, 8.6Hz, 1H), 4.18 - 4.09 (m, 1H), 3.86 - 3.72 (m, 1H), 3.65 - 3.50 (m, 1H), 3.33 - 3.21(m, 3H), 2.61 - 2.56 (m, 1H), 2.25 - 2.13 (m, 3H), 2.14 - 2.06 (m, 1H), 2.05- 1.98 (m, 1H), 1.77 - 1.67 (m, 2H), 1.49 - 1.35 (m, 1H), 1.25 - 1.13 (m, 3H), 1.13 - 1.07 (m, 1H). MS (ESI) m / z: [M+H] + The measured value is 675.2.

[0679] Example 2: N-((S)-(4,4-difluorocyclohexyl)(7-(((3R,5S)-3-(2-methoxyacetamido)-2-oxo 5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-4-(1,1-difluoroethyl) (base)-1,2,5- diazole-3-carboxamide

[0680]

[0681] Add 4-(1,1-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)-2-methoxyacetamide (18 mg, 0.035 mmol, intermediate 14) to a solution of N-((5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)-2-methoxyacetamide (18 mg, 0.035 mmol, intermediate 14) in DCM (1 mL) A solution of diazon-3-carboxylic acid (9.89 mg, 0.055 mmol, intermediate 8) in EtOAc (0.5 mL) was added to the resulting mixture. 1-Propanephosphonic anhydride (0.062 mL, 0.104 mmol, 50 wt.% EtOAc solution) and DIPEA (0.036 mL, 0.208 mmol) were added, and the mixture was stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (0% to 100% EtOAc / hexane) to give the major isomer (19% yield) as the title compound. 1 H NMR (500MHz, DMSO-d6) δ 8.23 ​​-8.18 (m, 1H), 7.91 (s, 1H), 7.82 (d, J = 8.6Hz, 1H), 7.76 - 7.72 (m, 1H),6.98 - 6.94 (m, 1H), 6.40 (s, 1H), 5.35 - 5.28 (m, 1H), 4.40 - 4.32 (m, 1H), 3.92 - 3.88 (m, 2H), 3.42 - 3.36 (m, 4H), 3.14 (d, J = 14.3Hz, 1H), 2.84 (dd,J = 9.7, 14.9Hz, 1H), 2.50 (dd, J = 4.6, 14.9Hz, 1H), 2.28 - 2.13 (m, 5H), 2.12 - 2.04 (m, 1H), 1.99 (d, J = 12.3Hz, 1H), 1.85 - 1.66 (m, 3H), 1.60 -1.49 (m, 1H), 1.44 - 1.33 (m, 1H). MS (ESI) m / z: [M+H] + The measured value is 679.5.

[0682] Example 3: N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo 5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-4-(difluoromethyl)-1, 2,5- diazole-3-carboxamide

[0683]

[0684] Step A: (S)-N-((7-clomizolo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-(difluoromethyl)-1,2,5- Diazole-3-carboxamide. A solution of trimethylaluminum in THF (4.70 mL, 9.31 mmol, 2.0 M) was added dropwise to a solution of (S)-(7-chloroimidazolo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methylamine (1.40 g, 4.66 mmol) in THF (30 mL) over 10 minutes at 0 °C. The resulting solution was stirred at room temperature for 1 hour, then the reaction mixture was cooled to 0 °C, and 4-(difluoromethyl)-1,2,5- A solution of ethyl diazole-3-carboxylate (1.30 g, 6.98 mmol) in THF (15 mL). The resulting mixture was heated to 70 °C and stirred at this temperature for 16 h. The reaction was cooled to room temperature and quenched with IPA (10 mL), followed by quenching with MeOH (10 mL) and saturated Na₂SO₄ aqueous solution (20 mL), and stirred at room temperature for 30 min. The reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous MgSO₄, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0% to 100% EtOAc / hexane) to give the title compound (73% yield). MS (ESI) m / z: [M+H] + The measured value is 447.1.

[0685] Step B: (4S)-4-((tert-butoxycarbonyl)amino)-2-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- (S)-N-((7-chloroimidazolo[1,2-b]pyridazin-7-yl)methyl)-5,5,5-trifluorovaleric acid was added to vial (1). Diazon-3-carboxamide (500 mg, 1.12 mmol, step A) and methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (81.5 mg, 0.11 mmol). In a separate vial (2), (5S)-2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl)-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (660 mg, 1.68 mmol, intermediate 7) was added, and both vials were placed in a glove box. 1,4-di Alkane (5.6 mL) was added to vial (2), and the resulting solution was added to vial (1). Then, a solution of K₂CO₃ (464 mg, 3.36 mmol) in water (1.12 mL) was added. The vials were sealed and removed from the glove box. The reaction was heated to 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous MgSO₄, filtered, and concentrated to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 696.2.

[0686] Step C: (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- (4S)-4-((tert-butoxycarbonyl)amino)-2-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-) (Diazol-3-carbamoyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-5,5,5-trifluorovaleric acid (778 mg, 1.12 mmol, step B) was added to a solution of DCM (22 mL) with DIPEA (0.96 mL, 5.60 mmol), and the resulting mixture was stirred at room temperature for 5 min. HATU (745 mg, 1.96 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0% to 100% EtOAc / hexane) to give the title compound (57% yield). MS (ESI) m / z: [M+H] + The measured value is 678.2.

[0687] Step D: (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- Diazol-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester. Under a positive N2 atmosphere at -78°C, to (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- (300 mg, 0.44 mmol, step C) tert-butyl diazonium-3-carboxamido(methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate (300 mg, 0.44 mmol, step C) was added dropwise to a solution of LiHMDS in THF (0.97 mL, 1 M, 0.97 mmol). The resulting solution was stirred at -78 °C for 30 min. Then, ethyl chloroformate (0.055 mL, 0.58 mmol) in THF (2 mL) was added dropwise over 5 min at -78 °C. The reaction mixture was then warmed to room temperature for 1 h. A solution of AcOH in EtOAc (4 mL, 0.11 M) was added dropwise at 0 °C, followed by water (10 mL). The mixture was diluted with EtOAc (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0% to 70% EtOAc / hexane) to give the title compound (47% yield). MS (ESI) m / z: [M+H] + The measured value is 750.2.

[0688] Step E: N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(difluoromethyl)-1,2,5- Diazole-3-carboxamide. At room temperature, it is converted to (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- Diazol-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester (30 mg, 0.04 mmol, step D) was added to a solution of methylamine (60 µL, 0.12 mmol, 2.0 M THF) in THF (0.2 mL). The mixture was cooled to 0 °C and trimethylaluminum solution (4.7 mL, 9.3 mmol, 2.0 M THF) was added dropwise. The resulting solution was heated at 70 °C for 1.5 h. The reaction was cooled to room temperature and quenched with IPA (0.5 mL), followed by quenching with MeOH (0.5 mL) and saturated Na2SO4 aqueous solution (1 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through diatomaceous earth and the filtrate was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The resulting residue was purified twice by silica gel chromatography (0% to 100% EtOAc / hexane, followed by 0% to 5% MeOH / EtOAc) to give a mixture of diastereomers (90:10 dr). The diastereomers were separated by chiral SFC (stationary phase: Chiralcel Whelk O1 SS, 5 mm, 250 × 21 mm; mobile phase: 20% methanol (containing 0.2% diethylamine), 80% CO2). The first eluting isomer was designated as the (3R) isomer, N-((S)-(4,4-difluorocyclohexyl)(7-(((3R5R)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(difluoromethyl)-1,2,5- Diazole-3-carboxamide. The second eluting isomer, namely the title compound (N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(difluoromethyl)-1,2,5- Diazole-3-carboxamide is the main diastereomer in the mixture. 1H NMR (500MHz, MeOH-d4) δ 8.27 (d, J = 2.1Hz, 1H), 8.11 (s,1H), 7.78 (d, J = 2.0Hz, 1H), 7.33 (t, J = 52.4Hz, 1H), 5.26 (d, J = 8.6Hz,1H), 4.56 (s, 1H), 4.24 – 4.16 (m, 1H), 3.30 – 3.28 (m, 1H), 3.05 (dd, J =14.1, 8.6Hz, 1H), 2.77 (s, 3H), 2.25 (q, J = 10.9Hz, 1H), 2.16 – 1.97 (m,4H), 1.87 – 1.60 (m, 4H), 1.53 – 1.38 (m, 4H). MS (ESI) m / z: [M+H] + The measured value is 635.2.

[0689] Example 4: N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo 5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-4-(1,1-difluoroethyl) (base)-1,2,5- diazole-3-carboxamide

[0690]

[0691] Step A: (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(1,1-difluoroethyl)-1,2,5- Ethyl diazol-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. Add DIPEA (0.051 mL, 0.30 mmol) to a solution of (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (25 mg, 0.050 mmol, intermediate 5) in DCM (0.25 mL). Then add 4-(1,1-difluoroethyl)-1,2,5- A solution of diazon-3-carboxylic acid (15 mg, 0.084 mmol, intermediate 8) in ethyl acetate (0.25 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 min, and then T3P (0.089 mL, 0.15 mmol, 50 wt% EtOAc solution) was added in a single addition, and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated to dryness and purified by silica gel chromatography (0% to 100% (10% MeOH in EtOAc solution) / hexane) to give the title compound as a grayish-white solid (70% yield). MS (ESI) m / z: [M+H] + The measured value is 664.1.

[0692] Step B: (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(1,1-difluoroethyl)-1,2,5- Lithium (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(1,1-difluoroethyl)-1,2,5-) Ethyl diazonium-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (23 mg, 0.035 mmol, step A) was added in a single dose of solid LiOH (3.4 mg, 0.14 mmol) to a solution of THF (0.25 mL) and water (0.15 mL). The reaction mixture was stirred at room temperature for 45 minutes. The mixture was then concentrated to dryness to give the title compound as a white solid, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 636.1.

[0693] Step C: N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(1,1-difluoroethyl)-1,2,5- Diazole-3-carboxamide. (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(1,1-difluoroethyl)-1,2,5- Lithium diazonium-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (70.0 mg, 0.109 mmol, step B) was added to a solution of DMA (0.59 mL) with methylamine (2 M THF solution, 0.20 mL, 0.40 mmol), followed by the addition of TCFH (63.8 mg, 0.227 mmol). The resulting mixture was stirred at room temperature for 1 hour, and the reaction mixture was then directly purified by preparative HPLC (0% to 100% ACN / 20 mM NH4OH) to give the title compound as a mixture of diastereomers. The diastereomers were separated by chiral SFC (stationary phase: Whelk O1 SS, 5 mm, 250 × 21 mm, mobile phase: 20% methanol, 80% CO2). The first eluting isomer is the (3R) isomer, N-((S)-(4,4-difluorocyclohexyl)(7-(((3R,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(1,1-difluoroethyl)-1,2,5- Diazole-3-carboxamide. The title compound, as the second eluting isomer, the major isomer, and the (3S) isomer (38% yield), is N-((S)-(4,4-difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-(1,1-difluoroethyl)-1,2,5- Diazole-3-carboxamide. 1 H NMR(500MHz, MeOH-d4) δ 8.32 – 8.29 (m, 1H), 8.11 (s, 1H), 7.82 – 7.79 (m, 1H), 5.35 – 5.24 (m, 1H), 4.31 – 4.16 (m, 1H), 3.35 – 3.34 (m, 3H), 3.34 – 3.31(m, 2H), 3.15 – 3.01 (m, 1H), 2.80 (s, 3H), 2.32 – 1.95 (m, 5H), 1.91 – 1.72(m, 2H), 1.73 – 1.65 (m, 1H), 1.59 – 1.40 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 649.2.

[0694] Example 5: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3R,5S)-3-(N-methylacetamide)) )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-1,2,5- diazole-3-carboxamide

[0695]

[0696] Step A: 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(((E)-(dimethylamino)methylene)amino)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-1,2,5- Diazol-3-carboxamide. To N-((1S)-(7-((((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- A 1:1 ratio of DMF:DMA (3.0 mL) was added to diazole-3-carboxamide (100 mg, 0.137 mmol, intermediate 11), and the mixture was then evacuated and refilled with N2. The mixture was stirred until homogeneous and then heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness to give the title compound (73% yield) as a brown oil, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 638.2.

[0697] Step B: 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(methylamino)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazol-3-carboxamide. 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(((E)-(dimethylamino)methylene)amino)-2-oxo-5-(trifluoromethyl)pyrrolid-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazole-3-carboxamide (90.0 mg, 0.141 mmol, step A), Pd / C (40.0 mg, 10 wt%), and Pd(OH)₂ / C (40.0 mg, 20 wt%) were suspended in MeOH (5.0 mL) in a flask, which was then evacuated and refilled with hydrogen. The resulting mixture was stirred at room temperature for 1 hour under hydrogen at one atmosphere. The reaction mixture was then filtered through a diatomaceous earth mat, and the filtrate was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a white solid. The solid was purified by silica gel chromatography (0% to 6% MeOH / DCM) to give the title compound as a white solid (13% yield). MS (ESI) m / z: [M+H] + The measured value is 597.3.

[0698] Step C: 4-Cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(N-methylacetamido)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazol-3-carboxamide. 4-Cyclopropyl-N-((1S)-(4,4-difluorocyclohexyl)(7-(((5S)-3-(methylamino)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- A mixture of diazole-3-carboxamide (20 mg, 0.034 mmol, step B) and NMM (10 mL, 0.091 mmol) in DCM (2 mL) was cooled to 0 °C in an ice-water bath. Acetyl chloride (4 mL, 0.056 mmol) was then added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (3 × 1 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give a yellow oil. The oil was purified by preparative HPLC (XSelectCSH C18, 5 μm, 250 × 19 mm, 32% to 57% ACN / H₂O (containing 0.1% FA)) to give the title compound (white solid), which was the major isomer (17% yield). 1H NMR (400MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.66(br s, 1H), 8.32 (d, J = 1.5Hz, 1H), 8.21 – 8.20 (m, 1H), 7.91 (d, J = 1.2Hz,1H), 5.22 – 5.20 (m, 1H), 4.17 – 4.10 (m, 1H), 3.24 – 3.21 (m, 2H), 3.03 (s,3H), 2.45 – 2.39 (m, 1H), 2.29 – 2.14 (m, 3H), 2.07 – 2.03 (m, 5H), 1.86 –1.72 (m, 3H), 1.61 – 1.58 (m, 1H), 1.43 – 1.23 (m, 2H), 1.12 – 1.08 (m, 2H), 0.97 – 0.93 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 639.2.

[0699] Example 6: N-((S)-(4,4-difluorocyclohexyl)(7-(((3R,5S)-3-(1-fluorocyclopropane-1-carboxamide)) )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-4-methoxy Base-1,2,5- diazole-3-carboxamide

[0700]

[0701] N-((1S)-(7-((((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- A mixture of diazole-3-carboxamide (25 mg, 0.044 mmol, intermediate 12), 1-fluorocyclopropane-1-carbonyl chloride (9.5 mg, 0.078 mmol), and NMM (15 mL, 0.14 mmol) in DCM (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was then quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (XBridge OBD C18, 5 μm, 150 × 30 mm, 29% to 59% ACN / H₂O (containing 10 mM NH₄HCO₃)) to give the title compound (white solid), which was the major isomer (49% yield). 1H NMR(400MHz, DMSO-d6) δ 9.33 (br s, 1H), 8.90 (br s, 1H), 8.71 (br s, 1H), 8.33(d, J = 2Hz, 1H), 8.20 (s, 1H), 7.97 (d, J = 1.6Hz, 1H), 5.17 – 5.15 (m, 1H),4.31 – 4.26 (m, 1H), 4.08 (s, 3H), 3.21 – 3.15 (m, 2H), 2.48 – 2.44 (m, 1H),2.33 – 2.19 (m, 2H), 2.18 – 2.02 (m, 2H), 1.99 – 1.70 (m, 3H), 1.64 – 1.58 (m, 1H), 1.38 – 1.34 (m, 3H), 1.30 – 1.22 (m, 1H), 1.21 – 1.13 (m, 2H). MS(ESI) m / z: [M+H] + The measured value is 659.1.

[0702] With a similar structure to N-((S)-(4,4-difluorocyclohexyl)(7-(((3R,5S)-3-(1-fluorocyclopropane-1-carbamate)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-4-methoxy-1,2,5- In the manner of diazole-3-carboxamide (Example 6), a suitable formate chloride is used instead of 1-fluorocyclopropane-1-carbonyl chloride, and a suitable amine is used instead of N-((1S)-(7-(((5S)-3-amino-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methoxy-1,2,5- The examples shown in Table 1 were prepared using diazole-3-carboxamide, as described in Table 2.

[0703]

[0704] Table 2 :

[0705]

[0706] Example 7. Further 2D-NMR analysis confirmed the absolute configuration of Example 7, as shown below: A stronger NOESY correlation was observed between the methylene proton 33a and the methylene proton 32b when compared to the NOESY correlation between protons 33a and 32a, confirming that protons 33a and 32b are on the same side of the lactam ring. A critical NOESY correlation was observed between the amine proton at the N-36 position and the methylene proton 32b, confirming that protons 33a and 32b, as well as the N-36 proton, are on the same side of the lactam ring. A NOESY correlation was also observed between methylene protons 30a, 30b, and 32a, confirming that the C-30 side chain is on the same side of the lactam ring as proton 32a, opposite to the side of protons 33a, 32b, and N-36. These correlations confirm the relative cis stereochemistry between the C-30 and C-39 side chains.

[0707] Example 10. Further 2D-NMR analysis confirmed the absolute configuration of Example 10, as shown below: A key HOESY correlation was observed from the CF3 group at C-33 to the methylene protons 32a and 32b, with a stronger HOESY correlation between the CF3 group and 32a, confirming that the CF3 group and proton 32a are on the same side of the lactam ring. A key NOESY correlation was observed between protons 33a and 32b, confirming that they are on the same side of the lactam ring, opposite to the side of the CF3 group and proton 32a. Further NOESY correlations were observed between proton 32a and the methylene protons 51 and 52, confirming that the C-30 side chain and proton 32a are on the same side of the lactam ring. These correlations confirm the relative cis stereochemistry between the C-30 and C-42 side chains.

[0708] Example 11. Further 2D-NMR analysis confirmed the absolute configuration of Example 11, as shown below: A key NOESY correlation was observed between the amine protons at positions 33a (methylene proton), 32b (methylene proton), and N-36, confirming that all three protons are on the same side of the lactam ring. Another key NOESY correlation was observed between the methylene protons 30a and 30b and the methylene proton 32a, confirming that the C-30 side chain and proton 32a are on the same side of the lactam ring, opposite to the side of protons 33a, 32b, and the N-36 proton. These correlations confirm the relative cis stereochemistry between the C-30 and C-40 side chains.

[0709] Example 13. Further 2D-NMR analysis confirmed the absolute configuration of Example 13, as shown below: As shown above, a key NOESY correlation was observed between proton 32a and methylene protons 30a and 30b, confirming that the C-30 side chain and proton 32a are on the same side of the lactam ring. Stronger NOE correlations between protons 33a and 32b, and between proton 32b and the amine proton at the N-36 position, confirm that protons 33a, 32b, and the N-36 side chain are all on the same side of the lactam, opposite to the side of the C-30 side chain and proton 32a. These correlations confirm the relative trans stereochemistry between the C-30 and C-39 side chains.

[0710] Example 15. Further 2D-NMR analysis confirmed the absolute configuration of Example 15, as shown below: Key NOESY correlations were observed between the methylene proton 37a and the methylene protons 36a and 36b, as well as between the proton at the C-4 position and protons 36a and 36b. Proton 36b showed a stronger NOE correlation with the corresponding protons 37a and at the C-4 position compared to proton 36a, confirming that protons 37a, 36b, and the C-4 side chain are all on the same side of the lactam ring. Further key NOESY correlations were observed between the methylene proton 37a and the proton at the C-4 position, further confirming their shared position on the lactam ring. Key NOESY correlations were also observed between the methylene protons 6a and 6b and the methylene proton 36a, confirming that proton 36a and the C-6 side chain are on the same side of the lactam ring, opposite to the C-4 side chain and the proton 37a side chain. These correlations confirm the relative cis stereochemistry between the C-6 and C-43 side chains.

[0711] Example 16: N-((S)-(7-(((3S,5S)-3-carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidine- 3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- diazole- 3-Formamide .

[0712]

[0713] Step A: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-cyano-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. Add (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 tert-butyl ester (700 mg, 1.11 mmol, intermediate 3) and THF (5 mL) to a flask, then evacuate the flask and refill it three times with N2. The solution was cooled to -78°C, and then LiHMDS (3.3 mL, 3.3 mmol, 1 M THF solution) was added dropwise over 5 minutes. The resulting mixture was stirred at -78°C for 50 minutes, and then 3-oxo-1,2-benzodiazepine-1-(3H)-formonitrile (605 mg, 2.22 mmol) in 5 mL THF solution was added dropwise over 5 minutes. The resulting mixture was warmed to -20°C for 10 minutes, and then stirred at -20°C for 4 hours. The pH of the reaction mixture was then adjusted to pH 4–5 by adding HOAc (0.1 M EtOAc solution). The mixture was diluted with 50 mL EtOAc and washed with saturated NH4Cl aqueous solution (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give a yellow oil. The oily substance was purified by silica gel chromatography (50% to 60% EtOAc / petroleum ether) to give the title compound as a yellow solid (34% yield). MS (ESI) m / z: [M+H] + The measured value is 657.4.

[0714] Step B: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. A mixture of (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-cyano-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.305 mmol, Step A), Perkin catalyst (6.5 mg, 0.015 mmol), EtOH (5 mL) and H2O (1 mL) was heated at 100 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness to give a yellow oil. The oil was purified by silica gel chromatography (30% to 60% EtOAc / petroleum ether) to give the title compound as a yellow solid (82% yield). MS (ESI) m / z: [(M-100)+H] + The measured value is 575.3.

[0715] Step C: (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxamide dihydrochloride.

[0716] As described for the synthesis of intermediate 10, step B, the title compound (94% yield) was prepared using (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (step B) instead of (5S)-3-azido-3-((2-(((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester). MS (ESI) m / z: [M+H + The measured value is 475.2.

[0717] Step D: N-((S)-(7-(((5S)-3-carbamoyl-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- Diazol-3-carboxamide. As described for the synthesis of intermediate 11, step A, (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxamide dihydrochloride (step C) is used instead of (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-3-azido-5-(trifluoromethyl)pyrrolidine-2-one hydrochloride and 4-cyclopropyl-1,2,5- Lithium diazole-3-carboxylate replaces 4-cyclopropyl-1,2,5- The title compound was prepared from diazon-3-carboxylic acid. The residue was purified by preparative HPLC (XBridge Prep OBD C18, 5 μm, 150 × 30 mm, 34% to 50% ACN / H2O (containing NH4HCO3 + 0.05% NH3)) to give the title compound (white solid), which was the major isomer (28% yield). 1 H NMR (300MHz, DMSO-d6)δ 9.48 (d, J = 9.0Hz, 1H), 9.01 (s, 1H), 8.36 (d, J = 1.8Hz, 1H), 8.22 (s,1H), 7.89 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 5.22 – 5.16 (m, 1H), 4.27 –4.25 (m, 1H), 3.17 – 3.12 (m, 1H), 2.90 – 2.83 (m, 1H), 2.50 – 2.30 (m, 3H), 2.07 – 1.87 (m, 5H), 1.81 – 1.54 (m, 2H), 1.45 – 1.33 (m, 1H), 1.31 – 1.21 (m, 1H), 1.15 – 1.06 (m, 2H), 0.99 – 0.91 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 611.2.

[0718] Example 17: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3S,5S)-3-(methylcarbamoyl) )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-1,2,5- diazole-3-carboxamide .

[0719]

[0720] (3R,5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- The mixture of diazon-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid (50 mg, 0.082 mmol, intermediate 6), methylamine hydrochloride (7 mg, 0.1 mmol), EDCI (47 mg, 0.25 mmol), HOBt (22 mg, 0.16 mmol), and NMM (41 mg, 0.41 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give a yellow oil. The oily substance was purified by preparative HPLC (SunFire C18 OBD, 5 μm, 250 × 19 mm, 37% to 67% ACN / H2O (containing 0.1% FA)) to give the title compound as a white solid, which was the major isomer (42% yield). 1 H NMR (300MHz, DMSO-d6) d 9.50 (d, J = 9.0Hz, 1H), 9.02(s, 1H), 8.30 (d, J = 1.8Hz, 1H), 8.22 (s, 1H), 7.86 - 7.82 (m, 2H), 5.22 -5.17 (m, 1H), 4.30 - 4.23 (m, 1H), 3.30 (s, 1H), 3.14 (d, J = 14.1Hz, 1H), 2.93 - 2.86 (m, 1H), 2.63 (d, J = 4.5Hz, 3H), 2.30 - 2.25 (m, 2H), 2.08 -1.87 (m, 5H), 1.78 - 1.58 (m, 2H), 1.45 - 1.22 (m, 2H), 1.14 - 1.08 (m, 2H), 0.98 - 0.93 (m, 2H). MS (ESI) m / z: [M+H] + The measured value was 625.2. Further 2D-NMR analysis confirmed the absolute configuration of Example 17, as shown below: The observed NOESY correlation between the methylene proton 25 and proton 31b is stronger than that between protons 35 and 31a, confirming that protons 25 and 31b are on the same side of the lactam ring. Further key NOESY correlations were observed between the methylene proton 31a and protons 46 and 47 at the C-10 position, confirming that the methylene proton 31a and the C-10 side chain are on the same side of the lactam ring, opposite to the side of protons 25 and 31b. These correlations confirm the relative cis stereochemistry between the C-10 and C-27 side chains.

[0721] Example 18: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3S,5S)-2-oxo-5-(trifluoro) methyl)-3-(ureomethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-1,2,5- diazole- 3-Formamide .

[0722]

[0723] N-((S)-(7-(((3S,5S)-3-(aminomethyl)-2-oxo-5-(trifluoromethyl)pyrrolidone-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-cyclopropyl-1,2,5- A mixture of diazole-3-carboxamide (57 mg, 0.096 mmol, intermediate 17), TEA (36 mL, 0.26 mmol), and trimethylsilyl isocyanate (15 mg, 0.13 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give a white solid. The solid was purified by preparative HPLC (XSelect CSH C18, 5 mm, 150 × 19 mm, 35% to 51% ACN / H2O (containing 0.1% FA)) to give the title compound (white solid), which was the major isomer (16% yield). 1HNMR (300MHz, DMSO-d6) d 9.49 (br s, 1H), 8.75 (br s, 1H), 8.32 (d, J = 1.8Hz,1H), 8.21 (s, 1H), 7.89 (d, J = 1.5Hz, 1H), 6.24 - 6.19 (m, 1H), 5.62 (br s,2H), 5.22 - 5.17 (m, 1H), 4.17 - 4.06 (m, 1H), 3.28 - 3.26 (m, 1H), 3.22 -3.05 (m, 1H), 2.95 - 2.90 (m, 1H), 2.79 - 2.74 (m, 1H), 2.38 - 2.23 (m, 2H),2.22 - 2.16 (m, 1H), 2.07 - 1.96 (m, 2H), 1.88 - 1.80 (m, 3H), 1.76 - 1.70(m, 1H), 1.64 - 1.57 (m, 1H), 1.45 - 1.22 (m, 2H), 1.15 - 1.06 (m, 2H), 0.97- 0.92 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 640.1.

[0724] Example 19: N-[(S)-[7-[[(3S,5S)-3-(cyclopropylcarbamoyl)-2-oxo-5-(trifluoromethyl) [pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]-4-(difluoromethyl)- 1,2,5- diazole-3-carboxamide .

[0725]

[0726] Step A: (3R,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- Diazol-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid ethyl ester. (5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- (Diazol-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester (30 mg, 0.04 mmol, Example 3, step D) and TFA (0.306 mL, 4.0 mmol) in DCM (0.8 mL) were stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 650.8.

[0727] Step B: (3R,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- Lithium (3R,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5-) Ethyl diazonium-3-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (26 mg, 0.040 mmol, step A) was prepared by adding LiOH (6 mg, 0.2 mmol) to a mixture of anhydrous THF (0.8 mL) and water (8 mL, 0.4 mmol). The resulting mixture was stirred at room temperature for 2 hours, and then additional LiOH (3 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 622.0.

[0728] Step C: N-[(S)-[7-[[(3S,5S)-3-(cyclopropylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl]methyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]-4-(difluoromethyl)-1,2,5- Diazole-3-carboxamide. To (3R,5S)-3-((2-((S)-(4,4-difluorocyclohexyl)(4-(difluoromethyl)-1,2,5- Lithium (25.1 mg, 0.04 mmol, step B) was added to a mixture of anhydrous N,N-dimethylacetamide (0.8 mL) with cyclopropylamine (8.3 mL, 0.12 mmol) and TCFH (22.5 mg, 0.080 mmol). The resulting mixture was stirred at room temperature for 3 hours, and then additional TCFH (25 mg, 0.089 mmol) and cyclopropylamine (10 mL, 0.14 mmol) were added. The reaction mixture was stirred at room temperature overnight. Additional TCFH (20 mg, 0.07 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified directly by preparative HPLC (10% to 100% MeCN (0.05% TFA) in H2O (0.05% TFA) solution). The major isomer obtained was the TFA salt of the title compound. The white TFA salt was then dissolved in MeOH and filtered through an alkaline silica gel column to give the title compound as a white solid in its free base form (30% yield). 1 H NMR (400MHz,MeOH-d4) d 8.36 (d, J = 2.0Hz, 1H), 8.19 (s, 1H), 7.85 – 7.82 (m, 1H), 7.33(t, J = 52.4Hz, 1H), 5.27 (d, J = 8.6Hz, 1H), 4.28 – 4.18 (m, 1H), 3.35 –3.34 (m, 2H), 3.10 – 3.01 (m, 1H), 2.68 – 2.62 (m, 1H), 2.32 – 2.22 (m, 1H),2.15 – 2.00 (m, 4H), 1.88 – 1.62 (m, 3H), 1.54 – 1.37 (m, 2H), 0.75 – 0.69 (m, 2H), 0.55 – 0.45 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 661.0.

[0729] Example 20: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3S,5S)-3-(2-(dimethylamino)) (3-yl)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl (base)-1,2,5- diazole-3-carboxamide .

[0730]

[0731] 2-((3S,5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Diazol-3-carboxamido)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)acetic acid (100 mg, 0.16 mmol, intermediate 18) was added to a solution of dimethylamine (0.13 mL, 0.26 mmol, 2 M MeOH solution) and DIPEA (0.083 mL, 0.48 mmol) in DMF (1.5 mL), and the resulting mixture was stirred at room temperature for 5 minutes. Then, HATU (79 mg, 0.21 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Further addition of dimethylamine (0.13 mL, 0.26 mmol, 2 M MeOH solution), DIPEA (0.083 mL, 0.48 mmol), and HATU (79 mg, 0.21 mmol) was made, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, subjected directly to preparative basic HPLC (10% to 100% ACN / water (containing 20 mM NH4OH)) and lyophilized. The lyophilized material was purified by SFC (stationary phase: Whelk O1 SS, 5 mm, 250 × 21 mm, mobile phase: 30% ((1:1) methanol:IPA (containing 0.2% isopropylamine)), 70% CO2) to give the title compound, which was the major isomer (49% yield). 1H NMR (500MHz, CDCl3) d 8.20 (d, J = 2.1Hz, 1H), 7.89 (s, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.73 (d, J = 1.8Hz, 1H), 5.80 (s, 1H), 5.34 - 5.29 (m,1H), 4.38 - 4.29 (m, 1H), 3.11 (d, J = 14.0Hz, 1H), 3.01 (s, 3H), 2.93 (s,3H), 2.92 - 2.90 (m, 1H), 2.62 - 2.58 (m, 2H), 2.52 (dd, J = 9.8, 14.1Hz,1H), 2.23 - 2.16 (m, 2H), 2.11 - 2.05 (m, 1H), 2.01 (d, J = 14.4Hz, 1H), 1.72- 1.65 (m, 2H), 1.35 (s, 2H), 1.28 (br s, 2H), 1.22 (d, J = 6.1Hz, 2H), 1.20-1.17 (m, 1H), 1.17-1.14 (m, 1H), 1.12-1.07 (m, 1H). MS (ESI) m / z: [M+H] + The measured value was 653.2. Further 2D-NMR analysis confirmed the absolute configuration of Example 20, as shown below: A key HOESY correlation was observed between the CF3 group at the C-33 position and the methylene proton 32a, confirming that the CF3 group and proton 32a are on the same side of the lactam ring. A key NOESY correlation was observed between protons 33a, 32b, and the proton at the C-36 position, confirming that protons 33a and 32b, as well as the C-36 side chain, are on the same side of the lactam ring, opposite to the side of the CF3 group and proton 32a. Further NOESY correlations were observed between protons 32a, 30a, and 30b, confirming that the C-30 side chain and proton 32a are on the same side of the lactam ring. These correlations confirm the relative cis stereochemistry between the C-30 and C-39 side chains.

[0732] Example 21: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3R,5S)-3-(methylcarbamoyl) )-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazine-2-yl)methyl)-1,2,5- diazole-3-carboxamide .

[0733]

[0734] Step A: (5S)-3-((2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester. (S)-((7-(bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate (106 mg, 0.230 mmol, intermediate 1) and (5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl)3-ethyl ester (74.7 mg, 0.230 mmol, intermediate 19) were dissolved in DMF (1 mL), and then K2CO3 (47.6 mg, 0.350 mmol) was added in a single addition. The reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was then diluted with brine (3 mL) and extracted with EtOAc (4 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 704.2.

[0735] Step B: Ethyl (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. 1-(tert-butyl)3-ethyl (5S)-3-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-1,3-dicarboxylic acid (161 mg, 0.230 mmol, Step A) was dissolved in DCM (0.5 mL), followed by a one-time addition of TFA (1.5 mL, 19.6 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated and azeotropically reacted with acetonitrile to give the title compound, which was used without further purification. MS (ESI) m / z: [M+H] + The measured value is 504.2.

[0736] Step C: (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Ethyl diazol-3-carboxamido(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. Add 4-cyclopropyl-1,2,5-dihydroxy(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (115 mg, 0.230 mmol, step B) in a single step to a solution of ethyl (5S)-3-((2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (115 mg, 0.230 mmol, step B) in acetonitrile (0.5 mL) and DIPEA (0.3 mL, 1.74 mmol). 2,5-dioxopyrrolidine-1-yl diazon-3-carboxylic acid (68.9 mg, 0.270 mmol, intermediate 9). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then concentrated, and the yellow residue was purified by silica gel chromatography (0% to 100% EtOAc / hexane) to give the title compound as a white solid (73% yield). MS (ESI) m / z: [M+H] + The measured value is 640.2.

[0737] Step D: (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5- Lithium diazonium-3-carboxamido(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate. (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-) Ethyl diazol-3-carboxamido(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (107 mg, 0.170 mmol, step C) was added in a single addition of LiOH (13.6 mg, 0.57 mmol) to a mixture of THF (1 mL) and water (0.21 mL), and the resulting mixture was stirred at room temperature for 3 hours. Then, an additional 5.6 mg, 0.23 mmol of LiOH was added, and the reaction mixture was stirred at room temperature for 19 hours. The reaction was then concentrated and azeotropically reacted with THF to give the title compound as a white solid, which was used directly without further purification. MS (ESI) m / z: [M+H] + The measured value is 612.2.

[0738] Step E: 4-Cyclopropyl-N-((S)-(4,4-Difluorocyclohexyl)(7-(((3R,5S)-3-(methylcarbamoyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1,2,5- Diazole-3-carboxamide. (5S)-3-((2-((S)-(4-cyclopropyl-1,2,5-) Lithium diazon-3-carboxamido(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (84 mg, 0.14 mmol, step D) was added in a single addition of methylamine (2 M THF solution, 0.69 mL, 1.38 mmol) to a solution in anhydrous DMA (1.0 mL), followed immediately by a single addition of TCFH (95 mg, 0.34 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, concentrated, and the residue was purified by preparative HPLC (XBridge C18, 5 µm, 100 × 50 mm, 0% to 100% MeCN / H2O (20 mM NH4OH)). The diastereomers were separated by chiral SFC (stationary phase: Chiralpak IB N3, 5 mm, 250 × 30 mm; mobile phase: 20% MeOH (containing 0.2% diethylamine), 80% CO2) to obtain the title compound, which is the major isomer and the second eluting isomer (19% yield). 1 H NMR (400MHz, MeOH-d4) δ8.31 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.87 – 7.80 (m, 1H), 7.80 – 7.71 (m,1H), 5.27 (d, J = 8.6Hz, 1H), 4.15 – 4.05 (m, 1H), 3.27 – 3.25 (m, 2H), 2.86 – 2.80 (m, 1H), 2.80 – 2.76 (m, 3H), 2.54 – 2.46 (m, 1H), 2.44 – 2.37 (m,1H), 2.29 – 1.99 (m, 5H), 1.89 – 1.65 (m, 3H), 1.56 – 1.32 (m, 3H), 1.18 –1.11 (m, 2H), 1.07 – 1.01 (m, 2H). MS (ESI) m / z: [M+H] + The measured value is 625.2.

[0739] In vitro biological data

[0740] IL-17A (FLAG-labeled): IL-17RA (His-labeled) binds to interrupt Eu-HTRF assays

[0741] An antibody targeting a FLAG tag for IL-17A (as described in SEQ ID NO:1 in U.S. Patent No. 11,691,979) is labeled with an HTRF donor chromophore (europium-cavitation compound). IL-17A exists as a dimer, which is “locked” into this quaternary structure by forming an intramolecular disulfide bridge across the ring. The construct of IL-17RA used in the assay does not include the outer membrane portion of the receptor and is fused with a C-terminal 10xHis tag (as described in SEQ ID NO:2 in U.S. Patent No. 11,691,979). An antibody targeting the His tag of the IL-17RA chimera is labeled with an HTRF receptor chromophore (“D2”). Fluorescence resonance energy transfer (FRET) depends on the proximity of the donor chromophore to the receptor, and disruption of binding between IL-17A and IL-17RA causes a reduction / loss of FRET. Therefore, this assay allows for the evaluation of the compound's effect on the binding of IL-17A and IL-17RA by monitoring the fluorescence intensity of the donor and acceptor. The assay is performed as described below.

[0742] 40 nL of a serially diluted compound solution (22 dilution points in total) was added to each well of a 1536-well white small-volume unbound plate (Greiner #782904). Then, 2 μL of FLAG-labeled IL-17A at a final concentration of 2× (1 nM) in PBS + 0.01% Triton-X100 solution was added to each well. The plate was briefly centrifuged and then incubated at room temperature for 1 h. A mixed solution containing 2×5 nM 10HIS×IL-17RA, 2×2.5 nM Eu-anti-FLAG (CISBIO), and 2×5 nM D2-anti-HIS (CISBIO) in PBS + 0.01% Triton-X100 + 200 mM potassium fluoride (Sigma 60238) was prepared and 2 μL of the mixture was added to each well of the plate. The plate was briefly centrifuged and then incubated at room temperature for 2 h. HTRF intensities at donor (615 nm) and acceptor (665 nm) wavelengths were measured using the BMG Pherastar. The ratio between the intensities at the two wavelengths was calculated and plotted against compound concentration. The data were then fitted to a unit-point competition model to generate the IC50 of the compound. 50 .

[0743] IL-17A acts directly on keratinocytes by binding to the dimer receptor IL-17RA / RC and drives the production of many inflammatory mediators known to be elevated in psoriatic lesions. Small molecule inhibitors of IL-17A that block the interaction between IL-17A and IL-17R inhibit IL-17A signaling in their target cells, such as keratinocytes. The effects of compound functional activity on IL-17A-induced G-CSF production in normal human keratinocytes (NHK) were evaluated.

[0744] NHK Measurement

[0745] Normal adult keratinocytes were cultured in keratinocyte growth medium (Lonza) in flasks until approximately 90% confluence was achieved, and then transferred to 384-well plates at a density of 3000–4000 cells / well. Recombinant human IL-17A (Gibco PHC9174) was pre-incubated with titrated compound or DMSO at room temperature for 1 h before being added to the cell culture plates. The final concentration of IL-17A was 5 ng / mL in a culture containing 5% FBS, and the final concentration of DMSO was 0.2%. Cells were cultured / treated at 37°C for 24 h. The supernatant was collected, and G-CSF production was measured using a human G-CSF kit (CisBio) via HTRF technology. G-CSF concentrations were extrapolated from the standard curve, and IC50 was calculated. 50 Cell viability was determined using GraphPad Prism. Cell viability was also assessed using the CellTiter-Glo kit (Promega), and the effects of the compounds on cell viability were compared to the DMSO control.

[0746] When a compound is tested more than once, IC 50 The value is calculated as a simple average of the measured values. This average is then used to classify the compound into one of the following ranges.

[0747] A: IC 50 <0.1mM;

[0748] B: 0.1mM ≤IC 50 ≤ 1.0mM;

[0749] C:IC 50 > 1mM

[0750] -not applicable

[0751] Table 3

[0752]

[0753] Table 4

[0754]

[0755] As shown in Table 4, unexpectedly and surprisingly, Example 17, with the (S)-configuration at the C-3 position, showed an increase of over 150-fold in HTRF potency and over 265-fold in NHK potency compared to its C-3 diastereomer, Example 21, which has the (R)-configuration at the C-3 position. This unexpected and surprising result demonstrates the significantly higher potency of the compounds of Formula I-1 as described and provided herein. It has the absolute configuration of the C-3 carbon adjacent to the carbonyl group of the lactam ring as shown herein (e.g., the (S)-configuration of the C-3 carbon in Example 17). Furthermore, Example 17, as a cis isomer, wherein the CF3 side chain at the C-5 position and the C-6 side chain at the C-3 position are on the same side of the lactam ring as described above, showed an unexpected and surprising increase in potency of over 150 times when compared with its corresponding trans isomer, Example 21 (where the CF3 side chain at the C-5 position and the C-6 side chain at the C-3 position are on opposite sides of the lactam ring), as described above. This unexpected and surprising result demonstrates the significantly higher potency of the compounds of formula Ib-1: Compounds of formula Ia-3 as described and provided herein, including but not limited to. It contains a cis configuration as shown in this paper, wherein R at position C-5 1 The side chain (e.g., -CF3) and the C-6 side chain at the C-3 position are on the same side of the lactam ring.

[0756] While the foregoing description teaches the principles of this disclosure and provides examples for illustrative purposes, it should be understood that the practice of the compounds and methods disclosed herein encompasses all conventional variations, alterations, and / or modifications falling within the scope of the appended claims and their equivalents.

[0757] Any and all journal articles, patent applications, granted patents, or other cited references in this article are incorporated in their entirety by reference.

Claims

1. A compound having the formula (I), (I-1), or (I-2): , or Or its pharmaceutically acceptable salt, in: Each R 1 Independently for those not replaced or by one to six R 1a -C substituent (1-3) alkyl; Each R 1a Independently halogenated; R 2 for or ; R 3 -C is either unsubstituted or substituted with one to six halogen atoms. (3-8) cycloalkyl; R 4 It is either not replaced or replaced by one or two Rs. 4a Five-membered heteroaryl groups substituted with functional groups; Each R 4a Independently for -C (1-6) Alkyl, -OC (1-6) Alkyl or -C (0-2) Alkyl-C (3-6) cycloalkyl, wherein the -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 one to six halogen atoms; R 5 H, -C (1-3) Alkyl or -C (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 5a Group substitution; Each R 5a Independently halogenated; R 6 H or -C (1-3) alkyl; R 7 H or -C (1-3) alkyl; R 8 For NH2, -C (1-3) Alkyl, -C (3-5) cycloalkyl, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl, wherein the -C (1-3) Alkyl and -C (3-5) Cycloalkyl groups are unsubstituted or have one to six R groups. 8a Group substitution; Each R 8a Independently halogenated, -OC (1-3) Alkyl or -OC (3-5) cycloalkyl; Each m is independently 0, 1, or 2; and Each n is independently 0 or 1.

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

3. The compound according to claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound having formula (Ib), formula (Ib-1), or formula (Ib-2). , or .

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 -C(R) 1a 3.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia-3). 。 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 for .

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein n is 0.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 5 For -CH3 and R 6 For H.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 for 。 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 for 。 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 4a for .

12. A compound, said compound being selected from the group consisting of: Or its pharmaceutically acceptable salt.

13. The compound of claim 12, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

14. The compound of claim 12, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

15. The compound of claim 12, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

16. The compound of claim 12, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

17. A compound, said compound being selected from the group consisting of: Or its pharmaceutically acceptable salt.

18. A pharmaceutical composition comprising at least one compound according to claims 1 to 17 or a pharmaceutically acceptable salt thereof.

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

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

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