WO2023049886A1 - Imidazopyridazine il-17 inhibitor compounds - Google Patents

Imidazopyridazine il-17 inhibitor compounds Download PDF

Info

Publication number
WO2023049886A1
WO2023049886A1 PCT/US2022/077000 US2022077000W WO2023049886A1 WO 2023049886 A1 WO2023049886 A1 WO 2023049886A1 US 2022077000 W US2022077000 W US 2022077000W WO 2023049886 A1 WO2023049886 A1 WO 2023049886A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
substituted
compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/077000
Other languages
English (en)
French (fr)
Inventor
Steven D. Goldberg
Deane GORDON
Steven A. LOSKOT
Stefan MCCARVER
Steven P. Meduna
Brock T. Shireman
Alexander E. VALDES
Dongpei Wu
Xiaohua XUE
Luke E. HANNA
Jennifer D. Venable
Douglas C. Behenna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to CN202280065020.XA priority Critical patent/CN118076606A/zh
Priority to AU2022348938A priority patent/AU2022348938A1/en
Priority to JP2024518817A priority patent/JP2024536863A/ja
Priority to MX2024003770A priority patent/MX2024003770A/es
Priority to CA3233625A priority patent/CA3233625A1/en
Priority to EP22790173.3A priority patent/EP4408529A1/en
Priority to KR1020247013538A priority patent/KR20240082371A/ko
Publication of WO2023049886A1 publication Critical patent/WO2023049886A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • FIELD Disclosed herein are imidazopyridazine compounds, and pharmaceutical compositions thereof, which modulate Interleukin-17A. Also disclosed herein is the therapeutic use of such compounds, for example, in treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease.
  • BACKGROUND Interleukin-17 (“IL-17”) also known as IL-17A and CTLA-8, is produced mainly by CD4+ Th17 cells, and also by other immune cells such as CD8+ T cells, ⁇ T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs).
  • IL-17A exists as a homodimer (A/A) or as a heterodimer (A/F) with IL-17F and signals through binding to dimeric receptor complex IL- 17RA and IL-17RC.
  • IL-17RA is ubiquitously expressed at particularly high levels by haematopoietic cell types, whereas IL-17RC is preferentially expressed by non-haematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol.2009, 9, 556–567).
  • IL-17A/IL-17R signaling induces de novo gene transcription by triggering NF-kB, C/EBP and MAPK pathways through ACT1–TRAF6–TRAF4.
  • IL-17A stimulates the release of inflammatory mediators including IL-6, IL-8, G-CSF, TNF- ⁇ , and IL-1 ⁇ that recruit and activate lymphocytes to the site of injury or inflammation and maintain a proinflammatory state.
  • IL-17A mRNA and/or protein levels are elevated in the lesional skin and blood of patients with psoriasis and correlate with disease severity.
  • IL-17A acts directly in synergy with other cytokines (such as TNF ⁇ , IFN ⁇ or IL-22) on keratinocytes triggering a self- amplifying inflammatory response in the skin and leading to the formation of psoriatic plaques.
  • cytokines such as TNF ⁇ , IFN ⁇ or IL-22
  • the blockade of IL-17A by means of antibodies to IL-17A or IL-23 results in complete reversal of the molecular and clinical disease features in majority of psoriasis patients, manifesting the significant role of IL-17A and IL-17-producing T-cells in the immunopathogenesis of psoriasis. (Hawkes et al., Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies.
  • IL-17A is mechanistically relevant to PsA through NF ⁇ B activation that triggers transcription of several PsA related genes including the receptor activator of nuclear factor ⁇ B ligand (RANKL).
  • RANKL triggers the differentiation of osteoclast precursor cells into activated osteoclasts, resulting in bone resorption and subsequently joint deformity in PsA (Adamopoulos I. and Mellins E. Nature reviews Rheumatology 2015; 11:189- 94).
  • PsA joint is enriched for IL-17+CD8+ T cells, and the levels of this T cell subset are correlated with disease activity (Menon B.
  • IL-17A has been recognized as critical to the progression of rheumatoid arthritis. “The recognition of IL-17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date through which T cells can capture and localize macrophage effector functions in rheumatoid arthritis” Stamp, L. et al., Immunol. Cell Biol.2004, 82(1): 1-9. Moreover, in rheumatoid arthritis IL-17A acts locally on synoviocytes and osteoblasts contributing to synovitis and joint destruction.
  • Robert and Miossec have proposed the use of synovial biopsies and/or biomarkers to precisely identify patients that would respond to IL-17A inhibition. Their work concludes that IL-17 inhibitors should now be considered in the development of precision medicine in RA. (Robert M. and Miossec P., Front. Med., 2019, 5:364).
  • AS Ankylosing Spondylitis
  • Various studies have reported elevated IL-17A and Th17 and other cells producing IL-17 in AS blood samples (Wendling D. et al., Joint Bone Spine.2007;74:304–305; Shen H. et al., Arthritis Rheum.2009;60(6):1647–56; Zhang L.
  • IL-17 is elevated in the blister fluid and perilesional skin of BP patients.
  • Exome sequencing of BP patients revealed mutations in twelve IL-17-related genes in one third of patients, providing the genetic link between IL-17 pathway and BP (Chakievska L. J Autoimmun.2019, 96:104-112).
  • IL-17A-/- mice are protected, and anti-IL-17A treatment significantly reduced skin lesions in wild type (Chakievska L.
  • AD atopic dermatitis
  • IL-17 was found to be elevated in peripheral blood and lesions in AD patients and Th17 cells infiltrated more markedly in acute than chronic lesions, suggesting its role in acute phase of AD (Koga C. et al., J. Invest. Dermatol.2008, 128, 2625– 2630).
  • Molecular profile analysis from ustekinumab Phase II suggest likely contribution of IL- 23/Th17/IL-17 pathway in AD (Khattri S. et al., Exp.
  • IL-17 expression is increased in PBMCs, cerebrospinal fluid (CSF) as well as in brain lesions and cells from MS patients (Lock, C. et al., Nat. Med. 2002, 8: 500–508; Matusevicius, D. et al., Mult. Scler.1999, 5: 101–104; Tzartos, J. et al., Am. J. Pathol.2008, 172: 146–155). IL-17–producing T cells are enriched in active MS lesions (Tzartos, J. et al., Am. J. Pathol.2008, 172: 146–155; Willing A. et al., J.
  • IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and correlated with the CSF/serum albumin quotient, a measure of blood-brain barrier (BBB) dysfunction, together with in vitro data that IL-17A in combination with IL-6 reduced the expression of tight junction -associated genes and disrupted monolayer integrity in a BBB cell line, highlighting the potential importance of targeting IL-17A in preserving BBB integrity in RRMS (Setiadi AF et al., J Neuroimmunol.2019, 332:147-154).
  • Anti-IL-17 antibody modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in chronic mouse asthma models (Camargo LdN. et al., Front Immunol.2018; 8:1835; dos Santos T. et al., Front. Physiol.2018, 9:1183).
  • COPD Chronic Obstructive Pulmonary Disease
  • An increase in Th17 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects, and inverse correlations were found between Th17 cells with lung function (Vargas- Rojas M. et al., Respir. Med.2011 Nov; 105(11):1648-54).
  • IL-17 promotes the release of inflammatory mediators from retinal pigment epithelium cell line, disrupting the retinal pigment epithelium barrier function (Chen Y. et al., PLoS One.2011;6:e18139). IL-17 levels were elevated in the serum or aqueous humor of uveitis patients (El-Asrar A.
  • Anti- IL-17 antibody delayed the onset of ocular inflammation and markedly inhibited the development of experimental autoimmune uveitis in rats (Zhang R. et al., Curr. Eye Res.2009 Apr;34(4):297-303).
  • Ustekinumab that blocks IL-23/IL-17 pathway was also reported to successfully treat a noninfectious uveitis patient who had severe concomitant psoriasis and PsA and failed to respond to conventional immune suppressants (Mugheddu C. et al., Dermatol. Ther.2017 Sep;30(5);e12527.).
  • MM myeloma
  • IL-17A serum levels were significantly higher in MM patients and also in patients with advanced stage compared with healthy subjects (Lemancewicz D. et al., Med. Sci. Monit.2012; 18(1): BR54–BR59).
  • IL-17 blockade may become a promising therapeutic strategy for SLE ( Koga T. et al., Expert Rev. Clin. Immunol.2019, 15 (6) 629-637).
  • animal and human studies have shown that IL-17A plays crucial role in pathogenesis of the multiple diseases and/or conditions discussed above.
  • the significance of targeting IL-17A has been demonstrated by the transformational efficacy of injectable IL-17A neutralizing antibodies in patients Despite the advances achieved with injectable IL-17A antagonist antibodies, there is a long-felt need for the development of an oral small molecule IL-17A inhibitor as it may broaden treatment options for many patients without access to biologics.
  • a safe and efficacious small molecule IL-17A inhibitor may offer significant benefits to patients over the injectable IL-17A neutralizing antibodies such as convenient dosing regimens and cost savings, which in turn may provide effective long-term disease management.
  • the development of an oral small molecule treatment has remained challenging. For example, no oral small molecule IL-17A inhibitor has progressed into late-stage clinical trials yet, and only two oral small molecule IL-17A inhibitors have progressed into phase I clinical trials (NCT04586920 and NCT04883333) as of September 28, 2021. Additionally, as of December 2021, one of these clinical trials (NCT04586920) was suspended due to safety review. .
  • the present application discloses a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are as defined herein.
  • the present application also discloses a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present application also discloses a method for treating and/or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.
  • DETAILED DESCRIPTION Definitions Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety.
  • administering means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.
  • Such methods include administering a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.
  • subject refers to a patient, which may be an animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application.
  • mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.
  • therapeutically effective amount or “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
  • IL-17 or “IL-17A” refers to interleukin 17A.
  • Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by a group of immune cells in response to their stimulation.
  • An exemplary amino acid sequence of human IL-17 is represented in GenBank Accession No. NP_002181.1, which can be encoded by a nucleic acid sequence such as that of GenBank Accession No. NM_002190.3.
  • modulator refers to any agents or molecules that can bind to IL-17, including small molecule compounds.
  • Active moiety refers to a molecule or ion responsible for a physiological or pharmacological action.
  • a compound of formula (I), as exemplified in the Examples and also described herein, is an active moiety.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treat,” “treating,” or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome or disorder, including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.
  • the term “QD” means once daily.
  • alkyl is a straight or branched saturated hydrocarbon.
  • an alkyl group can have 1 to 12 carbon atoms (i.e., (C 1 -C 12 )alkyl) or 1 to 6 carbon atoms (i.e., (C 1 - C 6 )alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-butyl (s-bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t- bu, t-butyl, -CH(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 ) CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH
  • C( a-b) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive.
  • C(1-4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.
  • cycloalkyl refers to a saturated or partially unsaturated all carbon ring system having 3 to 8 carbon atoms (i.e., C (3-8) cycloalkyl), and preferably 3 to 6 carbon atoms (i.e., C (3- 6)cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bicyclic form.
  • exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl group may be unsubstituted or substituted.
  • Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for example and without limitation, an example of a spiropentyl group is for example and without limitation, examples of spirohexyl groups include , and ; for example and without limitation examples of cycloheptyl groups include , , , and ; for example and without limitation examples of cyclooctyl groups include and Unless otherwise stated specifically in the specification, a siprocycloalkyl group may be unsubstituted or substituted.
  • Bicyclic cycloalkyl ring systems also include or The term “heteroaryl” refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroaryl includes single aromatic rings of from 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroaryl ring systems include but are not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.
  • halogen or “halo” refers to bromo (-Br), chloro (-Cl), fluoro (-F) or iodo (-I).
  • the compounds disclosed herein may accordingly exist as enantiomers or diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a “racemic” mixture is a 1:1 mixture of a pair of enantiomers.
  • a “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1:1.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, a scalemic mixture, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p- toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral column vial HPLC or SFC. In some instances rotamers of compounds may exist which are observable by 1 H NMR leading to complex multiplets and peak integration in the 1 H NMR spectrum.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence-rule procedure, and preceded when necessary by the appropriate locants (Pure & Appl. Chem.45, 1976, 11–30).
  • Certain examples contain chemical structures that are depicted or labelled as an (R*) or (S*).
  • (R*) or (S*) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established.
  • a compound designated as (R*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S)
  • a compound designated as (S*) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S).
  • any element in particular when mentioned in relation to a compound of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • a reference to hydrogen includes within its scope 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T).
  • the compounds described herein include a 2 H (i.e., deuterium) isotope.
  • the group denoted -C (1-6) alkyl includes not only -CH3, but also -CD3; not only -CH2CH3, but also -CD2CD3, etc.
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 15 O and 16 O and 17 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of the disclosure may include a radioactive isotope selected from the group comprising 3 H, 11 C, 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C (3-7) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or -C(3-5) cycloalkyl, wherein the - C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C (3- 5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-7)cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is -C(3-5)cycloalkyl, -C(2-3)alkyl-O-C(1-3)alkyl, or -
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-7)cycloalkyl, wherein the C (3-7) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(1-3)alkyl, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3- 5)cycloalkyl, wherein the -C(1-3)alkyl
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-7)cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3- 5)cycloalkyl, wherein the -C(1-3)alkyl
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3- 5)cycloalkyl, wherein the -C(1-3)alkyl, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, and
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(1-3)alkyl, -C(3-5)cycloalkyl, -C(1-3)alkyl-
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or -C(3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(1-3)alkyl, -C(3-5)cycloalkyl, -C(1-3)alkyl-
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-7) cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is -C (3-5) cycloalkyl, -C (2-3) alkyl-O-C (1-3) alkyl, or
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-7)cycloalkyl, wherein the C(3- 7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3- 5)cycloalkyl; R 3 is -C (1-6) alkyl, -C (1-6) alkyl, -C (1-6) alkyl
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-7)cycloalkyl, wherein the C(3- 7) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(1-3)alkyl, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3- 5)cycloalkyl; R 3 is -C (1-6) alkyl, -C (1-6) alkyl, -C (1-6) alkyl, -C (1-6) alkyl, wherein the
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-7) cycloalkyl, wherein the C (3- 7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (1-3) alkyl, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3- 5)cycloalkyl; R 3 is -C(1-6)alkyl, -C(1-6)alkyl-O-C(1-6)alkyl, -C(1-6)alkyl-O-C(3-5)cycloalkyl, or
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or -C(3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-5) cycloalkyl, wherein the C(3-5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl,
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-5) cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C (3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is -C(3-5)cycloalkyl, -C(2-3)alkyl-O-C(1-3)alkyl, or -C(
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C(1-6)alkyl, -C(1-4)alkyl-O-C(1-4)alkyl,
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl; R 3 is -C (1-6) alkyl, -C (1-4) alkyl-O-C (1-4) alkyl;
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl; R 3 is -C(1-6)alkyl, -C(1-4)alkyl-O-C(1-4)alkyl, -C(1-3)alkyl-O-C(3-5)cycloalkyl, or cyclohexyl, each of
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or -C(3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or -C(3-5) cycloalkyl, wherein the - C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C(3- 5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C(3-5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl or -C (3-5) cycloalkyl, wherein the - C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms and wherein the -C (3- 5)cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is -C(3-5)cycloalkyl or -C(1-3)alkyl-O-C(3-5)cycloalkyl, wherein the
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C(1-5)alkyl substituted with one -CF3, R 3a , R 3b , R 3
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C (1-5) alkyl substituted with one -CF 3 or R 3a , R 3b , R 3
  • R 1 is: ; R 1a independently for each occurrence is -C(1-3)alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl; R 3 is -C (1-5) alkyl substituted with one -CF 3 , R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 4 is a 5-membered heteroaryl that
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is: R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3; R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3)
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is: ; R 3a , R 3b , R 3c , and R 3d are each independently H or -CH
  • R 1 is: R 1a independently for each occurrence is -C(1-3)alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 0, 1, 2, or 3; R 2 is H, -C(3-5)cycloalkyl, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is: R 3a , R 3b , R 3c , and R 3d are each independently H or -CH 3 ; R 4 is a 5-membered heteroaryl that is unsubstituted or substituted with one to two R 4a groups; and
  • R 1 is: ; R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 1 or 2; R 2 is H, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C (1-5) alkyl substituted with one -CF 3 , 3 R a , R 3b , R 3c , and R 3d are each independently
  • R 1 is: R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 1 or 2; R 2 is H, -C(1-3)alkyl-O-C(1-3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C (1-5) alkyl substituted with one -CF 3 or R 3a , R 3b , R 3c , and R 3d are each independently H or -
  • R 1 is: ; R 1a independently for each occurrence is -C (1-3) alkyl, wherein the -C (1-3) alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms; m is 1 or 2; R 2 is -C(2-3)alkyl-O-C(1-3)alkyl or -C(1-3)alkyl-O-C(3-5)cycloalkyl; R 3 is -C (1-5) alkyl substituted with one -CF 3 , R 3a , R 3b , R 3c , and R 3d are each independently H or -CF 3 , R 3a , R 3b , R 3c , and R 3d are each independently H
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C (1- 3) alkyl or -C (3-5) cycloalkyl, wherein the -C (3-5) cycloalkyl is unsubstituted or substituted with one -CN group, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C (3-5) cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C(1- 3) alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-7)cycloalkyl, wherein the C(3-7)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C(1- 3)alkyl, wherein the -C(1-3)alkyl is unsubstituted or substituted with one to five fluorine atoms, or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3- 5) cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C (1- 3)alkyl or two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl, wherein the C(3-5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -CH3, -CH 2 F, -CHF 2 , -CF 3 , -CH(CH 3 ) 2 , -CH 2 CF 3 , cyclopropyl, cyanocyclopropyl, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C(3-5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -CH3, -CH 2 F, -CHF 2 , -CF 3 , or two R 1a groups together with the carbon atoms to which they are attached form a fused C (3-5) cycloalkyl, wherein the C (3-5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -CH 3 , -CH2F, -CHF2, -CF3, or two R 1a groups together with the carbon atoms to which they are attached form a fused C(5)cycloalkyl, wherein the C(5)cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -CH3, -CH(CH3)2, cyclopropyl, cyanocyclopropyl, or two R 1a groups together with the carbon atom or atoms to which they are attached form a spirocyclic or fused C(3-5)cycloalkyl, wherein the C(3- 5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -CH3 or two R 1a groups together with the carbon atoms to which they are attached form a fused C (5) cycloalkyl, wherein the C (5) cycloalkyl is unsubstituted or substituted with one to five fluorine atoms.
  • R 1a independently for each occurrence is -C (1- 3)alkyl that is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C (1-3) alkyl.
  • R 1a independently for each occurrence is -CH3, -CH2F, -CHF2, -CF3, -CH(CH3)2, or -CH2CF3.
  • R 1a is not -CF 3 .
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1a independently for each occurrence is -C (3-5) cycloalkyl that is unsubstituted or substituted with one -CN group.
  • R 1a independently for each occurrence is cyclopropyl or cyanocyclopropyl.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein two R 1a groups together with the carbon atom to which they are attached form a spirocyclic C(3-7)cycloalkyl that is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof wherein two R 1a groups together with the carbon atom to which they are attached form a spirocyclic C(3-5)cycloalkyl that is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein two R 1a groups together with the carbon atom to which they are attached form a spirocyclic C(3- 4)cycloalkyl that is unsubstituted or substituted with one to two fluorine atoms.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof wherein two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-7)cycloalkyl that is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein two R 1a groups together with the carbon atoms to which they are attached form a fused C(3-5)cycloalkyl that is unsubstituted or substituted with one to five fluorine atoms.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof wherein two R 1a groups together with the carbon atoms to which they are attached form a fused C(5)cycloalkyl that is unsubstituted or substituted with one to two fluorine atoms.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 0. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 1. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein m is 2. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is:
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is:
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is:
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(3-5)cycloalkyl, -C(2-3)alkyl-O-C(1- 3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl, wherein the -C (3-5) cycloalkyl, -C (2-3) alkyl-O-C (1-3) alkyl, and -C(1-3)alkyl-O-C(3-5)cycloalkyl groups are unsubstituted or substituted with one to six R 2a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is -C (3-5) cycloalkyl, -C (2-3) alkyl-O-C (1- 3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl, wherein the -C (3-5) cycloalkyl is unsubstituted or substituted with one -CN group.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is -C (3-5) cycloalkyl or -C (1- 3) alkyl-O-C (3-5) cycloalkyl, wherein the -C (3-5) cycloalkyl is unsubstituted or substituted with one - CN group.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -C (3-5) cycloalkyl, -C (1-3) alkyl-O-C (1- 3)alkyl, or -C(1-3)alkyl-O-C(3-5)cycloalkyl, wherein the -C(3-5)cycloalkyl is unsubstituted or substituted with one -CN group.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -C (3-5) cycloalkyl, -C (1- 3) alkyl-O-C (1-3) alkyl, or -C (1-3) alkyl-O-C (3-5) cycloalkyl.
  • R 2 is H, -C(3- 5) cycloalkyl, or -C (1-3) alkyl-O-C (1-3) alkyl.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -C (3-4) cycloalkyl, or -CH 2 OCH 3 .
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, -CH2OCH3, -CH2CH2OCH3, or - CH 2 O-cyclopropyl.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or -CH 2 OCH 3 .
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 2 OCH 3 .
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH2CH2OCH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH 2 O-cyclopropyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia: (Ia).
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-6) alkyl, -C (1-6) alkyl-O-C (1-6) alkyl, or - C (1-6) alkyl-O-C (3-5) cycloalkyl, each of which is unsubstituted or substituted with one to six fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C(1-6)alkyl, -C(1-4)alkyl-O-C(1-4)alkyl, - C (1-3) alkyl-O-C (3-5) cycloalkyl, or cyclohexyl, each of which is substituted or unsubstituted with one to six fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-6) alkyl, -C (1-6) alkyl-O-C (1-5) alkyl-CF 3 or cyclohexyl, wherein the -C (1-6) alkyl is substituted with one to three fluorine atoms and wherein the cyclohexyl is substituted with two fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1- 6) alkyl or -C (1-6) alkyl-O-C (1-5) alkyl-CF 3 , wherein the -C (1-6) alkyl is substituted with one to three fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-5) alkyl, -C (1-6) alkyl-O-C (1-5) alkyl-CF 3 or cyclohexyl, wherein the -C(1-5)alkyl is substituted with one -CF3 and wherein the cyclohexyl is substituted with two fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-5) alkyl or -C (1-6) alkyl- O-C (1-5) alkyl-CF 3 , wherein the -C (1-5) alkyl is substituted with one -CF 3 .
  • R 3 is -C (1-6) alkyl-O-C (1-5) alkyl-CF 3 or cyclohexyl, wherein the cyclohexyl is substituted with two fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-5) alkyl substituted with one -CF 3 , and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH 3 .
  • R 3 is -C(1-5)alkyl substituted with one -CF3 or ; and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH 3 .
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.
  • R 3 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C (1-5) alkyl substituted with one -CF 3 .
  • R 3 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C(3-5)alkyl substituted with one -CF3.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is: and R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is .
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-1: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic: wherein R 3a , R 3b , R 3c , and R 3d are each independently H or -CH 3 .
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof which is a compound of Formula Ic-1: (Ic-1), wherein R 3a , R 3b , R 3c , and R 3d are each independently H or -CH 3 .
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof which is a compound of Formula Ic-2: (Ic-2) , wherein R 3a , R 3b , R 3c , and R 3d are each independently H or -CH3.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Id is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Id: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Id-1: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Id-2: (Id-2).
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ie In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ie-1: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ie-2: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If-1: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If-2: (If-2).
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-membered heteroaryl that is unsubstituted or substituted with one or two R 4a groups.
  • R 4 is a 5- membered heteroaryl that is substituted with one or two R 4a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-membered heteroaryl comprising one to three heteroatoms selected from O and N, wherein the 5-membered heteroaryl is unsubstituted or substituted with one to two R 4a groups.
  • R 4 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, triazolyl, isoxazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • R 4 is pyrazolyl, triazolyl, or oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl or oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadizaolyl, 1,2,5- oxadiazolyl, or 1,3,4-oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, or 1,2,5-oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • R 4 is pyrazolyl, 1,2,4-triazolyl, or 1,2,5- oxadiazolyl.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyrazolyl or 1,2,5-oxadiazolyl, each of which is unsubstituted or substituted with one to two R 4a groups.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is -C (1-4) alkyl, -O-C (1-4) alkyl, -C (1-4) alkyl-O- C(1-4)alkyl, or -C(0-2)alkyl-C(3-4)cycloalkyl, wherein the -C(1-4)alkyl, -O-C(1-4)alkyl, -C(1-4)alkyl-O- C(1-4)alkyl, and -C(0-2)
  • R 4a is -C (1-6) alkyl or -C (0-2) alkyl-C (3- 6) cycloalkyl, each of which are unsubstituted or substituted with one to six substituents independently selected from fluorine, -CH3, -CD3, -CD2CD3, -CH2F, -CHF2, and -CF3.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is -C (1-4) alkyl or -C (0-2) alkyl-C (3-4) cycloalkyl, each of which are unsubstituted or substituted with one to six substituents independently selected from fluorine, - CH3, -CD3, -CD2CD3, -CH2F, CHF2, and -CF3.
  • R 4a is -C(1-6)alkyl, -O-C(1-6)alkyl, or -C(0-2)alkyl- C(3-6)cycloalkyl.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is -C (1-4) alkyl, -O-C (1-4) alkyl, or -C (0-2) alkyl- C (3-4) cycloalkyl.
  • R 4a is -C(1-6)alkyl or -C(0-2)alkyl-C(3- 6) cycloalkyl.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is -C(1-4)alkyl or -C(0-2)alkyl-C(3- 4)cycloalkyl.
  • R 4a is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, isopropyl, -CD 2 CD 3 , - CH2CH2CF3, methoxy, -OCH2CHF2, -CH2OCHF2, cyclopropyl, or -CH2-cyclopropyl.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, isopropyl, -CD 2 CD 3 , -CH 2 CH 2 CF 3 , -OCH 2 CHF 2 , - CH2OCHF2, cyclopropyl, or -CH2-cyclopropyl.
  • R 4a is methyl, -CD 2 CD 3 , isopropyl, methoxy, or cyclopropyl.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, -CD2CD3, isopropyl, or cyclopropyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is:
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 i In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is .
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a -C(3-5) cycloalkyl that is unsubstituted or substituted with one to two R 4b groups.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof wherein R 4 is a -C (3-5) cycloalkyl that is substituted with one to two R 4b groups.
  • R 4 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a cyclopropyl that is substituted with one to two R 4b groups.
  • R 4 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 is a -C(3-5) cycloalkyl that is unsubstituted or substituted with one -CF 3 group.
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4b is -C(1-3)alkyl that is unsubstituted or substituted with one to three fluorine atoms.
  • R 4b is CH 3 , CH2F, CHF2, or CF3.
  • R 4b is CF 3 .
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof that is a deuterated isotope comprising one to thirty deuterium atoms.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof that is a deuterated isotope comprising one to fifteen deuterium atoms.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof having a structure as shown in Table 1A, 1B, 1C, or 1D. Table 1A
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: .
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having the following structure: . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in Tables 2A, 2B, and 2C. Table 2A
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).
  • a pharmaceutical composition made by mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a process for making a pharmaceutical composition comprising mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present application is also directed to a method for treating and/or ameliorating an IL-17 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.
  • a method for treating or ameliorating an IL- 17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriasis.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is vitiligo.
  • a method for treating or ameliorating and/an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is asthma.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is uveitis.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is multiple myeloma.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).
  • the compound of Formula I or the pharmaceutically acceptable salt thereof is administered orally (e.
  • a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD.
  • the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.
  • disclosed herein is a method for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the IL-17A mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythemat
  • the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to100 mg BID.
  • a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.
  • a compound of Formula I or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.
  • a method for treating and/or ameliorating an IL-17 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • a method of treating and/or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing s
  • a method of treating or ameliorating an IL-17 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • methods of modulating IL-17 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, or pharmaceutically acceptable salt thereof.
  • Also disclosed herein is a method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • IV. Combination Therapy
  • a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents is selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.
  • the one or more additional therapeutic agents is selected from the group consisting of: anti-TNFalpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®/Imnovid®); anti-p40 antibody agents such as ustekinumab (Stelara®); and anti-p19 antibody agents such as guselkumab (Tremfya®), tildrakizumab (Ilumya TM /Ilumetri), risankizumab (Skyrizi TM ), and mirikizumab.
  • anti-TNFalpha agents such as infliximab (Remicade®),
  • a method of treating and/or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.
  • additional therapeutic agents such as anti-inflammatory agents, immunomodulatory agents, or immuno
  • a method of treating and/or ameliorating an IL- 17 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis.
  • the IL-17 mediated inflammatory syndrome, disorder or disease is psoriasis.
  • the IL-17 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis.
  • the IL-17 mediated inflammatory syndrome, disorder or disease is ankylosing spondylitis.
  • Dosage Regimen When employed as IL-17A modulators, the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably between about 0.5 mg to about 500 mg, in single or divided daily doses. In some embodiments, the dosage amount is about 5 mg to 400 mg. In some embodiments, the dosage amount is about 10 mg to 300 mg. In some embodiments, the dosage amount is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • a compound of Formula I, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 10 mg to 300 mg BID.
  • a compound of Formula I, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg BID. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg BID.
  • the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments. It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect.
  • optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition.
  • factors associated with the particular subject being treated including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.
  • the above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygal
  • Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH 3 , NH 4 OH, N-methyl-D-glucamine, piperidine, potassium, potassium-t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.
  • TMS tris(hydroxymethyl)aminomethane
  • compositions comprising any known pharmaceutically acceptable carriers.
  • exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
  • exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine.
  • compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
  • suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
  • Also disclosed herein is a method of making a pharmaceutical composition
  • a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or pharmaceutically acceptable salt thereof.
  • the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.
  • Aldehydes A-I can undergo reductive animation with diamines C-Ia.
  • Aldehydes A-I can be treated with diamines C-Ia, such as ethylene diamine, and a reducing agent such as NaCNBH3 in a solvent such as methanol in the presence of additives such as acetic acid.
  • the resulting adducts (structures not shown) are treated with a reagent such as triphosgene or CDI in a solvent such as DCM or THF to afford the corresponding cyclic ureas A-II.
  • Boc protected diamines C-Ib such as tert-butyl (S)-(1-aminopropan-2-yl)carbamate
  • a second step cyclization of the resulting reductive amination adducts (structure not shown) to the urea using reagents such as potassium tert-pentoxide in solvents such as tert-amyl alcohol affords the corresponding ureas A-II.
  • Compounds A-II can be treated with an acid such as TFA in a solvent such as DCM to afford compounds A-III. These conditions are herein known as “Boc deprotection conditions”.
  • Amide bond formation between amines A-III and carboxylic acids can be achieved through the use of a coupling agent, such as HATU or EDCI, in the presence of a base, such as DIPEA, in a solvent, such as DMF, MeCN, or DCM, with or without an additive, such as HOBt and DIPEA, to yield compounds I.
  • a coupling agent such as HATU or EDCI
  • DIPEA a base
  • a solvent such as DMF, MeCN, or DCM
  • additives such as HOBt and DIPEA
  • amines A-III can be treated with N-hydroxysuccinate esters in the presence of reagents such as DIPEA in a solvent such as acetonitrile to provide compounds of formula I.
  • reagents such as DIPEA
  • DIPEA a solvent such as acetonitrile
  • Scheme 2 Compounds Ia may be prepared as shown in Scheme 2. Cyclocondensation of aminopyridazines B-I with iodoketones C-II in a solvent such as DMA in the presence of 4 ⁇ molecular sieves affords compounds B-II.
  • the second step of this process is oxidative cleavage of the vinyl substituent using reagents, such as sodium periodate, in the presence of a catalyst, such as potassium osmate, in a solvent, such as aqueous 1,4-dioxane.
  • reagents such as sodium periodate
  • a catalyst such as potassium osmate
  • a solvent such as aqueous 1,4-dioxane.
  • Subsequent condensation of compounds D-II with (S)-(–)-2-methyl-2-propanesulfinamide gives the corresponding sulfinimide, that upon addition of nucleophilic carbon-containing reagents, such as alkyl magnesium halides, alkyl lithiums or metalated alkyl nitriles, yields sulfinamides D-III.
  • Conversion of compounds D-III to D-IV can be accomplished by treatment with an acid such as aqueous hydrochloric acid.
  • Compounds D-IV are converted to compounds D-V by treatment with compounds such as D-VIII in the presence of a base such as DIPEA or TEA in a solvent such as ACN, DCM or THF.
  • compounds D-IV can be converted to compounds D-V by reductive amination using a catalyst such as tetraethoxytitanium with a reducing agent such as NaCNBH3, in a solvent such as MeOH with an aldehyde such as CbzNH(C)(R 1a )mCHO.
  • Compounds D-V are converted to compounds D-VI by treating with H2 in the presence of a palladium catalyst such as Pd/C in a solvent such as methanol.
  • Compounds D-VI can be converted to compounds D-VII by treating with a reagent such as triphosgene or CDI in a solvent such as DCM or THF.
  • Compounds D-VII can be converted to compounds Ia as shown in Scheme 2 employing methods analogous to those describing the conversion of compounds B-III to compounds Ia.
  • Scheme 4 Compounds D-VIa can be prepared as shown in Scheme 4.
  • Compounds D-Ia can be converted to compounds D-IX by treatment with D-XI, in the presence of a catalyst, such as RuPhos Pd G3, with an additive such as K 3 PO 4 and in a solvent such as aqueous 1,4-dioxane.
  • a catalyst such as RuPhos Pd G3
  • an additive such as K 3 PO 4
  • a solvent such as aqueous 1,4-dioxane.
  • Compounds D-IX can be converted to compounds D-X by treatment with potassium osmate and sodium periodate, in a solvent, such as aqueous 1,4-dioxane.
  • Conversion of compounds D-X to compounds D-VIa can be accomplished by titanium isopropoxide-mediated imine formation with diamines C-Ia followed by reduction with a reducing agent such as NaCNBH3 in a solvent such as methanol in the presence of an additive such as acetic acid.
  • a reducing agent such as NaCNBH3
  • a solvent such as methanol
  • an additive such as acetic acid.
  • Compounds D-VIa can be converted to compounds such as D-VII as shown in Scheme 3.
  • Scheme 5 Compounds B-III may also be prepared as shown in Scheme 5.
  • Compounds E-III can be converted to compounds E-IV by sulfoxamine deprotection using reagents such as HCl in solvents such as EtOAc, phthalimide formation as shown above and amine deprotection using reagents such as sulfuric acid in solvents such as 1,4-dioxane or MeOH.
  • reagents such as HCl in solvents such as EtOAc
  • phthalimide formation such as shown above
  • amine deprotection using reagents such as sulfuric acid in solvents such as 1,4-dioxane or MeOH.
  • Treatment of compounds E-IV with compounds C-II using a base such as Na2HPO4 in a solvent such as NMP followed by phthalimide removal using reagents such as hydrazine in solvents such as EtOH provides imidazopyridazines E-V.
  • Compounds E-V are converted to compounds B-III by a three-step process shown above.
  • Compounds G-IV can be prepared as shown in Scheme 7. Treatment of aldehydes A-I with a reducing agent such as sodium borohydride in a solvent such as MeOH affords the corresponding alcohols G-I. Compounds G-I can be converted to compounds G-II by a two-step process comprising deprotection of compounds G-I using “Boc deprotection conditions” and subsequent amide bond formation using “amide bond formation” conditions with either R 4 CO2H or R 4 CO2Cl. Treatment of alcohols G-II with reagents such as carbon tetrabromide in solvents such as DCM with additives such as 1H-imidazole affords compounds G-III.
  • a reducing agent such as sodium borohydride in a solvent such as MeOH affords the corresponding alcohols G-I.
  • Compounds G-I can be converted to compounds G-II by a two-step process comprising deprotection of compounds G-I using “Boc deprotection
  • Aminopyridazines H-I can be prepared by protection of amines E-IV as the 2,2-dimethylpropanamide. Treatment of aminopyridazines H-I with reagents such as hydrazine in solvents such as EtOH affords amines H-II. Reaction of compounds H-II with oxathiazolidine dioxides H-VI using a base such as DIPEA or TEA in solvents such as ACN provides diamines H-III.
  • Step B tert-Butyl (S)-((4,4-difluorocyclohexyl)(7-((2-oxoimidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate.
  • reaction mixture was warmed to 60 °C for 1 h.
  • the reaction mixture was cooled to rt and treated with aqueous 3 M sodium hydroxide (2 mL).
  • reaction mixture was diluted with half saturated brine (100 mL) and EtOAc (50 mL), and the layers were separated.
  • the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to a gum that was used directly in the next step without further purification.
  • Step C (S)-1-((2-(Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)methyl)imidazolidin-2-one.
  • a cooled (0 °C) solution of tert-butyl (S)-((4,4- difluorocyclohexyl)(7-((2-oxoimidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2- yl)methyl)carbamate (0.89 mmol, Step B) in DCM (5.0 mL) was added TFA (3.7 mL, 65 mmol).
  • reaction mixture was concentrated to dryness, and diluted with EtOAc (20 mL), brine (30 mL), aqueous 3 M sodium hydroxide (5 mL), and saturated aqueous sodium bicarbonate (35 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the title compound as a yellow film (60.7%, over three steps) that was used without further purification.
  • Step B tert-Butyl ((S)-(4,4-difluorocyclohexyl)(7-(((S)-4-methyl-2-oxoimidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate.
  • Step C (S)-1-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)methyl)-4-methylimidazolidin-2-one.
  • reaction mixture was then diluted with 5% aqueous LiCl (about 30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated and purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound as a brown solid (65.2% yield).
  • Step B tert-Butyl ((R)-1-(7-((S)-2-methoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step C (S)-1-((S)-1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2- one.
  • reaction was stirred at 0 °C for 30 min before the cooling bath was removed and the reaction was allowed to warm to rt over 3 h.
  • LCMS analysis indicated the complete consumption of the starting material, the reaction was concentrated to remove most of the TFA and the resulting residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated to provide the title compound as a brown solid (99% yield) which was used without further purification.
  • Step A 4-Cyclopropyl-1,2,5-oxadiazole-3-carbonyl chloride.
  • a flask was charged with 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (200 mg, 1.30 mmol) and DCM (2.6 mL).
  • the solution 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 h as it warmed to rt.
  • Step B 2,5-Dioxopyrrolidin-1-yl 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylate.
  • a flask was charged with N-hydroxysuccinimide (231 mg, 1.95 mmol), DCM (3.25 mL) and DIPEA (0.336 mL, 1.95 mmol).
  • the reaction mixture was heated at 45 °C for 36 h, at which time an additional portion of tert-butyl (S)-(6,6,6-trifluoro-1-iodo-5,5-dimethyl-2-oxohexan-3-yl)carbamate (649 mg, 1.59 mmol) was added and heated at 45 °C for an additional 72 h.
  • the reaction mixture was cooled to rt, filtered over a pad of diatomaceous earth (e.g., Celite ® ), and the solids were washed with EtOAc and DCM. The filtrate was diluted with 5% aqueous LiCl, and the layers were separated.
  • Step B tert-Butyl ((S)-4,4,4-trifluoro-1-(7-((S)-2-methoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-3,3- dimethylbutyl)carbamate.
  • Step C (S)-1-((S)-1-(2-((S)-1-Amino-4,4,4-trifluoro-3,3-dimethylbutyl)imidazo[1,2- b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B 2,5-Dioxopyrrolidin-1-yl 1-isopropyl-1H-pyrazole-5-carboxylate.
  • a round bottom flask was charged with N-hydroxysuccinimide (1.1 g, 9.7 mmol), DCM (25 mL), and DIPEA (16 mL, 6.5 mmol), and cooled to 0 °C under a nitrogen atmosphere.
  • Step B N-(6-Chloro-5-iodopyridazin-3-yl)pivalamide.
  • Step C N-(6-Chloro-5-formylpyridazin-3-yl)pivalamide.
  • N-(6- chloro-5-iodopyridazin-3-yl)pivalamide 607 g, 1.79 mol, Step B) in THF (6.0 L) was added a 60% dispersion of NaH in mineral oil (93.0 g, 2.32 mol) in portions at 0 °C under a nitrogen atmosphere.
  • the resulting mixture was stirred for 30 min at rt under a nitrogen atmosphere and isopropylmagnesium chloride lithium chloride complex (1.99 L, 2.59 mol, 1.3 M in THF) was added dropwise at -60 °C.
  • Step D (R,E)-N-(5-(((tert-Butylsulfinyl)imino)methyl)-6-chloropyridazin-3- yl)pivalamide.
  • N-(6-chloro-5-formylpyridazin-3-yl)pivalamide (372 g, 1.54 mol, Step C) and (R)-2-methylpropane-2-sulfinamide (243 g, 2.00 mol) in DCM (2.20 L) was added potassium bisulfate (272 g, 2.00 mol) in portions at rt. The resulting mixture was stirred overnight at rt and then quenched with water (2 L) at rt.
  • reaction mixture was heated to 40 °C and mercuric chloride (4.72 g, 17.4 mmol) was added in portions and the reaction mixture was stirred for an additional 20 min at rt.
  • MOMBr (22.1 g, 177 mmol) in toluene (30 mL) was then added dropwise at rt and stirred for an additional 20 min.
  • the reaction mixture was then cooled to -15 °C followed by the addition of more MOMBr (200 g, 1.60 mol) in toluene (270 mL) dropwise and the resulting mixture was stirred for 40 min at -15 °C.
  • the layers were separated, and the organic layer was extracted with aqueous HCl (0.05 M, 2 x 50 mL).
  • the combined aqueous layers were diluted with EtOAc (50 mL) and the pH of the solution was adjusted to pH 11 with aqueous 3 M NaOH.
  • the layers were separated, and the aqueous layers were extracted with EtOAc (4 x 50 mL).
  • the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a solid (>99% yield, trace EtOAc was present), which was used without further purification.
  • Step B (S)-N-(6-Chloro-5-(1-(1,3-dioxoisoindolin-2-yl)-2-methoxyethyl)pyridazin-3- yl)pivalamide.
  • Step C (S)-2-(1-(6-Amino-3-chloropyridazin-4-yl)-2-methoxyethyl)isoindoline-1,3- dione.
  • a pear shaped flask was charged with (S)-N-(6-chloro-5-(1-(1,3-dioxoisoindolin-2-yl)-2- methoxyethyl)pyridazin-3-yl)pivalamide (1.2 g, 2.9 mmol, Step B), 1,4-dioxane (7.2 mL) and 6 M H 2 SO 4 (4.8 mL, 28.8 mmol) and the resulting yellow solution was heated at 60 °C for 11 h.
  • Step D tert-Butyl ((R)-1-(6-chloro-7-((S)-1-(1,3-dioxoisoindolin-2-yl)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Step E tert-Butyl ((R)-1-(7-((S)-1-amino-2-methoxyethyl)-6-chloroimidazo[1,2- b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step B Benzyl (S*)-(1,1,1-trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate.
  • a round- bottom flask was charged with methyl 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoate (2.3 g, 7.8 mmol, Step A) and MeOH (30 mL) and cooled to 0 °C.
  • NaBD 4 1.0 g, 24 mmol
  • the sides of the flask were rinsed with MeOH (5 mL). After 1.5 h at 0 °C, the reaction mixture was quenched with a small amount of water and then poured into brine.
  • Step C Benzyl (4S*)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22- oxide.
  • a stir bar, CH 3 CN (39 mL), and SOCl 2 (2.0 mL, 27 mmol) were added to a dry round- bottom flask under nitrogen, and the resulting solution cooled to -48 °C.
  • Step D Benzyl (S*)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d 2 2,2- dioxide.
  • reaction mixture was concentrated and purified initially by silica gel chromatography (0-100% EtOAc/DCM, then further purified by silica gel chromatography (0-5% (2 M NH 3 in MeOH) / DCM) to afford the title compound as a brown oil (55.5% yield).
  • Step B tert-Butyl ((R)-1-(7-((S)-1-(((S*)-2-amino-3,3,3-trifluoropropyl-1,1-d 2 )amino)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • the reaction mixture was placed under 3 atm of H2 for 2 h.
  • the reaction mixture was filtered through diatomaceous earth (e.g. Celite ® ), and the solids were washed with MeOH.
  • the filtrate was concentrated to give the title compound as a brownish foam (approximately 80% pure, 93% yield).
  • Step C tert-Butyl ((R)-1-(7-((S)-2-methoxy-1-((S*)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl-5,5-d2)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step D (S*)-1-((S)-1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2- one-5,5-d 2 .
  • Step D no CCl 4 was added and the mixture was stirred for an additional 4 h at rt.
  • Intermediate 14 Benzyl (R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide
  • the title compound was prepared as described for the synthesis of Intermediate 11 Steps A, C and D, using (R)-2-amino-3-methylbutan-1-ol in place of methyl 2-amino-3,3,3- trifluoropropanoate hydrochloride in Step A.
  • Step A the mixture was heated at 30 °C for 16 h instead of 0 °C for 1 h.
  • Step D no CCl 4 was added and the mixture was stirred for an additional 4 h at rt.
  • Intermediate 15 Benzyl 4-(2,2,2-trifluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide
  • the title compound was prepared as described for Intermediate 11 Steps A, C and D, using 2- amino-4,4,4-trifluorobutan-1-ol in place of methyl 2-amino-3,3,3-trifluoropropanoate hydrochloride in Step A.
  • Step A the residue was purified by silica gel chromatography (0- 25% EtOAc / petroleum ether).
  • Step C the mixture was stirred for 3 h at -30 °C instead of -35 °C for 2 h, and the oxathiazolidine oxide stereoisomers were separated by silica gel chromatography (0-30% EtOAc / petroleum ether).
  • Step D the benzyl (2R*)-4-(2,2,2- trifluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide isomer was utilized, and the residue was purified by silica gel chromatography (0-13% EtOAc / petroleum ether) to provide the title compound as a white solid.
  • Step B tert-Butyl ((1S)-(7-((1R)-((2-amino-4,4,4- trifluorobutyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step B The residue was purified by silica gel chromatography (0-15% MeOH / DCM) to provide the racemic title compound as a white solid (56% yield).
  • the first eluting diastereomer was designated R* (Intermediate 16), and was isolated as a white solid (40% yield).
  • the second eluting diastereomer was designated S* (Intermediate 17), and was isolated as a white solid (39% yield).
  • Intermediate 18 Benzyl (1-formylcyclopropyl)carbamate A mixture of benzyl (1-(hydroxymethyl)cyclopropyl)carbamate (500 mg, 2.26 mmol) and pyridinium chlorochromate (0.97 g, 4.5 mmol) in DCM (10 mL) was stirred at rt for 2 h. Then, the reaction mixture was filtered and concentrated to dryness.
  • Step B tert-Butyl ((S)-(7-((S)-amino(1-cyanocyclobutyl)methyl)imidazo[1,2- b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((S)-(((S)-2-(((benzyloxy)carbonyl)amino)-3,3,3- trifluoropropyl)amino)(1-cyanocyclobutyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step D tert-Butyl ((S)-(7-((S)-(((S)-2-amino-3,3,3-trifluoropropyl)amino)(1- cyanocyclobutyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step E tert-Butyl ((S)-(7-((S)-(1-cyanocyclobutyl)((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step F 1-((S)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)cyclobutane-1-carbonitrile.
  • Step B tert-Butyl (R)-(1-(7-(3-methoxyprop-1-en-2-yl)imidazo[1,2-b]pyridazin-2-yl)-2- ((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step C tert-Butyl (R)-(1-(7-(2-methoxyacetyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step D tert-Butyl ((1R)-1-(7-(1-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • the reaction was heated for 1 h at 50 °C then allowed to cool to rt, diluted with saturated aqueous NaHCO 3 and EtOAc, and filtered through diatomaceous earth (e.g. Celite ® ). The layers were separated then the organics washed with brine, dried over anhydrous Na2SO4, filtered, concentrated to dryness and was used without further purification.
  • diatomaceous earth e.g. Celite ®
  • Step E tert-Butyl ((1R)-1-(7-(2-methoxy-1-((S)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)carbamate.
  • reaction mixture was stirred at rt overnight then cooled to 0 °C and additional portions of DIPEA (0.13 mL, 0.83 mmol) and triphosgene (89 mg, 0.30 mmol) were added. After stirring for 1 h at 0 °C, the reaction was quenched with H2O and allowed to warm to rt. The mixture was concentrated to dryness then purified by silica gel chromatography (10-100% (10% MeOH / EtOAc) / (0.1% TEA / hexanes)) to afford the title compound in 59% yield.
  • Step F (4S)-1-(1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-methyl-4- (trifluoromethyl)imidazolidin-2-one.
  • Step B (S)-N-(6-Chloro-5-((2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)methyl)pyridazin-3-yl)pivalamide.
  • Step C (S)-1-((6-Amino-3-chloropyridazin-4-yl)methyl)-4- (trifluoromethyl)imidazolidin-2-one.
  • Step D tert-Butyl ((R)-1-(6-chloro-7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Step E tert-Butyl ((R)-1-(7-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Step F (S)-1-((2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • reaction mixture was concentrated and the pH was adjusted to pH 8 by the addition of 2 M NH 3 in MeOH (1.0 mL). Then the material was purified by preparative HPLC (10-100% CH3CN / (20 mM NH4OH in H2O)) to give the title compound (36% yield) as a brown film.
  • tributyl(methoxymethyl)stannane (1.41 g, 4.22 mmol) and THF (20.1 mL). This mixture was cooled to -78 °C and n-butyllithium (1.76 mL, 4.22 mmol, 2.4 M in hexanes) was added in a dropwise manner.
  • reaction mixture was treated with a solution of tert-butyl ((S)-(7-((E)-(((R)-tert- butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate (1.00 g, 2.01 mmol) in THF (5 mL) in a dropwise manner.
  • tert-butyl ((S)-(7-((E)-(((R)-tert- butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate (1.00 g, 2.01 mmol) in THF (5 mL) in a dropwise manner.
  • reaction mixture Upon stirring at -78 °C for an additional 2 h, the reaction mixture was quenched with EtOH (0.35 mL), allowed to warm to rt, and diluted with saturated aqueous NaHCO3 and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (40-100% acetone / hexanes) to give the title compound (39% yield) as the second eluting isomer.
  • Step B tert-Butyl ((S)-(7-((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step B (R)-1-(1-Amino-2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropane-1- carbonitrile.
  • Step C Benzyl (R)-(2-((tert-butyldiphenylsilyl)oxy)-1-(1- cyanocyclopropyl)ethyl)carbamate. (R)-1-(1-Amino-2-((tert- butyldiphenylsilyl)oxy)ethyl)cyclopropane-1-carbonitrile (500.
  • Step B was dissolved in CHCl3 (5.0 mL) and the solution was cooled to 0 °C.
  • DIPEA 319 mg, 2.47 mmol
  • benzyl chloroformate (0.235 mL, 1.65 mmol) were sequentially added dropwise and the reaction was allowed to gradually warm to rt while stirring for 1 h.
  • the reaction was then poured into water (10 mL) and was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness.
  • Step D Benzyl (R)-(1-(1-cyanocyclopropyl)-2-hydroxyethyl)carbamate.
  • Benzyl (R)-(2- ((tert-butyldiphenylsilyl)oxy)-1-(1-cyanocyclopropyl)ethyl)carbamate (2.00 g, 4.01 mmol, Step C) was dissolved in MeCN (10 mL) and then CsF (30.5 g, 201 mmol) and water (0.2 mL) were added sequentially.
  • Step E Benzyl (4R)-4-(1-cyanocyclopropyl)-1,2,3-oxathiazolidine-3-carboxylate 2- oxide.
  • Step A tert-Butyl ((S)-(7-((5R,8S)-5-(1-cyanocyclopropyl)-3-oxo-1-phenyl-2,10-dioxa- 4,7-diazaundecan-8-yl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step B tert-Butyl ((S)-(7-((S)-1-(((R)-2-amino-2-(1-cyanocyclopropyl)ethyl)amino)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((S)-1-((R)-4-(1-cyanocyclopropyl)-2-oxoimidazolidin-1-yl)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step D (S)-(7-((S)-1-((R)-4-(1-Cyanocyclopropyl)-2-oxoimidazolidin-1-yl)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanaminium 2,2,2- trifluoroacetate.
  • Step B Benzyl (4S)-4-(difluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide.
  • the title compound was synthesized in a manner analogous to Intermediate 11 Step C using benzyl (S)-(1,1-difluoro-3-hydroxypropan-2-yl)carbamate (Step A) in place of benzyl (S*)-(1,1,1- trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate.
  • the residue was purified by silica gel chromatography (0-22% EtOAc / petroleum ether) to provide the title compound in 85% yield.
  • Step C Benzyl (S)-4-(difluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.
  • the title compound was synthesized in a manner analogous to Intermediate 11 Step D using benzyl (4S)-4-(difluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (Step B) in place of benzyl (4S*)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-5,5-d22-oxide.
  • the residue was purified by silica gel chromatography (0-17% EtOAc / petroleum ether) to provide the title compound in 44% yield.
  • Step B tert-Butyl ((S)-(7-((S)-1-(((S)-2-amino-3,3-difluoropropyl)amino)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(4,4-difluorocyclohexyl)(7-((S)-1-((S)-4-(difluoromethyl)-2- oxoimidazolidin-1-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate.
  • Step D (S)-(4,4-Difluorocyclohexyl)(7-((S)-1-((S)-4-(difluoromethyl)-2- oxoimidazolidin-1-yl)-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)methanaminium chloride.
  • Step B (R)-N-Methoxy-N-methyl-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propanamide.
  • Step D (S)-2-Methyl-N-((R,E)-2-(((R)-1,1,1-trifluoropropan-2- yl)oxy)propylidene)propane-2-sulfinamide.
  • Step E (S)-N-((1R,2R)-1-Cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2- methylpropane-2-sulfinamide.
  • Step F O-((R)-1,1,1-Trifluoropropan-2-yl)-L-threonine hydrochloride.
  • (S)-N-((1R,2R)-1- Cyano-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)-2-methylpropane-2-sulfinamide (7.6 g, 25 mmol, Step E) was dissolved in 4 M HCl in 1,4-dioxane (120 mL) and water (20 mL). The resulting mixture was heated at 80 °C for 16 h.
  • Step G N-(tert-Butoxycarbonyl)-O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine.
  • a flask was charged with O-((R)-1,1,1-trifluoropropan-2-yl)-L-threonine hydrochloride (7.3 g, 25 mmol, Step F), THF (100 mL), and 1 M aqueous NaOH (101 mL) and the mixture was allowed to stir at rt for 0.5 h.
  • Boc 2 O (5.5 g, 25 mmol) was then added in one portion and the reaction was allowed to stir for 16 h at rt.
  • the reaction mixture was poured into water (100 mL) and the biphasic mixture was extracted with EtOAc (3 x 100 mL).
  • the pH of the aqueous layer was then adjusted to pH 3-4 by the addition of citric acid.
  • the acidic aqueous layer was then extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to afford the title compound in 88% yield, which was used without further purification.
  • Step H tert-Butyl ((3S,4R)-1-(dimethyl(oxo)- ⁇ 6 -sulfaneylidene)-2-oxo-4-(((R)-1,1,1- trifluoropropan-2-yl)oxy)pentan-3-yl)carbamate.
  • THF trimethylsulfoxonium iodide
  • Step I tert-Butyl ((3S,4R)-1-chloro-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan- 3-yl)carbamate.
  • Step J tert-Butyl ((3S,4R)-1-iodo-2-oxo-4-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pentan-3- yl)carbamate.
  • Step A Benzyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide
  • Step A Benzyl (S)-(1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate.
  • the title compound was synthesized in a manner analogous to Intermediate 11 Step A using (S)-2-amino-3,3,3- trifluoropropan-1-ol hydrochloride in place of methyl 2-amino-3,3,3-trifluoropropanoate hydrochloride.
  • the residue was purified by silica gel chromatography (40-50% EtOAc / petroleum ether) to provide the title compound in 85% yield.
  • Step B Benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide.
  • the title compound was synthesized in a manner analogous to Intermediate 11 Step C using benzyl (S)-(1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (Step A) in place of benzyl (S*)-(1,1,1- trifluoro-3-hydroxypropan-2-yl-3,3-d2)carbamate and was used without further purification.
  • Step C Benzyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.
  • Step B tert-Butyl ((1R,2R)-1-(7-((S)-1-amino-2-methoxyethyl)-6-chloroimidazo[1,2- b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propyl)carbamate.
  • Step C tert-Butyl ((1R,2R)-1-(6-chloro-7-((5S,8S)-3-oxo-1-phenyl-5-(trifluoromethyl)- 2,10-dioxa-4,7-diazaundecan-8-yl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan- 2-yl)oxy)propyl)carbamate.
  • Step D tert-Butyl ((1R,2R)-1-(7-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2- yl)oxy)propyl)carbamate.
  • the resulting heterogenous solution was heated at 85 °C for 1 h under a N 2 atmosphere.
  • the reaction mixture was then filtered through diatomaceous earth (e.g., Celite ® ), concentrated to dryness, and purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to afford the title compound in 46% yield.
  • diatomaceous earth e.g., Celite ®
  • Step E tert-Butyl ((1R,2R)-1-(7-((S)-2-methoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1- trifluoropropan-2-yl)oxy)propyl)carbamate.
  • Step F (1R,2R)-1-(7-((S)-2-Methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-(((R)-1,1,1-trifluoropropan-2-yl)oxy)propan-1-aminium 2,2,2-trifluoroacetate.
  • Step B ((4S)-4-Phenyl-2-(trifluoromethyl)oxazolidin-2-yl)methanol.
  • Step C (S)-3,3,3-Trifluoro-2-(((S)-2-hydroxy-1-phenylethyl)amino)-2-methylpropan-1- ol.
  • Step D (S)-2-Amino-3,3,3-trifluoro-2-methylpropan-1-ol hydrochloride.
  • palladium hydroxide on carbon (1.07 g, 7.60 mmol)
  • HCl in water (2 M, 11.4 mL, 22.8 mmol
  • Step E (S)-3,3,3-Trifluoro-2-methyl-2-((4-nitrophenyl)sulfonamido)propyl 4- nitrobenzenesulfonate.
  • Step F (S)-2-Methyl-1-((4-nitrophenyl)sulfonyl)-2-(trifluoromethyl)aziridine.
  • the resulting mixture was heated at 50 °C for 3 h.
  • the reaction mixture was then cooled to rt and AcOH (0.181 mL, 3.17 mmol), MeOH (0.71 mL) and sodium cyanoborohydride (119 mg, 1.90 mmol) were added.
  • the mixture was heated at 50 °C for 30 min.
  • the reaction mixture was then cooled to rt, diluted with saturated aqueous NaHCO 3 and EtOAc, and filtered through diatomaceous earth (e.g., Celite ® ). The filtrate was concentrated to remove the MeOH.
  • EtOAc 15 mL
  • Step B (S)-1-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)methyl)-4-methyl-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B tert-Butyl ((R)-1-(7-((S)-1-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)- 2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Thiophenol (15.7 ⁇ L, 0.15 mmol) in MeCN (0.5 mL) was cooled to 0 °C in an ice-water bath. Then, potassium carbonate (28.7 mg, 0.207 mmol) was slowly added.
  • Step C tert-Butyl ((R)-1-(7-((S)-2-methoxy-1-((S)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step D (S)-1-((S)-1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-methyl-4- (trifluoromethyl)imidazolidin-2-one.
  • reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to provide the title compound (48% yield).
  • Step B tert-Butyl ((S)-1-(7-((S)-1-(1,3-dioxoisoindolin-2-yl)-2- methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)carbamate.
  • Step C tert-Butyl ((S)-1-(7-((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)- 5,5,5-trifluoro-4,4-dimethylpentyl)carbamate.
  • the reaction mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth (e.g., Celite ® ) and the filtrate was concentrated to dryness.
  • the residue was purified by silica gel chromatography (0-100 % acetone / hexanes (0.1 % TEA)) to provide the title compound (76% yield).
  • Step B tert-Butyl ((R)-1-(7-((S)-1-amino-2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)- 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step C tert-Butyl ((R)-1-(7-((5S,8S)-3-oxo-1-phenyl-5-(trifluoromethyl)-2,10-dioxa-4,7- diazaundecan-8-yl-5,6,6-d 3 )imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Step D tert-Butyl ((R)-1-(7-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl-1,1,2-d 3 )amino)- 2-methoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate.
  • Step E tert-Butyl ((R)-1-(7-((S)-2-methoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl-4,5,5-d3)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate.
  • diatomaceous earth e.g., Celite ®
  • Step F (S)-1-((S)-1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2- one-4,5,5-d 3 .
  • Step B Benzyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d 3 2- oxide.
  • Step C Benzyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate-4,5,5-d32,2- dioxide.
  • Step B Ethyl (S,Z)-3,3,3-trifluoro-2-((2-hydroxy-1-phenylethyl)imino)propanoate.
  • Step C (S)-3,3,3-Trifluoro-2-(((S)-2-hydroxy-1-phenylethyl)amino)propan-1,1,2-d 3 -1-ol.
  • Step D (S)-2-Amino-3,3,3-trifluoropropan-1,1,2-d3-1-ol hydrochloride.
  • the filtrate was concentrated to dryness and purified sequentially by silica gel chromatography (20-50% acetone / hexanes) and chiral SFC (Chiralpak IF, 5 ⁇ m, 250 x 21 cm, 15% MeOH : isopropanol with 0.2% isopropylamine / 85% CO2) to afford the title compound as the first eluting isomer in 8% yield.
  • Step B tert-Butyl ((S)-1-(7-((S)-1-amino-2-cyclopropoxyethyl)-6-chloroimidazo[1,2- b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate.
  • Step C tert-Butyl ((S)-1-(7-((S)-1-(((S)-2-(((benzyloxy)carbonyl)amino)-3,3,3- trifluoropropyl)amino)-2-cyclopropoxyethyl)-6-chloroimidazo[1,2-b]pyridazin-2-yl)-4,4,4- trifluoro-3,3-dimethylbutyl)carbamate.
  • Step D tert-Butyl ((S)-1-(7-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2- cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutyl)carbamate.
  • Step E tert-Butyl ((S)-1-(7-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3,3- dimethylbutyl)carbamate.
  • Step F (S)-1-((S)-1-(2-((S)-1-Amino-4,4,4-trifluoro-3,3-dimethylbutyl)imidazo[1,2- b]pyridazin-7-yl)-2-cyclopropoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B tert-Butyl ((S)-1-(7-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4- dimethylpentyl)carbamate.
  • Step C (S)-1-((S)-1-(2-((S)-1-Amino-5,5,5-trifluoro-4,4-dimethylpentyl)imidazo[1,2- b]pyridazin-7-yl)-2-cyclopropoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B tert-Butyl ((S)-3-(((R*)-1-(3-chloro-6-pivalamidopyridazin-4-yl)-3- methoxypropyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate.
  • Step C N-(5-((R*)-1-(((S)-2-Amino-3,3,3-trifluoropropyl)amino)-3-methoxypropyl)-6- chloropyridazin-3-yl)pivalamide.
  • Step D N-(6-Chloro-5-((R*)-3-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)propyl)pyridazin-3-yl)pivalamide.
  • Step E (S)-1-((R*)-1-(6-Amino-3-chloropyridazin-4-yl)-3-methoxypropyl)-4- (trifluoromethyl)imidazolidin-2-one.
  • N-(6-chloro-5-((R*)-3-methoxy-1- ((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridazin-3-yl)pivalamide 210 mg, 0.48 mmol, Step D) in MeOH (3.6 mL) was added aqueous H2SO4 (3 M, 3.6 mL, 10.8 mmol) and the reaction mixture was heated at 55 °C for 18 h.
  • reaction mixture was cooled to rt, diluted with EtOAc and treated with aqueous 3 M NaOH until the pH of the mixture was pH >12.
  • the aqueous layer was extracted three times with EtOAc, twice with DCM, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound that was used without further purification.
  • Step B tert-Butyl ((S)-(4,4-difluorocyclohexyl)(7-((R*)-3-methoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)propyl)imidazo[1,2-b]pyridazin-2-yl)methyl)carbamate.
  • Step C (S)-1-((R*)-1-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)-3-methoxypropyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B (2R, 5S)-2-Isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5- dihydropyrazine.
  • (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.66 g, 3.59 mmol) in THF (7 mL) at -78 oC was added t-BuLi (2.33 mL, 3.95 mmol, 1.7 M in pentane), and the reaction was allowed to stir at -78 oC.
  • the second-eluting isomer designated as the R,R diastereomer, (2R,5R)-2-isopropyl-3,6- dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine, was isolated in 28% yield.
  • Step C Methyl (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate.
  • Step D Methyl (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5- dimethylhexanoate.
  • methyl (S)-2-amino-6,6,6-trifluoro-5,5- dimethylhexanoate 810.6 mg, 3.57 mmol, Step C) in DCM (15.1 mL) was added Boc2O (1.56 g, 7.14 mmol). After 24 h, the reaction was quenched with aqueous HCl (10 mL, 1 M), and the layers were separated.
  • Step E (S)-2-((tert-Butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid.
  • Step F tert-Butyl (S)-(1-(dimethyl(oxo)- ⁇ 6 -sulfaneylidene)-7,7,7-trifluoro-6,6-dimethyl- 2-oxoheptan-3-yl)carbamate.
  • Step B tert-Butyl (S)-(7,7,7-trifluoro-1-iodo-6,6-dimethyl-2-oxoheptan-3-yl)carbamate.
  • Step B (E)-N-(6-Chloro-5-(2-(dimethylamino)vinyl)pyridazin-3-yl)pivalamide.
  • N-(6- Chloro-5-methylpyridazin-3-yl)pivalamide 29.9 g, 131 mmol, Step A
  • 1,1-diethoxy-N,N- dimethylmethanamine 98.6 mL, 591 mmol
  • DMF (10.2 mL
  • Step C N-(6-Chloro-5-formylpyridazin-3-yl)pivalamide.
  • Step D N-(6-Chloro-5-(2-cyclopropoxy-1-hydroxyethyl)pyridazin-3-yl)pivalamide.
  • Tributyl(cyclopropoxymethyl)stannane (12.0 g, 33.1 mmol, Intermediate 49) and THF (50 mL) were added to an oven-dried and nitrogen-purged three-neck round-bottomed flask fitted with a thermometer, which was subsequently cooled to -65 °C.
  • Step E (S)-N-(6-Chloro-5-(2-cyclopropoxy-1-(1,3-dioxoisoindolin-2-yl)ethyl)pyridazin- 3-yl)pivalamide.
  • N-(6-Chloro-5-(2-cyclopropoxy-1-hydroxyethyl)pyridazin-3-yl)pivalamide (3.80 g, 12.1 mmol, Step D)
  • phthalimide (3.56 g, 24.2 mmol)
  • Ph 3 P (15.9 g, 60.6 mmol)
  • THF 160 mL
  • the resulting mixture was cooled to 0 °C then treated with DEAD (9.54 mL, 60.6 mmol) dropwise via syringe over 15 min at 0 °C.
  • the oil was initially purified by silica gel chromatography (0- 50% EtOAc / petroleum ether) and then further purified by SFC (DAICEL CHIRALPAK IG 10 mm, 250 x 50 mm, isocratic elution: 35% (0.1% NH3H2O in IPA) / 65% CO2) to afford the title compound as the first eluting isomer in 41% yield.
  • SFC DICEL CHIRALPAK IG 10 mm, 250 x 50 mm, isocratic elution: 35% (0.1% NH3H2O in IPA) / 65% CO2
  • Step B tert-Butyl ((S)-3-(((S)-1-(3-chloro-6-pivalamidopyridazin-4-yl)-2- cyclopropoxyethyl)amino)-1,1,1-trifluoropropan-2-yl)carbamate.
  • Step C N-(5-((S)-1-(((S)-2-Amino-3,3,3-trifluoropropyl)amino)-2-cyclopropoxyethyl)-6- chloropyridazin-3-yl)pivalamide.
  • Step D N-(6-Chloro-5-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)pyridazin-3-yl)pivalamide.
  • N- (5-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-cyclopropoxyethyl)-6-chloropyridazin-3- yl)pivalamide (193 mg, 0.455 mmol, Step C) in THF (2.3 mL) was added CDI (148 mg, 0.911 mmol).
  • N-(6-chloro-5-((S)-2-cyclopropoxy-1- ((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridazin-3-yl)pivalamide (618 mg, 1.03 mmol, Step D) in 1,4-dioxane (4 mL) was added aqueous H 2 SO 4 (3 M, 3.4 mL, 10.3 mmol) and the reaction mixture was heated at 60 °C for 6 h. The reaction mixture was cooled to rt, diluted with EtOAc (80 mL) and water (80 mL) and then cooled to 0 °C.
  • Step F tert-Butyl ((R)-1-(6-chloro-7-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)carbamate.
  • the reaction mixture was then diluted with EtOAc, water and saturated aqueous NaS 2 O 3 .
  • the layers were separated, and the aqueous phase was further extracted with EtOAc (x 3).
  • the combined organic extracts were washed with brine, dried over anhydrous Na2SO4 filtered and concentrated to dryness.
  • the residue was purified by silica gel chromatography (0-100% acetone / hexanes (0.1% TEA)) to afford the title compound in 70% yield.
  • Step G tert-Butyl ((R)-1-(7-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)carbamate.
  • Step H (S)-1-((S)-1-(2-((R)-1-Amino-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)imidazo[1,2-b]pyridazin-7-yl)-2-cyclopropoxyethyl)-4- (trifluoromethyl)imidazolidin-2-one.
  • diatomaceous earth e.g., Celite ®
  • Step B tert-Butyl (4S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide.
  • An oven dried round bottom flask was cooled and backfilled with N 2 , then a solution of SOCl 2 (0.56 mL, 7.7 mmol) in CH3CN (15 mL) was added.
  • Step C tert-Butyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide.
  • Step B tert-Butyl ((S)-(7-((S)-1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2- cyclopropoxyethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((S)-2-cyclopropoxy-1-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step D (S)-1-((S)-1-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)-2-cyclopropoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one.
  • Step B (2R, 5S)-2-Isopropyl-3,6-dimethoxy-5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5- dihydropyrazine.
  • (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.66 g, 3.59 mmol) in THF (7 mL) at -78 oC was added t-BuLi (2.33 mL, 3.95 mmol, 1.7 M in pentane), and the reaction mixture was allowed to stir at -78 oC.
  • the second-eluting isomer designated as the R,R diastereomer, (2R,5R)-2-isopropyl-3,6-dimethoxy- 5-(4,4,4-trifluoro-3,3-dimethylbutyl)-2,5-dihydropyrazine, was isolated in 28% yield.
  • Step C Methyl (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate.
  • Step D Methyl (S)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluoro-5,5- dimethylhexanoate.
  • methyl (S)-2-amino-6,6,6-trifluoro-5,5-dimethylhexanoate 811 mg, 3.57 mmol, Step C) in DCM (15.1 mL) was added Boc 2 O (1.56 g, 7.14 mmol) and the resulting mixture was stirred at rt for 24 h.
  • Step E (S)-2-((tert-Butoxycarbonyl)amino)-6,6,6-trifluoro-5,5-dimethylhexanoic acid.
  • Step F tert-Butyl (S)-(1-(dimethyl(oxo)- ⁇ 6 -sulfaneylidene)-7,7,7-trifluoro-6,6-dimethyl- 2-oxoheptan-3-yl)carbamate.
  • mixture C was filtered through diatomaceous earth (e.g., Celite ® ), the filter cake rinsed with THF, and the filtrate was concentrated and purified via silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound (56% yield) as a white foam.
  • diatomaceous earth e.g., Celite ®
  • Step B tert-Butyl (S)-(5,5,5-trifluoro-4,4-dimethyl-1-(7-vinylimidazo[1,2-b]pyridazin-2- yl)pentyl)carbamate.
  • Step C tert-Butyl (S)-(5,5,5-trifluoro-1-(7-formylimidazo[1,2-b]pyridazin-2-yl)-4,4- dimethylpentyl)carbamate.
  • a solution of NaIO4 (2.43 g, 11.4 mmol) in water (55 mL) was added to a solution of tert-butyl (S)-(5,5,5-trifluoro-4,4-dimethyl-1-(7-vinylimidazo[1,2-b]pyridazin-2- yl)pentyl)carbamate (8.81 g, 22.5 mmol, Step B) in 1,4-dioxane (55 mL).
  • Step A tert-Butyl ((S)-1-(7-((((S)-2-amino-3,3,3-trifluoro-2- methylpropyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)-5,5,5-trifluoro-4,4- dimethylpentyl)carbamate.
  • Step B tert-Butyl ((S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((S)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate.
  • Step C (S)-5,5,5-Trifluoro-4,4-dimethyl-1-(7-(((S)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentan-1-aminium 2,2,2-trifluoroacetate.
  • Step B tert-Butyl ((S)-5,5,5-trifluoro-4,4-dimethyl-1-(7-(((R)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentyl)carbamate.
  • Step C (S)-5,5,5-Trifluoro-4,4-dimethyl-1-(7-(((R)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)pentan-1-aminium 2,2,2-trilfuoroacetate.
  • reaction mixture was dissolved in DMSO and purified by preparative HPLC (C18, 5 ⁇ m, 50 x 250 mm, 10-100% MeCN / water (20 mM NH4OH)) to give the title compound as a white solid (23.3% yield).
  • Step A tert-Butyl ((1S)-(7-(((2-((tert-butoxycarbonyl)amino)-4,4- difluorocyclopentyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • the resulting mixture was stirred for 2 h at 25 °C, and was then treated with NaBH3CN (59 mg, 0.94 mmol), methanol (0.25 mL) and AcOH (0.077 mL). The resulting mixture was stirred for another 2 h at 25 °C. The reaction mixture was then poured into saturated aqueous NaHCO 3 , the pH of the reaction mixture was adjusted to pH 11 by the addition of 3 M aqueous NaOH and then the resulting solution was extracted with DCM (40 mL x 3).
  • Step B tert-Butyl ((1S)-(7-((5,5-difluoro-2-oxohexahydrocyclopenta[d]imidazol-1(2H)- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step C 1-((2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)methyl)-5,5-difluorohexahydrocyclopenta[d]imidazol-2(1H)-one.
  • Step D 4-Cyclopropyl-N-((1S)-(7-((5,5-difluoro-2-oxohexahydrocyclopenta[d]imidazol- 1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5- oxadiazole-3-carboxamide.
  • a reaction vial was charged with 4-cyclopropyl-1,2,5-oxadiazole-3- carboxylic acid (22.3 mg, 0.145 mmol), EtOAc (0.36 mL), T3P (0.078 mL, 0.13 mmol, 50% w/v solution in EtOAc), and DIPEA (0.05 mL, 0.29 mmol) and the reaction mixture was allowed to stir at rt for 5 min.
  • reaction mixture was then concentrated to remove solvent, dissolved in minimal MeOH, and applied directly to acidic reverse phase HPLC purification (Waters XSelect CSH C18, 5 ⁇ m, 19 x 100 mm; 25 – 60% H2O (with 0.16% TFA) in MeCN (with 0.16% TFA)) to afford the title compound (25% yield) as a white powder after lyophilization.
  • Step E 4-Cyclopropyl-N-((S)-(7-(((3aR*,6aS*)-5,5-difluoro-2- oxohexahydrocyclopenta[d]imidazol-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide.4-Cyclopropyl-N-((1S)-(7-((5,5- difluoro-2-oxohexahydrocyclopenta[d]imidazol-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2- yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide (10.6 mg, Step D) was purified by chiral S
  • the first eluting diastereomer was 4-cyclopropyl-N-((S)-(7- (((3aR*,6aS*)-5,5-difluoro-2-oxohexahydrocyclopenta[d]imidazol-1(2H)- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3- carboxamide (Example 7, 17% yield) that was isolated as a white solid after lyophilization.
  • the second eluting diastereomer was 4-cyclopropyl-N-((S)-(7-(((3aS*,6aR*)-5,5-difluoro-2- oxohexahydrocyclopenta[d]imidazol-1(2H)-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-1,2,5-oxadiazole-3-carboxamide (Example 8, 18% yield) that was isolated as a white solid after lyophilization.
  • Step B tert-Butyl ((S)-(7-((R)-(((R)-2-amino-2- cyclopropylethyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((R)-cyclopropyl((R)-4-cyclopropyl-2-oxoimidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step D (R)-1-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)(cyclopropyl)methyl)-4-cyclopropylimidazolidin-2-one dihydrochloride.
  • Step E N-[(S)-[7-[(R)-Cyclopropyl-[(4R)-4-cyclopropyl-2-oxo-imidazolidin-1- yl]methyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • Step B tert-Butyl ((S)-(7-((R)-(((R)-2-amino-3- methylbutyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((R)-cyclopropyl((R)-4-isopropyl-2-oxoimidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step D (R)-1-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)(cyclopropyl)methyl)-4-isopropylimidazolidin-2-one hydrochloride.
  • Step E N-[(S)-[7-[(R)-Cyclopropyl-[(4R)-4-isopropyl-2-oxo-imidazolidin-1- yl]methyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • Step B (R*)-1-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)(cyclopropyl)methyl)-4-(2,2,2-trifluoroethyl)imidazolidin-2-one.
  • Step C N-((S)-(7-((R)-Cyclopropyl((R*)-2-oxo-4-(2,2,2-trifluoroethyl)imidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • Step B (S*)-1-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2- b]pyridazin-7-yl)(cyclopropyl)methyl)-4-(2,2,2-trifluoroethyl)imidazolidin-2-one.
  • Step C N-((S)-(7-((R)-Cyclopropyl((S*)-2-oxo-4-(2,2,2-trifluoroethyl)imidazolidin-1- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • Step B tert-Butyl ((S)-(7-((R)-(((1- aminocyclopropyl)methyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)carbamate.
  • Step C tert-Butyl ((S)-(7-((R)-cyclopropyl(5-oxo-4,6-diazaspiro[2.4]heptan-6- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate.
  • Step D 6-((R)-(2-((S)-Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)(cyclopropyl)methyl)-4,6-diazaspiro[2.4]heptan-5-one hydrochloride.
  • Step E N-[(S)-[7-[(R)-Cyclopropyl-(6-oxo-5,7-diazaspiro[2.4]heptan-5- yl)methyl]imidazo[1,2-b]pyridazin-2-yl]-(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • the second eluting diastereomer was designated as N- ((R)-1-(7-((S)-2-methoxy-1-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-4- methyl-1,2,5-oxadiazole-3-carboxamide and was obtained in 29% yield.
  • the first eluting diastereomer was designated as 4-methyl-N-((S)-5,5,5-trifluoro-1-(7-((S)-2-methoxy-1- ((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)- 4,4-dimethylpentyl)-1,2,5-oxadiazole-3-carboxamide and was obtained in 37% yield.
  • the first eluting isomer was designated as the (1R*,2R*) isomer, Example 32, (15.2% yield) and the second eluting isomer was designated as the (1S*,2S*) isomer, Example 33, (16% yield).
  • Example 36 1-Isopropyl-N-((R)-1-(7-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1H- 1,2,4-triazole-5-carboxamide
  • Example 44 N-((S)-(7-((R)-2-Cyclopropoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)ethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H- pyrazole-5-carboxamide
  • the title compounds were synthesized in a manner analogous to Example 10 using (S)-1-((S)-1- (2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)-2- cyclopropoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (Intermediate 52) in place of (S)-1- ((S)-1-(2-((R)-1-amino-2-((
  • the diastereomers were separated via SFC (Stationary phase: Whelk O1 SS 5 ⁇ m, 250 x 21 mm, Mobile phase: 20% methanol, 80% CO 2 ) to afford the first eluting isomer (Example 43) in 33% yield and the second eluting isomer (Example 44) in 5% yield.
  • Step B (S)-(2-(Amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7- yl)methanol.
  • Step C (S)-(2-((4,4-Difluorocyclohexyl)(1-isopropyl-1H-pyrazole-5- carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl 1-isopropyl-1H-pyrazole-5- carboxylate.
  • Step D (S)-N-((4,4-Difluorocyclohexyl)(7-(hydroxymethyl)imidazo[1,2-b]pyridazin-2- yl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
  • Step E (S)-N-((7-(Bromomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
  • the reaction mixture was stirred for 30 min while the ice bath was allowed to warm to rt.
  • the reaction was cooled to 0 °C and additional polymer-bound triphenylphosphine (156 mg, 0.47 mmol), 1H-imidazole (32.1 mg, 0.47 mmol), and carbon tetrabromide (155 mg, 0.47 mmol) were added.
  • the resulting mixture was stirred for 40 min while the ice bath was allowed to warm to rt.
  • the reaction mixture was filtered, the solids rinsed with DCM, and the filtrate concentrated to dryness. The residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound (21% yield).
  • Step F tert-Butyl (S)-(1-(((((2-((4,4-difluorocyclohexyl)(1-isopropyl-1H-pyrazole-5- carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)amino)methyl)-3,3- difluorocyclobutyl)carbamate.
  • Step G (S)-N-((7-(((((1-Amino-3,3- difluorocyclobutyl)methyl)amino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
  • Step H (S)-N-((7-((2,2-Difluoro-6-oxo-5,7-diazaspiro[3.4]octan-7- yl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H- pyrazole-5-carboxamide.
  • Protocol 1 40 nL of 2-fold serial diluted compound solution for total 22 dilution points is added into each well of a 1536-well, white, low-volume, non-binding plate (Greiner #782904), then 2 ⁇ l of FLAG tagged IL-17A at 2x final concentration (2.5 nM) in solution of PBS+ 0.01% Triton-X100 is added to each well. The assay plate is briefly centrifuged then incubated for 1 h at rt.
  • a mixed solution is prepared containing 2x 5nM 10HISxIL-17RA, 2x 2.5nM Eu-anti-FLAG (CISBIO), 2x 5nM D2-anti-HIS (CISBIO) in PBS + 0.01% Triton-X100 + 200 mM Potassium Fluoride (Sigma 60238) and 2 ⁇ l of mix is added to each well of the assay plate. The plate is briefly centrifuged then incubated for 2 h at rt. The HTRF intensities at the wavelength of donor (620 nm) and acceptor (665 nm) are measured using BMG Pherastar.
  • Protocol 2 2.40 nl of 2-fold serial diluted compound solution for total 22 dilution points is added into each well of a 1536-well, white, low-volume, non-binding plate (Greiner #782904), then 2 ⁇ l of FLAG tagged IL-17A at 2x final concentration (1 nM) in solution of PBS+ 0.01% Triton-X100 is added to each well. The assay plate is briefly centrifuged then incubated for 1 h at rt.
  • a mixed solution is prepared containing 2x 5nM 10HISxIL-17RA, 2x 2.5nM Eu-anti-FLAG (CISBIO), 2x 5nM D2-anti-HIS (CISBIO) in PBS + 0.01% Triton-X100 + 200 mM Potassium Fluoride (Sigma 60238) and 2 ⁇ l of mix is added to each well of the assay plate. The plate is briefly centrifuged then incubated for 2 h at rt. The HTRF intensities at the wavelength of donor (615 nm) and acceptor (665 nm) are measured using BMG Pherastar.
  • IL-17A acts directly on keratinocytes through binding to dimeric receptor IL-17RA/RC and drives the production of a number of inflammatory mediators known to be elevated in psoriasis lesional tissue.
  • IL-17A small molecule inhibitors that block the IL-17A to interact with IL-17R would inhibit the IL-17A signaling in its targeted cells such as keratinocytes.
  • the compound functional activity is evaluated for its impact on IL-17A-induced G-CSF production in human normal keratinocyte (NHK).
  • NHK assay Adult normal human keratinocytes are cultured in keratinocyte growth medium (Lonza) in a flask till reaching ⁇ 90% confluence, then cells are transferred to a 384-well plate at density of 3000-4000 cell/well.
  • Recombinant human IL-17A (Gibco PHC9174) is pre-incubated with titrated compound or DMSO for 1 h at rt then added to the cell culture plate. The final concentration of IL-17A is 5 ng/mL and DMSO is 0.2%, in the culture containing 5% FBS. Cells are cultured/treated for 24 h at 37 °C.
  • SEQ ID NO: 1 Name: IL-17A-Flag
  • SEQ ID NO: 2 Name: IL-17RA

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US2022/077000 2021-09-27 2022-09-26 Imidazopyridazine il-17 inhibitor compounds Ceased WO2023049886A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN202280065020.XA CN118076606A (zh) 2021-09-27 2022-09-26 咪唑并哒嗪il-17抑制剂化合物
AU2022348938A AU2022348938A1 (en) 2021-09-27 2022-09-26 Imidazopyridazine il-17 inhibitor compounds
JP2024518817A JP2024536863A (ja) 2021-09-27 2022-09-26 イミダゾピリダジンｉｌ－１７阻害剤化合物
MX2024003770A MX2024003770A (es) 2021-09-27 2022-09-26 Compuestos de imidazopiridazina inhibidores de il-17.
CA3233625A CA3233625A1 (en) 2021-09-27 2022-09-26 Imidazopyridazine il-17 inhibitor compounds
EP22790173.3A EP4408529A1 (en) 2021-09-27 2022-09-26 Imidazopyridazine il-17 inhibitor compounds
KR1020247013538A KR20240082371A (ko) 2021-09-27 2022-09-26 이미다조피리다진 il-17 억제제 화합물

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163248563P 2021-09-27 2021-09-27
US63/248,563 2021-09-27
US202163273407P 2021-10-29 2021-10-29
US63/273,407 2021-10-29
US202263371910P 2022-08-19 2022-08-19
US63/371,910 2022-08-19

Publications (1)

Publication Number Publication Date
WO2023049886A1 true WO2023049886A1 (en) 2023-03-30

Family

ID=83693127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/077000 Ceased WO2023049886A1 (en) 2021-09-27 2022-09-26 Imidazopyridazine il-17 inhibitor compounds

Country Status (10)

Country Link
US (2) US12215111B2 (https=)
EP (1) EP4408529A1 (https=)
JP (1) JP2024536863A (https=)
KR (1) KR20240082371A (https=)
AU (1) AU2022348938A1 (https=)
CA (1) CA3233625A1 (https=)
MX (1) MX2024003770A (https=)
TW (1) TW202329933A (https=)
UY (1) UY39957A (https=)
WO (1) WO2023049886A1 (https=)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024115662A1 (en) 2022-12-02 2024-06-06 Leo Pharma A/S Small molecule modulators of il-17
WO2024138286A1 (en) * 2022-12-26 2024-07-04 Usynova Pharmaceuticals, Ltd. Il-17a modulators
WO2024163365A1 (en) * 2023-01-30 2024-08-08 Dice Alpha, Inc. Benzimidazole and aza-benzimidazole based il-17a modulators and uses thereof
US12215111B2 (en) 2021-09-27 2025-02-04 Janssen Pharmaceutica Nv Imidazopyridazine IL-17 inhibitor compounds
WO2025202922A1 (en) * 2024-03-27 2025-10-02 Janssen Pharmaceutica Nv Imidazopyridazine il-17 inhibitor compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN121311483A (zh) * 2023-03-28 2026-01-09 詹森药业有限公司 含内酰胺的咪唑并哒嗪il-17抑制剂化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146194A1 (en) * 2019-01-07 2020-07-16 Eli Lilly And Company Imidazo[1,2-b]pyridazine il-17a inhibitors
WO2020261141A1 (en) * 2019-06-26 2020-12-30 UCB Biopharma SRL Imidazopyridine derivatives as il-17 modulators

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20230019507A (ko) 2020-04-30 2023-02-08 얀센 파마슈티카 엔.브이. Il-17의 조절제로서의 이미다조피리다진
WO2023025783A1 (en) 2021-08-23 2023-03-02 Leo Pharma A/S Small molecule modulators of il-17
KR20240082371A (ko) 2021-09-27 2024-06-10 얀센 파마슈티카 엔브이 이미다조피리다진 il-17 억제제 화합물
CN116143777A (zh) 2021-11-04 2023-05-23 四川海思科制药有限公司 一种可抑制il-17a的杂环化合物及其用途
TW202413363A (zh) 2021-11-04 2024-04-01 大陸商西藏海思科製藥有限公司 一種可抑制il-17a之雜環化合物及其用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146194A1 (en) * 2019-01-07 2020-07-16 Eli Lilly And Company Imidazo[1,2-b]pyridazine il-17a inhibitors
WO2020261141A1 (en) * 2019-06-26 2020-12-30 UCB Biopharma SRL Imidazopyridine derivatives as il-17 modulators

Non-Patent Citations (66)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. NM 002190.3
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
ADAMOPOULOS I.MELLINS E., NATURE REVIEWS RHEUMATOLOGY, vol. 11, 2015, pages 189 - 94
AMATYA N., TRENDS IN IMMUNOLOGY, vol. 38, 2017, pages 310 - 322
ANGEW. CHEM. INT. ED. ENGL., vol. 21, 1982, pages 567 - 583
APPEL H. ET AL., ARTHRITIS RES. THER., vol. 13, no. 3, 2011, pages R95
BAETEND. ET AL., ANN. RHEUM. DIS., vol. 77, no. 9, 2018, pages 1295 - 1302
BLAUVELT A.CHIRICOZZI A.: "The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis", CLIN REV ALLERGY IMMUNOL., vol. 55, no. 3, 2018, pages 379 - 390, XP036632999, DOI: 10.1007/s12016-018-8702-3
CAMARGO LDN. ET AL., FRONT IMMUNOL., vol. 8, 2018, pages 1835
CHAKIEVSKA L., J AUTOIMMUN., vol. 96, 2019, pages 104 - 112
CHAKIR J. ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 111, no. 6, 2003, pages 1293 - 8
CHEN X. ET AL., J. CLIN. IMMUNOL., vol. 30, no. 2, March 2010 (2010-03-01), pages 221 - 5
CHEN Y. ET AL., PLOS ONE., vol. 201, pages el8139
CHRISTENSON S. ET AL., J. CLIN. INVEST., vol. 129, no. 1, 2019, pages 169 - 181
DEODHAR A. ET AL., ARTHRITIS RHEUMATOL., vol. 71, no. 2, 2019, pages 258 - 270
DICK A. ET AL., OPHTHALMOLOGY, vol. 120, no. 4, 2013, pages 777 - 87
DOS SANTOS T. ET AL., FRONT. PHYSIOL., vol. 9, 2018, pages 1183
EBY J. ET AL., PIGMENT CELL & MELANOMA RES., vol. 27, no. 6, November 2014 (2014-11-01), pages 1075 - 85
EL-ASRAR A. ET AL., CLIN. IMMUNOL., vol. 141, no. 2, 2011, pages 197 - 204
HAVRDOVA, E. ET AL., J. NEUROL., vol. 263, 2016, pages 1287 - 1295
HAWKES ET AL.: "Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies", J ALLERGY CLIN IMMUNOL., vol. 140, no. 3, 2017, pages 645 - 653, XP085165342, DOI: 10.1016/j.jaci.2017.07.004
JANSEN D. ET AL., RHEUMATOLOGY (OXFORD)., vol. 54, no. 4, April 2015 (2015-04-01), pages 728 - 735
JAWAD S. ET AL., OCUL. IMMUNOL. INFLAMM., vol. 21, no. 6, 2013, pages 434 - 9
KELLY G. ET AL., BRITISH J. DERMATOL., vol. 173, no. 6, December 2015 (2015-12-01), pages 1431 - 9
KHATTRI S. ET AL., EXP. DERMATOL., vol. 26, no. 1, January 2017 (2017-01-01), pages 28 - 35
KOGA C. ET AL., J. INVEST. DERMATOL., vol. 128, 2008, pages 2625 - 2630
KOGA T. ET AL., EXPERT REV. CLIN. IMMUNOL., vol. 15, no. 6, 2019, pages 629 - 637
KUIPER J. ET AL., AM. J. OPHTHALMOL., vol. 152, no. 2, 2011, pages 177 - 182
LE JAN S. ET AL., J. INVEST. DERMATOL., vol. 134, no. 12, 2014, pages 2908 - 2917
LEMANCEWICZ D. ET AL., MED. SCI. MONIT., vol. 18, no. 1, 2012, pages 54 - 59
LETKO E. ET AL., OPHTHALMOLOGY, vol. 122, no. 5, 2015, pages 939 - 948
LOCK, C. ET AL., NAT. MED., vol. 8, 2002, pages 500 - 508
MA J. ET AL., CLIN. RHEUMATOL., vol. 29, no. 11, 2010, pages 1251 - 1258
MATUSEVICIUS, D. ET AL., MULT. SCLER., vol. 5, 1999, pages 101 - 104
MEASE P. ET AL., EUR. J. RHEUMATOL., vol. 6, no. 3, 1 July 2019 (2019-07-01), pages 113 - 121
MEASE, P. ET AL., ANN RHEUM DISS, vol. 79, 2020, pages 123 - 131
MENON B ET AL., ARTHRITIS & RHEUMATOLOGY, vol. 66, 2014, pages 1272 - 81
MOLET S. ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 108, no. 3, 2001, pages 430 - 8
MORANB ET AL., J. INVEST. DERMATOL., vol. 137, no. 11, 2017, pages 2389
MUGHEDDU C. ET AL., DERMATOL. THER., vol. 30, no. 5, September 2017 (2017-09-01), pages e12527
NASH P. ET AL., RHEUMATOL. THER., vol. 5, no. 1, 2018, pages 99 - 122
NAT. REV. IMMUNOL., vol. 9, 2009, pages 556 - 567
PRABHALA R. ET AL., LEUKEMIA, vol. 30, no. 2, February 2016 (2016-02-01), pages 379 - 389
PRUSSICK L. ET AL., BRITISH J. DERMATOL., vol. 181, no. 3, September 2019 (2019-09-01), pages 609 - 611
PURE & APPL. CHEM., vol. 45, 1976, pages 11 - 30
ROBERT M.MIOSSEC P., FRONT. MED., vol. 5, 2019, pages 364
SCHLAPBACH C. ET AL., J. AM. ACAD. DERMATOL., vol. 65, no. 4, 2011, pages 790
SETIADI AF ET AL., J NEUROIMMUNOL., vol. 332, 2019, pages 147 - 154
SHEN H. ET AL., ARTHRITIS RHEUM., vol. 60, no. 6, 2009, pages 1647 - 56
SINGH R. ET AL., AUTOIMMUN. REV, vol. 15, no. 4, April 2016 (2016-04-01), pages 397 - 404
STAMP, L. ET AL., IMMUNOL. CELL BIOL., vol. 82, no. 1, 2004, pages 1 - 9
STRAND V. ET AL., J. COMP. EFF. RES., vol. 8, no. 7, 2019, pages 497 - 510
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
THOMI R. ET AL., JAMA DERMATOL., vol. 154, no. 5, 2018, pages 592
TZARTOS, J. ET AL., AM. J. PATHOL., vol. 172, 2008, pages 146 - 155
VAN VOLLENHOVEN R. ET AL., LANCET, vol. 392, 2018, pages 1330 - 39
VARGAS-ROJAS M. ET AL., RESPIR. MED., vol. 105, no. 11, November 2011 (2011-11-01), pages 1648 - 54
WEN, Z. ET AL., PLOS ONE, vol. 8, 2013, pages e58161
WENDLING D. ET AL., JOINT BONE SPINE., vol. 74, 2007, pages 304 - 305
WILLING A. ET AL., J. IMMUNOL., vol. 200, no. 3, 2018, pages 974 - 982
WONG C. ET AL., CLINICAL IMMUNOLOGY., vol. 127, no. 3, 2008, pages 385 - 393
WONG C. ET AL., LUPUS, vol. 9, no. 8, 2000, pages 589 - 593
XING Q. ET AL., RHEUMATOL. INT., vol. 32, no. 4, April 2012 (2012-04-01), pages 949 - 58
ZHANG L. ET AL., PLOS ONE, vol. 7, no. 4, 2012, pages e31000
ZHANG R. ET AL., CURR. EYE RES., vol. 34, no. 4, April 2009 (2009-04-01), pages 297 - 303
ZHAO X-F. ET AL., MOL. BIOL. REP., vol. 37, no. 1, January 2010 (2010-01-01), pages 81 - 5

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12215111B2 (en) 2021-09-27 2025-02-04 Janssen Pharmaceutica Nv Imidazopyridazine IL-17 inhibitor compounds
WO2024115662A1 (en) 2022-12-02 2024-06-06 Leo Pharma A/S Small molecule modulators of il-17
US12065429B2 (en) 2022-12-02 2024-08-20 Leo Pharma A/S Small molecule modulators of IL-17
WO2024138286A1 (en) * 2022-12-26 2024-07-04 Usynova Pharmaceuticals, Ltd. Il-17a modulators
WO2024139171A1 (en) * 2022-12-26 2024-07-04 Usynova Pharmaceuticals, Ltd. Il-17a modulators
WO2024163365A1 (en) * 2023-01-30 2024-08-08 Dice Alpha, Inc. Benzimidazole and aza-benzimidazole based il-17a modulators and uses thereof
WO2025202922A1 (en) * 2024-03-27 2025-10-02 Janssen Pharmaceutica Nv Imidazopyridazine il-17 inhibitor compounds

Also Published As

Publication number Publication date
US12215111B2 (en) 2025-02-04
MX2024003770A (es) 2024-06-19
CA3233625A1 (en) 2023-03-30
US20230147458A1 (en) 2023-05-11
UY39957A (es) 2023-04-14
EP4408529A1 (en) 2024-08-07
AU2022348938A1 (en) 2024-05-16
TW202329933A (zh) 2023-08-01
US20250206744A1 (en) 2025-06-26
JP2024536863A (ja) 2024-10-08
KR20240082371A (ko) 2024-06-10

Similar Documents

Publication Publication Date Title
WO2023049886A1 (en) Imidazopyridazine il-17 inhibitor compounds
US11702422B2 (en) Imidazopyridazines as modulators of IL-17
EP3559009B1 (en) Compositions and methods for inhibiting arginase activity
EP4408847A1 (en) Imidazopyridazine il-17 inhibitor compounds
US12559496B2 (en) Imidazopyrimidines as modulators of IL-17
WO2023049885A1 (en) Benzimidazole and azabenzimidazole il-17 inhibitor compounds
EP4688156A1 (en) Lactam-containing imidazopyridazine il-17 inhibitor compounds
CN118076606A (zh) 咪唑并哒嗪il-17抑制剂化合物
EA049269B1 (ru) Соединения ингибиторов il-17 на основе имидазопиридазина
CN118317962A (zh) 咪唑并哒嗪il-17抑制剂化合物
HK40056484A (en) Compositions and methods for inhibiting arginase activity
HK40011974A (en) Compositions and methods for inhibiting arginase activity
HK40011974B (en) Compositions and methods for inhibiting arginase activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22790173

Country of ref document: EP

Kind code of ref document: A1

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024004857

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2024518817

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3233625

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 202280065020.X

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 202417031425

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20247013538

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: AU2022348938

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022790173

Country of ref document: EP

Effective date: 20240429

ENP Entry into the national phase

Ref document number: 2022348938

Country of ref document: AU

Date of ref document: 20220926

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112024004857

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20240312