Use of linked-ring-containing compound for treating psoriasis

Abstract

The present disclosure relates to the field of medicinal chemistry, and provides a use of a linked-ring-containing compound (I) for treating psoriasis.

Description

Use of bi-cyclic containing compounds for the treatment of psoriasis

[0001] Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411081292.6, filed on August 7, 2024, in the State Intellectual Property Office of the People’s Republic of China, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicinal chemistry, and provides use of bi-cyclic containing compounds for the treatment of psoriasis. BACKGROUND

[0004] Immune mechanisms play an important role in the occurrence of psoriasis, and the interaction between innate immunity and adaptive immunity leads to the production of inflammatory mediators, thereby inducing inflammation and leading to excessive proliferation of keratinocytes. Janus kinase (JAK) is a family of intracellular non-receptor tyrosine kinases, and there are four members in this kinase family: JAK1, JAK2, JAK3 and TYK2. The homology of different subtypes of JAK family is 40% to 70%. The downstream pathway of JAK is the Signal Transducers and Activators of Transcription (STAT) family. The JAK-STAT signal transduction pathway is involved in the development, differentiation, maturation, apoptosis and functional expression of various immune and hematopoietic cells, and has important influence on the regulation of immune response, immune cell differentiation and development, and inflammatory response. Inhibitors targeting tyrosine kinase 2 (TYK2) have potential therapeutic effects on psoriasis. Inhibition of TYK2 is expected to affect various immune-mediated disorders through its influence on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and the regulation of various immune pathways and cell types driven by type I interferons. IL-23 stimulates the production of key pro-inflammatory cytokines by Thl7 cells, including IL-17A, IL-17F and IL-22, all of which are effector molecules important for the pathogenesis of diseases such as psoriasis. SUMMARY

[0005] The present disclosure provides a method of treating psoriasis in a subject, comprising administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0006] wherein T 7 , T 8 , T 9 , T10 , T 11 , and T 12 are each independently selected from CH, C, NH, N, O, or a bond, wherein one or two are selected from NH or N;

[0007] each R 3 is independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl, said C 1-3 alkyl or C 3-6 cycloalkyl being optionally substituted with one or more halogen, hydroxyl, amino, or cyano;

[0008] m is selected from 1 or 2.

[0009] In some embodiments, X is selected from CH or X.

[0010] In some embodiments, the present disclosure provides a method of treating psoriasis in a subject, comprising administering to the subject the compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0011] wherein, T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 are each independently selected from CH, C, NH, N, O, or a bond, wherein at least one or two are selected from NH or N;

[0012] each R 3 is independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-3 alkyl or C 3-6 cycloalkyl, said C 1-3 alkyl or C 3-6 cycloalkyl being optionally substituted with one or more halogen, hydroxyl, amino, or cyano;

[0013] m is selected from 1 or 2,

[0014] X is N.

[0015] In some embodiments, the method of treating psoriasis in a subject comprises administering to the subject an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating psoriasis in a subject comprises administering to the subject a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the T 7 , T 8 , T 9 , T10 , T 11 , and T 12 are each independently selected from CH, C, NH, N, O, or a bond, wherein one, two, or three are selected from NH or N.

[0017] In some embodiments, each R 3 is independently selected from F, methyl optionally substituted with one or more F, or cyclopropyl.

[0018] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

[0019] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound A, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound B, or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound C, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound D, or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound E, or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound F, or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered in a single dose or in multiple doses.

[0026] In another aspect, the present disclosure provides the compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating psoriasis.

[0027] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-F), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating psoriasis.

[0028] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-F), or a pharmaceutically acceptable salt thereof, in treating psoriasis.

[0029] In another aspect, the present disclosure provides a kit comprising the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof, and instructions for using the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof to treat or prevent psoriasis. In some embodiments, in the kit, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof is present in a single dose or multiple doses.

[0030] In another aspect, the present disclosure provides the use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing psoriasis. The present disclosure provides a method of treating or preventing psoriasis, comprising administering to a subject in need thereof an effective amount of a kit of the present disclosure. The present disclosure provides the use of a kit of the present disclosure in the treatment or prevention of psoriasis. The present disclosure provides a kit of the present disclosure for use in the treatment or prevention of psoriasis.

[0031] In some embodiments, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof can be in the form of a pharmaceutical composition.

[0032] In another aspect, the present disclosure provides a pharmaceutical composition for treating psoriasis, comprising a compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present disclosure provides a method of treating psoriasis in a subject, comprising administering to the subject a pharmaceutical composition of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating psoriasis in a subject comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, the present disclosure provides the use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating psoriasis.

[0035] In another aspect, the present disclosure provides the use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof in the treatment of psoriasis. In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof to treat psoriasis. In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0036] In another aspect, the present disclosure provides a method of treating psoriasis in a subject, comprising administering to the subject Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

[0037] In some embodiments, the present disclosure relates to a method of treating psoriasis in a subject, comprising administering to the subject an effective amount of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, the present disclosure provides Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, for use in treating psoriasis.

[0039] In another aspect, the present disclosure provides the use of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating psoriasis.

[0040] In another aspect, the present disclosure provides the use of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, in treating psoriasis.

[0041] In another aspect, the present disclosure provides a kit comprising Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, and instructions for using Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, to treat or prevent psoriasis. In some embodiments, in the kit, Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is present in a single dose or multiple doses.

[0042] In some embodiments, Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, can be in the form of a pharmaceutical composition.

[0043] In another aspect, the present disclosure provides a pharmaceutical composition for treating psoriasis, comprising Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, the present disclosure provides a method of treating psoriasis in a subject, comprising administering to the subject a pharmaceutical composition of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating psoriasis in a subject comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof.

[0045] In yet another aspect, the present disclosure provides use of a pharmaceutical composition of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating psoriasis.

[0046] In yet another aspect, the present disclosure provides use of a pharmaceutical composition of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, in treating psoriasis. In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit further comprising instructions for using Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, to treat psoriasis. In some embodiments of the present disclosure, the pharmaceutical composition further contains a pharmaceutically acceptable excipient.

[0047] In some embodiments, Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is administered in a single dose or multiple doses.

[0048] Psoriasis

[0049] In some embodiments, the psoriasis is selected from plaque psoriasis.

[0050] In some embodiments, the psoriasis is selected from moderate-to-severe psoriasis.

[0051] In some embodiments, the psoriasis is selected from moderate-to-severe plaque psoriasis.

[0052] In some embodiments, the psoriasis is selected from psoriasis suitable for systemic treatment or phototherapy.

[0053] In some embodiments, the psoriasis is selected from stable moderate-to-severe plaque psoriasis and psoriasis with a history of > 6 months.

[0054] In some embodiments, the psoriasis is selected from psoriasis without changes in lesion morphology or significant flares of disease.

[0055] In some embodiments, the psoriasis is selected from psoriasis suitable for systemic treatment or phototherapy.

[0056] In some embodiments, the psoriasis is selected from psoriasis with a PASI score of > 12 points, BSA of > 10%, and sPGA of > 3 points.

[0057] In some embodiments, the psoriasis is selected from psoriasis that meets the following conditions simultaneously:

[0058] (1) stable moderate-to-severe plaque psoriasis and a history of > 6 months without changes in the morphology of the skin lesions or a significant flare of the disease;

[0059] (2) eligible for systemic treatment or phototherapy;

[0060] (3) PASI score of > 12, BSA of > 10%, sPGA of > 3 at screening and baseline.

[0061] In some embodiments, the phototherapy is selected from ultraviolet light therapy (e.g., NB-UVB therapy).

[0062] In some embodiments, the patient (subject) having psoriasis is an adult patient.

[0063] In some embodiments, the patient (subject) having psoriasis is an adult patient with moderate-to-severe plaque psoriasis eligible for systemic treatment or phototherapy.

[0064] In some embodiments, the psoriasis is not guttate psoriasis, generalized pustular psoriasis, erythrodermic psoriasis, or psoriatic arthritis.

[0065] In some embodiments, the psoriasis is not selected from psoriasis that has received systemic treatment for psoriasis or immunosuppressive therapy within 4 weeks, including but not limited to retinoids, glucocorticoids, methotrexate, cyclosporine, azathioprine, JAK inhibitors, and the like.

[0066] In some embodiments, a mean reduction of about 25% or greater in PASI is achieved.

[0067] In some embodiments, a mean reduction of about 35% or greater in PASI is achieved.

[0068] In some embodiments, a mean reduction of about 45% or greater in PASI is achieved.

[0069] In some embodiments, a mean reduction of about 25% to 50% in PASI is achieved.

[0070] In some embodiments, a mean reduction of about 50% to 75% in PASI is achieved.

[0071] In some embodiments, a mean reduction of about 75% to 100% in PASI is achieved.

[0072] In some embodiments, a physician's global assessment (sPGA) of 0, 1, or 2 is achieved.

[0073] In some embodiments, a physician's global assessment (sPGA) of 0 or 1 is achieved.

[0074] In some embodiments, a physician's global assessment (sPGA) of 0 is achieved.

[0075] In some embodiments, the Dermatology Life Quality Index (DLQI) score is reduced by about 1 to 30.

[0076] In some embodiments, the proportion of subjects with PASI 50 is greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95%. In some embodiments, the proportion of subjects with PASI 50 is greater than 60%, e.g., 60%-95%, 60%-90%, or 70%-90%; in some embodiments, the proportion of subjects with PASI 50 is about 80%.

[0077] In some embodiments, the proportion of subjects with PASI 75 is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, or greater than 85%. In some embodiments, the proportion of subjects with PASI 75 is greater than 60%, e.g., 60%-95%, or 60%-80%. In some embodiments, the proportion of subjects with PASI 75 is about 70%.

[0078] In some embodiments, the proportion of subjects with PASI 90 is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, or greater than 60%. In some embodiments, the proportion of subjects with PASI 90 is greater than 25%, e.g., 25%-70%; or 25%-50%; in some embodiments, the proportion of subjects with PASI 90 is about 40%.

[0079] In some embodiments, the proportion of subjects with PASI 100 is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, or greater than 40%; in some embodiments, the proportion of subjects with PASI 100 is greater than 5%, e.g., 5%-50%, or 5%-35%, e.g., about 10%.

[0080] In some embodiments, the proportion of sPGA 0 / 1 subjects is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, or greater than 90%. In some embodiments, the proportion of sPGA 0 / 1 subjects is greater than 60%, e.g., 60-85%, or 65-75%; in some embodiments, the proportion of sPGA 0 / 1 subjects is about 70%.

[0081] In some embodiments, the proportion of sPGA 0 subjects is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%.

[0082] In some embodiments, the proportion of sPGA 1 subjects is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, or greater than 90%. In some embodiments, the proportion of sPGA 1 subjects is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%.

[0083] In some embodiments, the BSA score is reduced by about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 30-40%. Or reduced by about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100% relative to baseline.

[0084] In some embodiments, the DLQI score can be reduced by about 1 to 3, about 3 to 6, about 6 to 9, about 9 to 12; or can be reduced by about 15, about 15 to 18, about 18 to 21, about 21 to 24, about 24 to 27, or about 27 to 30, relative to baseline. Alternatively, the DLQI score can be reduced by about 5, or about 6 to 9, relative to baseline.

[0085] In some embodiments, the proportion of subjects achieving PASI 50 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks), or longer, is greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, or greater than 85%; in some embodiments, greater than 60%, e.g., 60%-95%, 60%-90%, or 70%-90%; in some embodiments, about 80%.

[0086] In some embodiments, the proportion of subjects achieving PASI 75 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks), or longer, is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, or greater than 85%; in some embodiments, greater than 60%, e.g., 60%-95%, or 60%-80%; in some embodiments, about 70%.

[0087] In some embodiments, the proportion of subjects achieving PASI 90 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks), or longer, is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, or greater than 60%; in some embodiments, greater than 25%, e.g., 25%-70%; or 25%-50%; in some embodiments, about 40%.

[0088] In some embodiments, the proportion of subjects achieving PASI 100 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks), or longer, is greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, or greater than 40%; in some embodiments, greater than 5%, e.g., 5%-50%, or 5%-35%, e.g., about 10%.

[0089] In some embodiments, the proportion of subjects achieving sPGA 0 / 1 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, or greater than 90%. In some embodiments, the proportion of subjects achieving sPGA 0 / 1 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer is greater than 60%, e.g., 60-85%, or 65-75%; in some embodiments, about 70%.

[0090] In some embodiments, the proportion of subjects achieving sPGA 0 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, or greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%.

[0091] In some embodiments, the proportion of subjects achieving sPGA 1 at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer is greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, or greater than 40%, or greater than 50%, or greater than 60%, or greater than 70%.

[0092] In some embodiments, the BSA score is reduced by about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 30-40% relative to baseline at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer. Alternatively, the BSA score is reduced by about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100% relative to baseline at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer.

[0093] In some embodiments, the DLQI score is reduced by about 1 to 3, about 3 to 6, about 6 to 9, about 9 to 12 relative to baseline at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer. Alternatively, the DLQI score is reduced by about 15, about 15 to 18, about 18 to 21, about 21 to 24, about 24 to 27, or about 27 to 30 relative to baseline at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer. Alternatively, the DLQI score is reduced by about 5, or about 6 to 9 relative to baseline at weeks 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) or longer.

[0094] In some embodiments, the method achieves improvement in Psoriasis Disease Activity Score at week 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) of treatment. In some embodiments, the method achieves improvement in Physician's Global Assessment of Psoriasis, e.g., at week 12-52 (e.g., 12 weeks, 16 weeks, 24 weeks, or 52 weeks) of treatment.

[0095] In some embodiments, the method achieves improvement in Psoriasis Disease Activity Score at week 12 of treatment. In some embodiments, the method achieves improvement in Physician's Global Assessment of Psoriasis, e.g., at week 12 of treatment.

[0096] Dosing regimen

[0097] In some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from the group consisting of 2-64 mg; in some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from the group consisting of 2-32 mg; or the daily (or each) dose is selected from the group consisting of 4-28 mg; or the daily (or each) dose is selected from the group consisting of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing values; or the daily (or each) dose is selected from the group consisting of 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg; or the daily (or each) dose is selected from the group consisting of 6 mg, 12 mg, or 18 mg; or the daily (or each) dose is selected from the group consisting of 18 mg, 24 mg, or 32 mg.

[0098] In some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from the group consisting of 2-64 mg; in some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from the group consisting of 2-32 mg; or the daily (or each) dose is selected from the group consisting of 4-28 mg; or the daily (or each) dose is selected from the group consisting of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing values; or the daily (or each) dose is selected from the group consisting of 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg; or the daily (or each) dose is selected from the group consisting of 6 mg, 12 mg, or 18 mg; or the daily (or each) dose is selected from the group consisting of 18 mg, 24 mg, or 32 mg.

[0099] In some embodiments, the single or multiple doses of the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof are administered (or applied) in an amount selected from the group consisting of 2-64 mg; in some embodiments, the single or multiple doses of the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof are administered (or applied) in an amount selected from the group consisting of 2-32 mg; or the single or multiple doses are selected from the group consisting of 4-28 mg; or the single or multiple doses are selected from the group consisting of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or the single or multiple doses are selected from the group consisting of 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg; or the single or multiple doses are selected from the group consisting of 6 mg, 12 mg, or 18 mg; or the single or multiple doses are selected from the group consisting of 18 mg, 24 mg, or 32 mg.

[0100] In some embodiments, the daily dose of the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is administered to the patient in a single administration dose or in multiple administration doses.

[0101] In some embodiments, the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose or in multiple daily doses.

[0102] In some embodiments, the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is administered to the patient every day for, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks or more, or a range formed by any of the foregoing.

[0103] In some embodiments, the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is administered to the patient every day for a period of 2 weeks to 52 weeks, or more; or for a period of 12 weeks, 16 weeks, 24 weeks, 48 weeks, 52 weeks, or a range formed by any of the foregoing.

[0104] In some embodiments, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof is administered daily for about 1 day to 7 days, about 1 week to 3 weeks, about 3 weeks to 6 weeks, about 6 weeks to 9 weeks, about 12 weeks, or longer. Alternatively, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof is administered daily for about 12 weeks, about 12 weeks to 15 weeks, or about 15 weeks to 18 weeks, or about 15 weeks to 52 weeks, or longer.

[0105] In some embodiments, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof is administered orally to the patient daily.

[0106] In some embodiments, the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof is administered orally on an empty stomach at the same time (± 2 hours) daily. In some embodiments, the administration is once daily. In some embodiments, the administration is continuous for 12-52 weeks or longer. In some embodiments, the administration is continuous for 12 weeks, 16 weeks, 24 weeks, 52 weeks, or longer. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally on an empty stomach at the same time (± 2 hours) daily, the administration is once daily, and the administration is continuous for 12-52 weeks or longer (e.g., continuous for 12 weeks, 16 weeks, 24 weeks, 52 weeks, or longer).

[0107] In some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg once daily. In some embodiments, the daily (or each) dose of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from 18 mg, 24 mg, or 32 mg once daily. In some embodiments, the single dose or multiple doses of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg once daily. In some embodiments, the single dose or multiple doses of the compound of Formula I (e.g., Compound A-F) or a pharmaceutically acceptable salt thereof administered (or administered) is selected from 18 mg, 24 mg, or 32 mg once daily.

[0108] In some embodiments, for a single dose or multiple doses, or a daily (or each) dose of 18 mg, 24 mg, or 32 mg: the 12-week PASI 50 response rate is no less than 60%, or no less than 65%, or no less than 70%, or no less than 75%, or no less than 80%, or no less than 85%, or no less than 90%, or no less than 95%.

[0109] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg: the 12-week PASI 50 response rate is about 60-90%, or 70-90%; e.g., about 80%.

[0110] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg, 24 mg, or 32 mg: the 12-week PASI 75 response rate is no less than 60%, or no less than 65%, or no less than 70%, or no less than 75%, or no less than 80%, or no less than 85%, or no less than 90%.

[0111] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg: the 12-week PASI 75 response rate is about 60-95%, or 60-80%, e.g., about 70%.

[0112] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg, 24 mg, or 32 mg: the 12-week PASI 90 response rate is no less than 25%, or no less than 30%, or no less than 35%, or no less than 40%, or no less than 45%, or no less than 50%, or no less than 55%.

[0113] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg: the 12-week PASI 90 response rate is about 25-70%, or 25-50%, e.g., about 37%.

[0114] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg, 24 mg, or 32 mg: the 12-week PASI 100 response rate is no less than 5%, or no less than 10%, or no less than 15%, or no less than 20%, or no less than 25%, or no less than 30%, or no less than 35%.

[0115] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg: the 12-week PASI 100 response rate is about 5-50%, or 5-40%; e.g., about 10%.

[0116] In some embodiments, for a single dose or multiple doses, or a daily (per-visit) dose of 18 mg, 24 mg, or 32 mg: the 12-week sPGA 0 / 1 response rate is no less than 60%, or no less than 65%, or no less than 70%, or no less than 75%, or no less than 80%, or no less than 85%, or no less than 90%.

[0117] In some embodiments, the 18 mg: 12 week sPGA 0 / 1 response rate is about 60-90%, or 60-85%; e.g., about 70% for a single dose or multiple doses, or daily (per dose).

[0118] In some embodiments, the patients show similar or better results for the efficacy measures PASI 75, PASI 90, PASI 50, PASI 100, sPGA 0 / 1, etc. for a single dose or multiple doses, or daily (per dose) of 24-32 mg (e.g., 24 mg or 32 mg). In some embodiments, the patients show similar or better results for the efficacy measures PASI 75, PASI 90, PASI 50, PASI 100, sPGA 0 / 1, etc. at 12 weeks for a single dose or multiple doses, or daily (per dose) of 24-32 mg (e.g., 24 mg or 32 mg).

[0119] a compound of Formula I-1 or a pharmaceutically acceptable salt thereof

[0120] The compounds of Formula I (e.g., Compounds A-F) of the present disclosure can be administered in the form of their free bases, or in the form of a pharmaceutically acceptable salt, hydrate, and prodrug thereof, which can be converted to the free base form of the compound of Formula I in vivo.

[0121] The compounds of Formula I (e.g., Compounds A-F) of the present disclosure, or a pharmaceutically acceptable salt thereof, can also be administered in the form of a pharmaceutical composition. The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0122] In some embodiments, the daily (or per dose) dose of the compound of Formula I (e.g., Compounds A-F) of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 2-32 mg or 4-28 mg; or 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing values of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Alternatively, the daily (or per dose) dose of the compound of Formula I (e.g., Compounds A-F) of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 6 mg, 12 mg, or 18 mg of the compound of Formula I (e.g., Compounds A-F), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Alternatively, the daily (or per dose) dose of the compound of Formula I (e.g., Compounds A-F) of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 18 mg, 24 mg, or 32 mg of the compound of Formula I (e.g., Compounds A-F), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0123] In some embodiments, the pharmaceutical composition of the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, including but not limited to tablets or capsules.

[0124] In some embodiments, the pharmaceutical composition of the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is a single dose or a multiple dose of 2-32 mg or 4-28 mg. Specifically, the pharmaceutical composition is selected from a single dose or a multiple dose of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or any value within a range formed by any of the foregoing. In some embodiments, the single dose or the multiple dose of the pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 6 mg, 12 mg, or 18 mg. In some embodiments, the single dose or the multiple dose of the pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 18 mg, 24 mg, or 32 mg.

[0125] In some embodiments, the pharmaceutical composition comprising the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be composed of multiple single dose pharmaceutical compositions comprising the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be composed of single dose pharmaceutical compositions comprising the compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof of 2 mg or 8 mg.

[0126] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound F or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound F or a pharmaceutically acceptable salt thereof.

[0127] The compounds of the present disclosure, Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, can be administered in the form of their free bases, or in the form of a pharmaceutically acceptable salt, hydrate, and prodrug thereof, which can be converted into the free base form of the compounds in vivo.

[0128] The Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, of the present disclosure can also be administered in the form of a pharmaceutical composition thereof. The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0129] In some embodiments, the daily (or per administration) dose of the Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present disclosure is selected from 2-32 mg or 4-28 mg; or from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the aforementioned values. Alternatively, the daily (or per administration) dose of the Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present disclosure is selected from 6 mg, 12 mg, or 18 mg of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Alternatively, the daily (or per administration) dose of the Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present disclosure is selected from 18 mg, 24 mg, or 32 mg of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0130] In some embodiments, the pharmaceutical composition of the Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is selected from a solid pharmaceutical composition, including but not limited to a tablet or a capsule.

[0131] In some embodiments, the pharmaceutical composition of the Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is a pharmaceutical composition of single or multiple doses of 2-32 mg or 4-28 mg. Specifically, the pharmaceutical composition is selected from a pharmaceutical composition of single or multiple doses of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the aforementioned values. In some embodiments, the single or multiple doses of the pharmaceutical composition comprising Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is selected from 6 mg, 12 mg, or 18 mg. In some embodiments, the single or multiple doses of the pharmaceutical composition comprising Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof, is selected from 18 mg, 24 mg, or 32 mg.

[0132] In some embodiments, the pharmaceutical composition of Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof is a multiple-dose pharmaceutical composition, which can consist of multiple single-dose pharmaceutical compositions of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is a multiple-dose pharmaceutical composition, which can consist of single-dose pharmaceutical compositions of 2 mg, or 8 mg of the compound or a pharmaceutically acceptable salt thereof.

[0133] For example, in some embodiments, the pharmaceutical composition of Compound C or a pharmaceutically acceptable salt thereof is a multiple-dose pharmaceutical composition, which can consist of multiple single-dose pharmaceutical compositions of Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising Compound C or a pharmaceutically acceptable salt thereof is a multiple-dose pharmaceutical composition, which can consist of single-dose pharmaceutical compositions of 2 mg, or 8 mg of Compound C or a pharmaceutically acceptable salt thereof.

[0134] In one embodiment, the pharmaceutical combination of the present disclosure can be formulated into a pharmaceutical composition suitable for single or multiple administration. In one embodiment, the pharmaceutical combination of the present disclosure can be a single-dose or multiple-dose pharmaceutical composition.

[0135] Definitions and Descriptions

[0136] Unless otherwise indicated, the following terms used in the present disclosure have the following meanings. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood according to the ordinary meaning in the art.

[0137] The word "comprise" or "comprises" and its variations such as "comprises" or "comprising" and its equivalents are to be understood as open-ended, non-exclusive, i.e., "including but not limited to," meaning that other unmentioned elements, components, and steps are also encompassed.

[0138] The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, provided that the valency of the particular atom is normal and that the resulting compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot occur on an aromatic group.

[0139] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), mono-substituted (e.g., -CH2CH2F), poly-substituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). It will be understood by those skilled in the art that, for any group containing one or more substituents, such group does not include any substitution or substitution pattern that is not

[0140] C m-n in this document is a moiety having an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0141] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0142] The term "alkyl" means a hydrocarbon group of formula C n H 2n+1 The alkyl group can be straight-chained or branched. For example, the term "C 1-6 alkyl" means an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). For another example, the term "C 1-4 alkyl" means an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, etc.).

[0143] The term "cycloalkyl" means a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, preferably a 4- to 6-membered ring, or a 3- to 6-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0144] The term "bond" can be a single bond or a double bond.

[0145] Unless otherwise indicated, the dosages provided herein for a compound of Formula I (e.g., Compounds A-F) or a pharmaceutically acceptable salt thereof, and ranges thereof, are based on the molecular weight of the free base of the compound of Formula I (e.g., Compounds A-F).

[0146] The terms "administering" or "administered" or "administration" mean physically introducing a therapeutic agent or a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. The terms "administering" or "administered" or "administration" are used interchangeably herein.

[0147] The term "treatment" generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely arresting or reversing the symptoms of a disease and / or side effects caused by the disease. As used herein, "treatment" covers any treatment of a patient, including: (a) inhibiting the disease state, i.e., arresting its development; or (b) relieving the disease state, i.e., causing regression of the disease or symptoms.

[0148] The term "effective amount" or "therapeutically effective amount" means the amount of a compound of the disclosure that will elicit the biological or medical response of a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial consideration.

[0149] The terms "subject," "patient," or "host" are used interchangeably herein and refer to an animal, preferably a mammal, more preferably a primate, including humans and non-human primates (such as apes, monkeys, chimpanzees, and gorillas, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), and most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented.

[0150] As used in the present disclosure, the compounds of Formula I (e.g., Compounds A-F) or pharmaceutically acceptable salts thereof can be administered by any of the routes and methods known to those skilled in the art, for example, by oral or parenteral (e.g., intravenous) administration.

[0151] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the disclosure or a pharmaceutical combination thereof or a salt thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure or a pharmaceutical combination thereof to a subject.

[0152] The term "pharmaceutically acceptable excipient" means an excipient that is compatible with the active ingredients of the pharmaceutical composition for use in the methods of the present disclosure and that does not destroy the pharmacological activity of the active compounds. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0153] The pharmaceutical composition of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, e.g., can be formulated into solid preparations such as tablets, pills, capsules, and the like.

[0154] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying or lyophilizing processes.

[0155] The term "pharmaceutically acceptable" is in relation to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0156] Solid oral pharmaceutical compositions can be prepared by conventional mixing, compounding or tabletting processes. For example, the active compounds can be mixed with a solid excipient, optionally ground, and if necessary, with other suitable excipients, and then processed into granules, tablets or capsules. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavorants.

[0157] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means a salt of a compound of the present disclosure that is within the scope of the definition of "pharmaceutically acceptable." The terms "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" are used interchangeably herein.

[0158] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. The use of "or" means "and / or" unless context clearly indicates otherwise.

[0159] In this document, the terms "comprising," "including," and "containing" or any variation thereof, are intended to indicate that the products include the specified elements, but not excluding others. Thus, these terms specify the presence of the stated elements, but do not preclude the presence of additional elements.

[0160] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug product, for example, a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose; or each tablet in a box of medicine is a single dose. The term "multiple dose" is composed of multiple single doses.

[0161] The terms "day", "daily" and the like in connection with a dosage regimen refer to a period of time within a calendar day beginning at midnight and ending at the next midnight.

[0162] In this document, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0163] Unless otherwise indicated, in this document, the parameter values representing the amount or physico-chemical properties of ingredients or reaction conditions, etc. should be understood to be modified by the term "about" in all instances. When the term "about" is used to describe the present disclosure, the term "about" means that there is an error value present, for example, within ±5% of a certain particular value, such as ±1% or ±0.1%.

[0164] For the purposes of description and disclosure, all patents, patent applications, and other publications identified in this document are expressly incorporated herein by reference. These publications are provided solely for their disclosure prior to the filing date of the present disclosure. All statements as to the date or dates of these publications are based on the available information from the applications and are believed to be accurate, but are not admitted as evidence as to the correctness of the dates of such publications. Furthermore, in any country, any reference in this document to such publications is not an admission that such publications are part of the prior art in that country.

[0165] Technical effects

[0166] The compound of formula I or a pharmaceutically acceptable salt thereof of the present disclosure has better efficacy, safety, pharmacokinetic properties and pharmacodynamic properties in the treatment of psoriasis (such as plaque psoriasis).

[0167] Safety: All adverse events will be graded according to NCI-CTCAE version 5.0, and statistical description will be made for the incidence of adverse events, the analysis of adverse events and test drug correlation, and the analysis of severity, etc. according to subjects. Descriptive statistics will be made for the data of laboratory examination, vital signs, 12-lead electrocardiogram, etc. and their changes relative to baseline. In addition, if applicable, the changes in clinical significance after baseline will be analyzed in the form of cross table for applicable safety indicators before and after treatment. According to the method of the present disclosure, the incidence of all adverse events (AEs), serious adverse events (SAEs) and adverse events during treatment (TEAEs) is low and the severity is not high. Moreover, the overall safety is good according to the method of the present disclosure, the adverse events are mainly laboratory examinations, and most of them recover to normal, and no serious adverse events and adverse events above grade 3 occur.

[0168] Pharmacokinetics: According to the actual sampling time, the AUC 0-24 , T max,ss , C min,ss , C max,ss , C av，ss , AUC 0-t,ss , AUC 0-∞,ss , CL t,ss , R ac were calculated by non-compartmental analysis (NCA). Based on PKPS, the results of main pharmacokinetic parameter analysis were summarized and displayed according to dose groups by sample size, arithmetic mean, standard deviation, coefficient of variation, median value, minimum value, maximum value, and geometric mean and coefficient of variation.

[0169] Pharmacodynamics: Based on PDS, the mean values, standard deviations, medians, quartiles, minimum values and maximum values of the average detection values of IL-17A, IL-19, β-defensin, etc. at different detection time points of each group and the change values relative to baseline were described; the change values of IL-17A, IL-19, β-defensin, etc. at different detection time points of each group relative to baseline were compared with the placebo group by analysis of variance or non-parametric test method.

[0170] Efficacy analysis: Based on EAS (efficacy analysis set), the PASI score, sPGA score, DLQI score and the change from baseline, BSA score and the change from baseline, and the proportion of patients achieving sPGA 0 / 1, PASI 50, PASI 75, PASI 90, PASI 100 in each group from Week 12 to Week 52 or longer (e.g. 12 weeks, 16 weeks, 24 weeks, 48 weeks or 52 weeks) were described with mean, standard deviation, median, quartile, minimum and maximum; the comparison between groups was analyzed by chi-square test. Linear contrast method was used for trend test to test whether there was a dose-effect relationship between each dose group, and further to identify the optimal dose by appropriate method.

[0171] Terminology

[0172] PASI (Psoriasis area and severity index) is a tool to measure the severity and extent of psoriasis, with a total score ranging from 0 to 72. Generally, a PASI score of less than 5 is mild, 5-10 is moderate, and more than 10 is severe. The treatment goal of psoriasis is complete or almost complete clearance of symptoms and lesions, corresponding to PASI 100 (PASI reduced by 100% compared with the previous one), PASI 90 (PASI reduced by 90% compared with the previous one). Generally, achieving PASI 75 (PASI reduced by 75% compared with the previous one) is considered a treatment success.

[0173] sPGA (static Physician’s Global Assessment) is used to assess the overall condition of psoriasis in a subject at a given time point. Among them, the redness, infiltration, and scales are graded, and the average of the three scales is taken to get the final sPGA score, with a total score of 0-4.

[0174] BSA (Body Surface Area) score estimates 1% of the subject's total body surface area as the size of one palm area, and estimates the lesion area to roughly judge the severity of the disease. Generally, BSA < 3% is considered mild, 3%-10% is moderate, and > 10% is severe.

[0175] The DLQI (Dermatology Life Quality Index) is a widely used measure of quality of life in patients with psoriasis. It comprises 10 questions covering symptoms, feelings, daily activities, leisure, work, school, personal relationships and treatment, and is a self-completion tool for patients. Each question is scored as follows: "not relevant" and "not at all" = 0, "a little" = 1, "a lot" = 2 and "a great deal" = 3. Total scores 0-1 = no effect, 2-5 = mild effect, 6-10 = moderate effect, 11-20 = severe effect, 21-30 = extremely severe effect.

[0176] In the present text, the following terms are defined as follows, unless otherwise stated:

[0177] PASI 50 is defined as a reduction of > 50% in PASI score from baseline;

[0178] PASI 75 is defined as a reduction of > 75% in PASI score from baseline;

[0179] PASI 100 is defined as a reduction of > 100% in PASI score from baseline; i.e. complete resolution of lesions;

[0180] sPGA 0 / 1 is defined as an sPGA score of 0 or 1, i.e. complete or almost complete resolution of lesions. DETAILED DESCRIPTION

[0181] For the sake of clarity, the present disclosure is further illustrated by way of examples, which are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0182] The compounds of formula I, e.g. compounds A-F, can be prepared according to the methods disclosed in WO2022166917.

[0183] Test Example 1

[0184] Objective: The objective of this test is to evaluate the efficacy of the test articles (compounds A-F) in a C57BL / 6 mouse psoriasis model induced by mIL-23.

[0185] Methods: This test uses C57BL / 6 mice, 7 weeks old, female, randomly divided into groups, 8 in each group.

[0186] Respectively:

[0187] Normal control group;

[0188] Model group, orally administered with solvent (5% DMSO + 95% PEG400, 10 mL / kg);

[0189] Reference drug group (Deucravacitinib), oral, 16 mg / kg;

[0190] Test article low-dose group, oral, 4 mg / kg; test article mid-dose group, oral, 8 mg / kg; test article high-dose group, oral, 16 mg / kg.

[0191] In addition to the normal control group, the rest of the groups of mice were induced with psoriasis model by intradermal injection of mIL-23 in the right ear from Day 0, 1 μg / each / time, once a day, for 9 consecutive days, a total of 9 times. From Day 0, oral administration was performed twice a day, and administration was performed until Day 7, and administration was performed once in the morning of Day 8, a total of 17 times. After administration in the morning of Day 8, plasma was collected from each group at 0, 0.25, 0.5, 1, 4, 8, and 24 hours for PK analysis.

[0192] The test article was evaluated for efficacy by ear thickness, ear tissue cytokine detection, and ear HE pathological staining.

[0193] Test results:

[0194] During the test period, no obvious abnormalities were observed in the clinical observation of the animals. The body weight of all mice was not significantly abnormal, and the body weight of each administration group was comparable to that of the model group, indicating that the mice were well tolerated at this dose.

[0195] Ear thickness measurement results: compared with the normal control group, the ear thickness of the model group was significantly increased from Day 1 to Day 8 (P<0.001); compared with the model group, the ear thickness of the test article low-dose group was significantly decreased from Day 4 to Day 8 (P<0.05), the ear thickness of the test article mid-dose group was significantly decreased from Day 3 to Day 8 (P<0.01), and the ear thickness of the test article high-dose group was significantly decreased from Day 3 to Day 8 (P<0.001).

[0196] Compared with the reference drug group, the ear thickness of the test article high-dose group was significantly decreased on Day 5, Day 7-Day 8 (P<0.05). Each treatment group of the test article improved the ear thickness, and had a dose-dependent trend, and the improvement of the test article on the ear thickness at the dose of 16 mg / kg was better than that of the reference drug.

[0197] Ear weight measurement results at the end of the test: compared with the normal control group, the ear weight of the model group was significantly increased (P<0.001). Compared with the reference drug group, the ear weight of the test article high-dose group had a decreasing trend. Each treatment group of the test article improved the ear weight, and had a dose-dependent trend, and the improvement of the test article on the ear weight at the dose of 16 mg / kg was better than that of the reference drug.

[0198] The results of cytokine detection in ear tissue at the end of the test: compared with the normal control group, the level of mIL-17A in the model group was significantly increased (P<0.01); compared with the model group, the level of mIL-17A in the high-dose group of the test product was significantly decreased (P<0.01), and the level of mIL-17A in the low-dose group of the test product had a downward trend. Compared with the reference drug, the level of mIL-17A in the high-dose group of the test product had a downward trend. The test product in each treatment group of the test product improved the cytokine mIL-17A in the ear tissue, and had a dose-dependent trend. The improvement of the test product on the ear thickness at the dose of 16 mg / kg was better than that of the reference drug. The results are shown in Table 1.

[0199] Table 1 mIL-17A detection data (pg / mg protein) **P<0.01; ##P<0.01.

[0200] The results of epidermis thickness in ear tissue pathology: each treatment group of the test product improved the epidermis thickness of the ear tissue, and the low-dose group and the medium-dose group had a dose-dependent trend.

[0201] The results of ear tissue pathology inflammation score: the average value of pathological inflammation score of ear tissue epidermis (microabscess, hyperkeratosis, parakeratosis, acantholysis, granular layer deficiency) and dermis (lymphocyte infiltration, hyperemia) was calculated, and the results showed that compared with the normal control group, the ear tissue pathological inflammation score of the model group was significantly increased (P<0.001); compared with the model group, the ear tissue pathological inflammation score of the test product group was significantly decreased (P<0.05, preferably P<0.01, more preferably P<0.001). Each treatment group of the test product improved the ear tissue pathological inflammation score, and had a dose-dependent trend. The results of the average value of the total score of ear tissue pathological inflammation score of the test product at the dose of 16 mg / kg are shown in Table 2.

[0202] Table 2 Average value of total score of ear tissue pathological inflammation score ***P<0.001; ###P<0.001.

[0203] The results of pharmacokinetic detection: the drug exposure of each test product in mice showed a good dose-dependent relationship. The drug exposure of the test product in mice was better than that of the control drug at the same dose, and the drug exposure of the test product in the ear tissue of mice was also better than that of the control drug at the same dose. The results are shown in Table 3.

[0204] Table 3 Pharmacokinetic parameters

[0205] In summary, in the mIL-23-induced psoriasis model of C57BL / 6 mice, the model control group showed obvious characteristics similar to psoriasis, the ear was significantly thickened, the ear weight was significantly increased, the ear tissue cytokine content and pathological score were significantly increased, indicating that the model was successfully established. The test product at a dose of 4 mg / kg, 8 mg / kg, and 16 mg / kg twice a day orally was well tolerated in mice. The test product at a dose of 4 mg / kg, 8 mg / kg, and 16 mg / kg significantly improved ear thickness, ear weight, ear tissue cytokines, ear tissue epidermal thickness, and ear tissue pathological inflammation score.

[0206] The test product at a dose of 4 mg / kg, 8 mg / kg, and 16 mg / kg had different degrees of therapeutic effect on the mIL-23-induced psoriasis model of C57BL / 6 mice, and the therapeutic effect had a dose-dependent effect, and the safety was good. At a dose of 16 mg / kg, the test product had better therapeutic effect than the control drug in terms of ear thickness, ear weight, ear tissue cytokines, etc.

[0207] The compound of the present disclosure has different degrees of therapeutic effect on the mIL-23-induced psoriasis model of C57BL / 6 mice at various doses, and the therapeutic effect has a dose-dependent effect, and the safety is good; and shows therapeutic effect in terms of ear thickness, ear weight, ear tissue cytokines, etc.

[0208] Test Example 2

[0209] Only subjects who meet all the following inclusion criteria can be selected:

[0210] 1) Clinically diagnosed as stable moderate to severe plaque psoriasis,

[0211] 2) The investigator determines that it is suitable to receive systemic treatment or phototherapy,

[0212] 3) At screening and baseline, the PASI score is ≥12 points, the BSA is ≥10%, and the sPGA is ≥3 points;

[0213] Alternatively, subjects who meet all the following inclusion criteria can be selected:

[0214] 1) Clinically diagnosed as stable moderate to severe plaque psoriasis and with a history of ≥6 months (from randomization), the investigator assesses that there is no change in skin lesion morphology or significant flare of the disease,

[0215] 2) The investigator determines that it is suitable to receive systemic treatment or phototherapy,

[0216] 3) At screening and baseline, the PASI score is ≥12 points, the BSA is ≥10%, and the sPGA is ≥3 points.

[0217] Anyone who has one of the following conditions cannot be selected as a subject:

[0218] 1) with other forms of psoriasis (such as guttate psoriasis, generalized pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis) other than plaque psoriasis.

[0219] 2) received systemic treatment for psoriasis or immunosuppressive therapy within 4 weeks before randomization, including but not limited to retinoids, glucocorticoids, methotrexate, cyclosporine, azathioprine, JAK inhibitors, etc.

[0220] Drugs and usage:

[0221] Compound C capsules, specifications: 2 mg and 8 mg;

[0222] Once a day, 2-32 mg each time, for example, 6 mg, 12 mg, 18 mg, 24 mg, 32 mg, etc.

[0223] Effectiveness analysis:

[0224] Based on EAS, the PASI value, sPGA value, DLQI score and change from baseline, BSA score and change from baseline, and the proportion of patients reaching sPGA 0 / 1, PASI 50, PASI 75, PASI 90, PASI 100 of each group from 12-52 weeks or longer (such as 12 weeks, 16 weeks, 24 weeks, 48 weeks or 52 weeks) are described using mean, standard deviation, median, quartile, minimum and maximum; the chi-square test is used for inter-group comparison. The linear comparison method is used for trend test to test whether there is a dose-effect relationship between each dose group, and further identify the optimal dose using appropriate methods.

[0225] Pharmacokinetic analysis:

[0226] Based on PDS, the average detection value of IL-17A, IL-19, beta-defensin, etc. at different detection time points of each group and the change from baseline are described using mean, standard deviation, median, quartile, minimum and maximum; the variance analysis or non-parametric test method is used to compare the change from baseline of IL-17A, IL-19, beta-defensin, etc. at different detection time points of each group with the placebo group.

[0227] Safety analysis:

[0228] All adverse events will be graded according to NCI-CTCAE version 5.0, and the incidence of adverse events, adverse event and test drug correlation analysis, and severity analysis will be statistically described by treatment group.

[0229] Patient efficacy:

[0230] The efficacy results for patients are as follows:

[0231] For the 18 mg qd dose group, some trial results show good efficacy, with the 12-week efficacy indicators of PASI 50 response rate not less than 70%, PASI 75 response rate not less than 60%, PASI 90 response rate not less than 30%, or sPGA 0 / 1 response rate not less than 60%. For the 24-32 mg qd dose group, patients show similar or better results in the efficacy indicators of PASI 50, PASI 75, PASI 90, sPGA 0 / 1, etc.

[0232] The average efficacy of the compounds of the present disclosure is significantly better than the placebo response rate for the same indication, with good efficacy; and better safety.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis, wherein, T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2; X is CH or N.

2. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to claim 1, wherein T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one, two or three are selected from NH or N; Optionally, each R 3 are each independently selected from F, methyl optionally substituted with F, or cyclopropyl.

3. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to claim 1 or 2, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

4. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-3, wherein the psoriasis is selected from plaque psoriasis. Optionally, the psoriasis is selected from moderate-to-severe (moderate to severe) psoriasis. Optionally, the psoriasis is selected from moderate-to-severe plaque psoriasis. Optionally, the psoriasis is selected from psoriasis suitable for systemic therapy or phototherapy. Optionally, the psoriasis is selected from stable moderate-to-severe plaque psoriasis and with a disease history of > 6 months. Optionally, the psoriasis is selected from psoriasis without changes in lesion morphology or significant flares of disease. Optionally, the psoriasis is selected from psoriasis with a PASI score of > 12, BSA of > 10%, sPGA of > 3.

5. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-4, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 2-32 mg; or the daily dose is selected from 4-28 mg; or the daily dose is selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or the daily dose is selected from 6 mg, 12 mg, or 18 mg.

6. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-5, wherein the single dose or multiple doses of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from 2-32 mg; or the single dose or multiple doses is selected from 4-28 mg; or the single dose or multiple doses is selected from 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or the single dose or multiple doses is selected from 6 mg, 12 mg, 18 mg, 24 mg, or 32 mg; or the single dose or multiple doses is selected from 18 mg, 24 mg, or 32 mg.

7. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-6, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the patient in a single daily dose or multiple daily doses.

8. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-7, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the patient for 2 weeks to 52 weeks; or for 12 weeks, 16 weeks, 24 weeks, 48 weeks, 52 weeks, or a range formed by any of the foregoing. Optionally, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered daily for about 1 day to 7 days, about 1 week to 3 weeks, about 3 weeks to 6 weeks, about 6 weeks to 9 weeks, about 12 weeks; or for about 12 weeks, about 12 weeks to 15 weeks, or about 15 weeks to 18 weeks, or about 15 weeks to 52 weeks.

9. The compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of psoriasis according to any one of claims 1-8, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally to the patient daily.

10. A pharmaceutical composition for treating psoriasis, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2, X is N.

11. The pharmaceutical composition for use in the treatment of psoriasis according to claim 10, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof:

12. A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and instructions for treating or preventing psoriasis with a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein T 7 , T 8 , T 9 , T 10 , T 11 , T 12 are each independently selected from CH, C, NH, N, O or a bond, wherein one or two are selected from NH or N; Each R 3 Each group is independently selected from halogen, hydroxyl, amino, cyano, nitro, and C groups. 1-3 Alkyl or C 3-6 cycloalkyl, the C 1-3 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one or more halogens, hydroxyl groups, amino groups, or cyano groups; m is selected from 1 or 2, X is N. m is selected from 1 or 2, X is N.

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