TW202135816A - Treatment of ulcerative colitis with kinase inhibitors - Google Patents

Abstract

Method for treating ulcerative colitis using compounds and analogues which inhibit certain kinases including Janus Kinase (JAK), said method comprising the step of administering to the subject in need thereof (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

Description

Treating ulcerative colitis with kinase inhibitors

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽。The present invention provides a method for treating ulcerative colitis using compounds or analogs that inhibit certain kinases including Janus Kinase (Janus Kinase, JAK), such compounds or analogs, particularly inhibitors of Tyk2, and more particularly Compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈係口服上生物可利用之高度選擇性Tyk2抑制劑(Tyk2 inhibitor, Tyk2i)。(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈正在患有斑癬及其他自體免疫性疾病之參與者中進行研究。基於其細胞激素抑制特性，預期(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈藉由抑制Tyk2直接靶向第一型輔助性T細胞(T-helper 1, Th1)、第十七型輔助性T細胞(T-helper 17, Th17)、及第I型IFN訊息傳導途徑。此應該在治療由Th1/Th17及干擾素免疫反應所驅使之發炎性病況中提供治療益處。 在患有中度至重度潰瘍性結腸炎之個體中，有效、安全、及耐受良好的治療需求仍有待解決。UC之標誌性臨床症狀包括與直腸急迫(rectal urgency)及裏急後重相關之出血性下痢(bloody diarrhea)。臨床病程係以惡化及緩解為特徵。UC之診斷係根據臨床懷疑並藉由診斷測試、及排除感染病因來支持。Dignass A, Eliakim R, Magro F, et al., J Crohn's Colitis. 2012; 6(10):965-90)。UC之最嚴重的腸徵象係毒性巨結腸及穿孔。腸外併發症包括關節炎(周邊或軸向受累(involvement))、皮膚病況(結節性紅斑、口瘡口炎、及壞疽性膿皮病(pyoderma gangrenosum))、眼部炎症(眼色素層炎)、肝功能異常(原發性硬化性膽管炎)。患有UC之患者得結腸癌的風險增加，且該風險隨著疾病之持續時間以及受疾病所影響之結腸範圍而增加。Rutter M, Saunders B, Wilkinson K, et al., Gastroenterology, 2004; 126(2):451-9。 UC之醫學治療旨在控制炎症並減輕症狀。可用的醫藥療法有限，總是無法完全減輕發炎性過程，且可能具有顯著的不良作用。輕度至中度活動性UC之療法包括5-胺基柳酸衍生物及免疫抑制劑。本文中所揭示者係發現抑制某些激酶諸如Tyk2的化合物及類似物，且特別是化合物(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈有用於治療UC。因此，本文中所揭示者係減輕人類個體之UC症狀嚴重度的方法，具有更快的起效時間(onset of action)及更低的不良作用發生率。Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, and are roughly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity caused by mutations, overexpression, or inappropriate regulation, dys-regulation or de-regulation, and overproduction or underproduction of growth factors or cytokines involves many Diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological disorders and neurodegenerative disorders (such as Azihai (Alzheimer's disease)). Inappropriate kinase activity triggers various biological cell responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell migration related to the aforementioned and related diseases. Therefore, protein kinases have been shown to be an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play an important role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Cytokines activate JAK after binding to their receptors. JAK then phosphorylates the cytokine receptors, which are signal transduction molecules, especially signal transducers and activator of transcription (STAT) that ultimately lead to gene expression. Family members establish docking sites. Many cytokines are known to activate the JAK family. These cytokines include interferon (IFN) family (IFN-α, IFN-β, IFN-ω, Limitin), IFN-γ, IL-10, IL-19, IL-20, IL-22 ), gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), γC family ( IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single Chain family (EPO, GH, PRL, TPO), receptor tyrosine kinase (EGF, PDGF, CSF-1, HGF), and G protein coupled receptor (AT1). Tyk2 is paired with JAK1 to mediate type I interferon (IFN) signaling, and Tyk2 is paired with JAK2 to transmit interleukin (IL) IL-12 and IL-23 signaling. Both types of key cell hormones are involved in the pathophysiology of inflammatory bowel disease (IBD). Allocca M, et al., Best Practice & Research Clinical Gastroenterology 2018; 32-33; 95-102. According to the results of clinical studies in the induction and maintenance phases, ustekinumab (a monoclonal antibody against the p40 subunit of IL-12/IL-23 receptor) or mirikizumab (Anti-IL-23 receptor p19 subunit monoclonal antibody) therapy induces and maintains clinical remission in a significant proportion of individuals with ulcerative colitis (UC) with moderate to severe disease activity. Sandborn WJ, et al., J Crohn's and Colitis 2018; 13 (Supp. 1):S024-26; Sandborn WJ, et al., Gastroenterology 2018; 154(6):Supp. 1:S1360-S1361. IL-12 and IL-23 require Tyk2 for signal transduction, which suggests that inhibiting Tyk2-mediated signal transduction may be an effective treatment for UC. Floss DM, et al., Mol Biol Cell. 2016; 27(14):2301-16. Compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile is a highly selective and bioavailable Tyk2 inhibitor (Tyk2i) for oral administration. (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile is being studied among participants with tinea rash and other autoimmune diseases. Based on its cytokine inhibitory properties, (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile directly targets type 1 helper T cells (T-helper 1, Th1) and type 17 by inhibiting Tyk2 T helper cells (T-helper 17, Th17), and type I IFN signaling pathway. This should provide therapeutic benefit in the treatment of inflammatory conditions driven by Th1/Th17 and interferon immune responses. In individuals with moderate to severe ulcerative colitis, the need for effective, safe, and well-tolerated treatment remains to be resolved. The hallmark clinical symptoms of UC include blood diarrhea associated with rectal urgency and tenesmus. The clinical course is characterized by deterioration and remission. The diagnosis of UC is based on clinical suspicion and is supported by diagnostic tests and excluding the cause of infection. Dignass A, Eliakim R, Magro F, et al., J Crohn's Colitis. 2012; 6(10):965-90). The most serious bowel signs of UC are toxic megacolon and perforation. Extraintestinal complications include arthritis (peripheral or axial involvement), skin conditions (erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum), inflammation of the eye (uveitis) , Abnormal liver function (primary sclerosing cholangitis). Patients with UC have an increased risk of colon cancer, and this risk increases with the duration of the disease and the extent of the colon affected by the disease. Rutter M, Saunders B, Wilkinson K, et al., Gastroenterology, 2004; 126(2):451-9. The medical treatment of UC aims to control inflammation and relieve symptoms. The available medical therapies are limited, always unable to completely reduce the inflammatory process, and may have significant adverse effects. Therapies for mild to moderately active UC include 5-aminosalicylic acid derivatives and immunosuppressive agents. The persons disclosed herein have discovered compounds and analogues that inhibit certain kinases such as Tyk2, and especially the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl) -1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile is useful for the treatment of UC. Therefore, the method disclosed in this article is a method for reducing the severity of UC symptoms in human individuals, which has a faster onset of action and a lower incidence of adverse effects.

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成臨床緩解，其中個體達成內視鏡檢反應(endoscopic response)。 在另一具體實施例中，本發明提供JAK抑制劑，(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈用於製造使用於治療如本文中所述之潰瘍性結腸炎的藥劑之用途。 將從僅藉由實施例之方式給出的下列描述來進一步理解本發明。儘管本發明不限於此，但將透過下列討論及實施例獲得對本發明之各種態樣的理解。 如本文中所使用，「個體(subject)」係指人類。 術語「不良作用(adverse effect, AE)」係個體或臨床研究參與者暫時地與投予JAK抑制劑相關的任何不幸醫療事件。 術語「QD」或「Q.D.」意指每天一次投予劑量。 術語「治療(treating/treatment)」意指減輕與疾病、病症、或病況相關之症狀，或阻止那些症狀進一步進展或惡化。取決於個體之疾病或病況，如本文中所使用之術語「治療(treatment)」可包括治癒、緩和、及預防性治療中之一或多者。治療亦可包括將本發明之醫藥調配物與其他療法組合投予。 術語「治療有效(therapeutically-effective)」指示劑對預防、或改善病症之嚴重度，同時避免典型與替代療法相關之不良副作用的能力。片語「治療有效(therapeutically-effective)」應理解為等同於片語「有效治療、預防、或改善(effective for the treatment, prevention, or amelioration)」，且兩者皆意欲限定每種用於組合療法之劑的量，該量將在每種劑本身之治療期間達成改善疾病、或疼痛、或其其他症狀之嚴重度，及發病率之頻率，同時避免典型與替代療法相關之不良副作用的目的。 「醫藥上可接受(pharmaceutically acceptable)」意指適合用於「個體(subject)」。 術語「中度至重度潰瘍性結腸炎(moderate to severe ulcerative colitis)」係定義為具有5至9的經調適之梅歐得分(Adapted Mayo score)，且內視鏡檢分項得分(endoscopy subscore)為2或3。 www.clinicaltrials.gov/ct2/show/NCT03934216。 術語「臨床緩解(clinical remission)」係基於12分制的總梅歐得分(total Mayo score)：總梅歐得分≤2，且無個別分項得分＞1。 術語「臨床反應(clinical response)」係總梅歐得分自基線起至少減少3分且至少30%變化，伴隨直腸出血分項得分至少減少一分或0或1之絕對得分。 術語「內視鏡檢緩解(endoscopic remission)」係指梅歐內視鏡檢分項得分(Mayo endoscopy subscore) 0。 術語「內視鏡檢反應(endoscopic response)」係指梅歐內視鏡檢分項得分0或1。 術語「內視鏡檢改善(endoscopic improvement)」係指梅歐內視鏡檢分項得分減少≥1分或絕對內視鏡檢得分為≤1。 術語「黏膜癒合(mucosal healing)」係指梅歐內視鏡檢分項得分0或1且吉布斯(Geboes)組織學分項得分0或1。Aranzazu, J-E., et al. Journal of Crohn's and Colitis, Volume 11(3), 2017, 305–313 術語「症狀緩解(symptomatic remission)」係指總梅歐得分為2分或更低，且無個別分項得分超過1分，並且直腸出血及糞便頻率分項得分均為0。 術語「深度緩解(deep remission)」係指總梅歐得分為2分或更低，且無個別分項得分超過1分，並且內視鏡檢及直腸出血分項得分均為0。 術語「臨床緩解(clinical remission)」係基於9分制的總梅歐得分：總梅歐得分≤2，且直腸出血分項得分為0。 縮寫「梅歐(Mayo)」意指用於評定潰瘍性結腸炎活動性的梅歐得分系統(Mayo Scoring System)。「調適性梅歐得分(Adaptive Mayo Score)」係指該調適性梅歐得分系統具有梅歐得分之3項分項得分，範圍從0至9，且無PGA分項得分。The present invention provides a method of treating ulcerative colitis in an individual, which comprises administering any compound disclosed herein that inhibits JAK, such as Tyk2, to an individual in need. In some embodiments, the present invention provides a method for achieving clinical remission of moderate to severe ulcerative colitis in an individual, which comprises: (i) administering to the individual orally for up to 8 weeks (1r, 3r)- 3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, wherein the individual achieves an endoscopic response. In another specific embodiment, the present invention provides a JAK inhibitor, (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4) -Yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile is used for the manufacture of a medicament for the treatment of ulcerative colitis as described herein. The present invention will be further understood from the following description given only by way of examples. Although the present invention is not limited to this, an understanding of various aspects of the present invention will be gained through the following discussion and examples. As used herein, "subject" refers to humans. The term "adverse effect (AE)" refers to any unfortunate medical event temporarily related to the administration of JAK inhibitors by individuals or clinical research participants. The term "QD" or "QD" means a dose administered once a day. The term "treating/treatment" means alleviating symptoms associated with a disease, disorder, or condition, or preventing those symptoms from further progressing or worsening. Depending on the individual's disease or condition, the term "treatment" as used herein may include one or more of cure, alleviation, and prophylactic treatment. The treatment can also include the administration of the pharmaceutical formulation of the present invention in combination with other therapies. The term "therapeutically-effective" indicates the ability of the indicator to prevent or ameliorate the severity of the disease, while avoiding the undesirable side effects typically associated with alternative therapies. The phrase "therapeutically-effective" should be understood to be equivalent to the phrase "effective for the treatment, prevention, or amelioration", and both are intended to limit the use of each in combination The amount of the treatment agent, which will achieve the purpose of improving the severity of the disease, pain, or other symptoms, and the frequency of morbidity during the treatment of each agent itself, while avoiding the typical adverse side effects associated with alternative therapies . "Pharmaceutically acceptable" means suitable for "subject". The term "moderate to severe ulcerative colitis" is defined as having an adapted Mayo score of 5 to 9 and an endoscopy subscore (endoscopy subscore) It is 2 or 3. www.clinicaltrials.gov/ct2/show/NCT03934216. The term "clinical remission" is based on the total Mayo score on a 12-point scale: the total Mayo score is ≤ 2, and there is no individual sub-item score> 1. The term "clinical response (clinical response)" refers to the total Mayo score decreased by at least 3 points and at least 30% change from baseline, accompanied by a decrease of at least one point in the rectal bleeding sub-item score or an absolute score of 0 or 1. The term "endoscopic remission" refers to the Mayo endoscopy subscore 0. The term "endoscopic response" refers to a score of 0 or 1 for the Mayo endoscopic sub-item. The term "endoscopic improvement" refers to a reduction of ≥1 point in Mayo’s endoscopic sub-item score or an absolute endoscopic score of ≤1. The term "mucosal healing" refers to a score of 0 or 1 in the Mayo endoscopy sub-item and a score of 0 or 1 in the Geboes histology sub-item. Aranzazu, JE., et al. Journal of Crohn's and Colitis, Volume 11(3), 2017, 305–313 The term "symptomatic remission" refers to a total Mayo score of 2 or lower, and no individual The sub-item score exceeds 1 point, and the sub-items scores for rectal bleeding and stool frequency are both 0. The term "deep remission" means that the total Mayo score is 2 points or lower, and no individual sub-item score exceeds 1 point, and the endoscopy and rectal bleeding sub-item scores are both 0. The term "clinical remission" refers to the total Mayo score based on the 9-point system: the total Mayo score is ≤2, and the rectal bleeding sub-item score is 0. The abbreviation "Mayo" means the Mayo Scoring System used to assess the activity of ulcerative colitis. "Adaptive Mayo Score (Adaptive Mayo Score)" refers to the adaptive Mayo score system with 3 sub-items of Mayo score, ranging from 0 to 9, and no PGA sub-item score.

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成臨床緩解，且其中個體達成內視鏡檢反應。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。在一些具體實施例中，步驟(ii)中之量係200或400 mg QD。 在某些具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之臨床緩解的方法，包含： (i)向個體口服投予長達8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成臨床緩解，且其中臨床緩解係糞便頻率分項得分為小於或等於1，直腸出血分項得分為0，且內視鏡檢分項得分為小於或等於1。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。在特定具體實施例中，步驟(ii)中之量係200或400 mg QD。 在某些其他具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之臨床緩解的方法，其包含向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg 的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成臨床緩解，且其中臨床緩解係糞便頻率分項得分為小於或等於1，且直腸出血分項得分為0。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。 在某些具體實施例中，本發明提供該後述之方法進一步包含維持個體之中度至重度潰瘍性結腸炎之臨床緩解，其包含向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量，其中個體臨床緩解維持至少52週。在特定具體實施例中，該量係200或400 mg QD。 在某些其他具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之臨床反應的方法，其包含： (i)向個體口服投予長達8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成臨床反應，且其中臨床反應係經調適之梅歐得分自基線起減少大於或等於2分且自基線起減少大於或等於30百分比，伴隨(i)大於或等於1之直腸出血分項得分減少或(ii)小於或等於1之絕對直腸出血分項得分(absolute rectal bleeding subscore)。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。在特定具體實施例中，步驟(ii)中之量係200或400 mg QD。 在一些具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之臨床反應的方法，其包含向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量； 由此個體達成臨床反應，且其中臨床反應係經調適之梅歐得分自基線起減少大於或等於2分且自基線起減少大於或等於30百分比，伴隨(i)大於或等於1之直腸出血分項得分減少或(ii)小於或等於1之絕對直腸出血分項得分。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。 在其他具體實施例中，本發明提供該後述之方法，其進一步包含維持個體之中度至重度潰瘍性結腸炎之臨床反應，其包含向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量，其中個體臨床反應維持至少52週。在特定具體實施例中，該量係200或400 mg QD。 在某些具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之內視鏡檢緩解的方法，其包含： (i)向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成內視鏡檢緩解，且其中內視鏡檢緩解係內視鏡檢分項得分為0。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。在特定具體實施例中，步驟(ii)中之量係200或400 mg QD。 在其他具體實施例中，本發明提供該後述之方法，其進一步包含維持個體之中度至重度潰瘍性結腸炎之內視鏡檢緩解，其包含向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量，其中個體內視鏡檢緩解維持至少52週。在特定具體實施例中，該量係200或400 mg QD。 在某些具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之內視鏡檢改善的方法，其包含： (i)向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；及， (ii)向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成內視鏡檢改善，且其中內視鏡檢改善係內視鏡檢分項得分為小於或等於1。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。在特定具體實施例中，步驟(ii)中之量係200或400 mg QD。 在某些其他具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之內視鏡檢改善的方法，其包含向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成內視鏡檢改善，且其中內視鏡檢改善係內視鏡檢分項得分為小於或等於1。在特定具體實施例中，步驟(i)中之量係100 mg QD。在其他特定具體實施例中，步驟(i)中之量係200 mg QD。在一些具體實施例中，步驟(i)中之量係300 mg QD。在某些具體實施例中，步驟(i)中之量係400 mg QD。在某些其他具體實施例中，步驟(i)中之量係600 mg QD。 在一些具體實施例中，本發明提供該後述之方法進一步包含維持個體之中度至重度潰瘍性結腸炎之內視鏡檢改善，其包含向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量，其中個體內視鏡檢改善維持至少52週。在特定具體實施例中，該量係200或400 mg QD。 在某些其他具體實施例中，本發明提供達成個體之中度至重度潰瘍性結腸炎之內視鏡檢反應的方法，其包含向個體口服投予至少8週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量；由此個體達成內視鏡檢反應，且其中內視鏡檢反應係梅歐內視鏡檢分項得分0或1。在特定具體實施例中，該量係100 mg QD。在其他特定具體實施例中，該量係200 mg QD。在一些具體實施例中，該量係300 mg QD。在某些具體實施例中，該量係400 mg QD。在某些其他具體實施例中，該量係600 mg QD。 在某些具體實施例中，本發明提供該後述之方法，其進一步包含維持個體之中度至重度潰瘍性結腸炎之內視鏡檢反應，其包含向個體口服投予至少52週的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽，其量足以遞送100、200、300、400、600、或1200 mg QD的(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈游離鹼當量，其中個體內視鏡檢反應維持至少52週。在特定具體實施例中，該量係200或400 mg QD。 在進一步具體實施例中，本發明提供化合物(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈、或其醫藥上可接受之鹽用於根據上文中所述之任何方法製備用於治療潰瘍性結腸炎的藥劑之用途。 在治療個體之病症的治療用途中，本發明之化合物、或其醫藥組成物可口服、非經腸胃、局部、直腸、經黏膜、或腸內投予。非經腸胃投予包括間接注射以產生全身性作用或直接注射至患部。局部投予包括藉由局部施加(例如，眼部或耳部)來治療容易觸及之皮膚或器官。亦包括經皮遞送以產生全身性作用。直腸投予包括塞劑形式。較佳的投予路徑係口服、局部、及非經腸胃。 本發明之醫藥組成物可藉由本領域已知之方法來製造，例如，藉由習知混合、溶解、造粒、糖衣製造、研碎、乳化、膠囊充填、包覆、冷凍乾燥製程、或噴霧乾燥之方式。 根據本發明所使用之醫藥組成物可以習知方式使用一或多種醫藥上可接受之載劑(包含賦形劑及輔助劑)調配，該等賦形劑及輔助劑有助於將活性化合物處理成醫藥上可使用之製劑。適當的調配物取決於所選擇之投予路徑。醫藥上可接受之賦形劑及載劑係發明所屬技術領域中具有通常知識者通常已知的，且因此被包括在本發明中。此類賦形劑及載劑描述於，例如Remington’s Pharmaceutical Sciences, Mack Pub.Co., New Jersey (1991)中。本發明之調配物可經設計成短效的(short-acting)、快速釋放的(fast-releasing)、長效的(long-acting)、及持續釋放的(sustained-releasing)。因此，亦可調配醫藥調配物以用於控制釋放或用於緩慢釋放。 此外，應當理解的是，所投予之初始劑量可增加超過以上上限水平以便迅速達到所欲之血漿濃度。另一方面，初始劑量可小於最佳值，且在治療病程期間取決於特定情況可逐步增加每日劑量。如果有需要，每日劑量亦可被分成投予的多次劑量，例如每天兩次至四次。 [化學合成] 本發明之化合物可藉由本領域已知之任何方法製備。特別是，本發明之化合物可藉由參考其揭示之現有技術參考文獻所述之程序來製備。 對於特異性抑制Tyk2的那些化合物(包括(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈)，製備方法係揭示於美國專利案第10,144,738號中，該專利之內容係以其全文併入本文中。 實施例 所呈現之下列非限制性實施例僅用於說明本發明。發明所屬技術領域中具有通常知識者將理解的是，存在許多未例示之等同物及變型，但其仍形成本教示之一部分。 實施例1 治療潰瘍性結腸炎之方法 研究係由長達4週的篩檢期、8週的誘導治療期、52週的開放標籤延伸治療期、及4週的安全性追蹤期所組成。在篩檢期之後，將符合資格的參與者以總體2:2:1:1隨機比例隨機分配以接受(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈600 mg(每日一次(QD))、300 mg QD、100 mg QD、或匹配的安慰劑，並基於曾曝露於UC生物治療及在基線時使用口服皮質類固醇進行分層。已完成8週誘導治療而無安全性發現或不符合停藥標準的所有參與者將符合進入52週的開放標籤延伸治療期的資格。符合資格的參與者將接受(1r,3r)-3-(氰基甲基)-3-(4-(6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡

-4-基)-1H-吡唑-1-基)環丁烷-1-甲腈400 mg QD，且如果有需要，在開放標籤治療期中將劑量逐步降低(de-escalation)至200 mg QD。 實施例2 內視鏡檢 內視鏡檢(大腸鏡檢或可撓式乙狀結腸鏡檢)必須在篩檢期間進行，較佳地在已驗證所有其他合格性標準 (eligibility criteria)之後並在基線前5至7天(不超過10天)內進行，以允許在基線訪視時獲得中心讀取內視鏡檢分項得分，以用於總梅歐得分計算。 中心讀取者(Central Reader)之內視鏡檢分項得分必須在基線訪視時獲得。中心讀取者之評定將用於衍生總梅歐得分以用於研究合格。基於在篩檢期間所進行之日誌數據及內視鏡檢及在基線時所獲得之醫師總體評定(Physician Global Assessment, PGA)的糞便頻率、直腸出血、及中心讀取之內視鏡檢分項得分將用於判定合格。在原始文件中必須有內視鏡檢報告及病理報告。 內視鏡檢亦在第8週與第60週/可能提早中止訪視期間進行，但如果有需要可在現場訪視前最多-7天進行。腸道準備方案(bowel prep)應按當地程序進行。內視鏡之位置將基於在各種插入程度下儀器之長度以及在篩檢內視鏡檢(screening endoscopy)期間所看到之腸的形態特徵。內視鏡檢報告及在過程中所拍攝之任何照片及/或影像記錄應歸檔在參與者的圖表中。 內視鏡檢分項得分將按基於中心讀取者之梅歐得分進行報告，且對於梅歐內視鏡檢分項得分為1，將註明是否存在易脆性(friability)。符合以下2個標準之任一之參與者被認為有結腸直腸癌的風險且必須在隨機分組前進行結腸鏡檢。在原始文件中必須有結腸鏡檢及病理學報告(如果獲得活體組織切片)。 • 如果參與者年齡係≥50歲，則需有在篩檢之10年內的結腸鏡檢以排除腺瘤性息肉。經篩檢內視鏡檢確定患有腺瘤性息肉之參與者將在完成瘜肉切割術(polypectomy)且病理學報告為陰性之後才符合資格。 • 如果參與者已患有廣泛型(即大於左側)結腸炎＞8年或疾病局限於結腸之左側(即，結腸脾彎遠端)≥10年，則無論年齡，必須有在篩檢訪視之1年內的結腸鏡檢以檢查發育不良。經活體組織切片確定患有發育不良或癌症之參與者將被排除在外。 實施例3 參與者糞便日誌 研究參與者將使用電子日誌以便在篩檢訪視時開始及在整個研究中在每日基礎上記錄下列訊息： • 每天糞便之「正常」次數(當沒有發紅(flare)時)。此問題僅會在篩檢訪視時問。 • 在患有UC之前每天糞便之「正常」次數。此問題僅會在篩檢訪視時問。 • 在過去24小時內，個體具有多少次腸蠕動，包括導致下列任一種情況的如廁：具有腸蠕動的同時有血、或黏膜、或糞便。 • 在過去24小時內，當不在廁所卻具有腸蠕動時，個體經歷多少次排泄物、血、黏膜、或液體從肛門之洩漏? • 糞便中存在血(如果有的話)。 • 糞便中血之描述(如果有的話)，僅當註明存在時。 個體總體印象嚴重度(Subject Global Impression of Severity, PGIS)問題將評估過去24小時內你的潰瘍性結腸炎之嚴重度。為了鼓勵一致的日誌記錄，參與者應在篩檢訪視時開始輸入日誌數據並在整個研究中持續下去。在篩檢時將對參與者提供完成日誌的說明並在後續訪視時複查。 實施例4 潰瘍性結腸炎活動性之梅歐得分 梅歐得分係經設計用於量測UC疾病活動性之工具。梅歐得分系統由四個分項得分所組成，每項等級為0至3，且得分越高指示更嚴重的疾病活動性(參見下文及第10.9.3節)。總梅歐得分係所有4個分項得分之彙總，範圍從0至12分。 • 糞便頻率(分項得分0至3)。 • 直腸出血(分項得分0至3)。 • 內視鏡檢發現(分項得分0至3)。 • 醫師總體評定(分項得分0至3)。 計算梅歐得分需要參與者的糞便頻率及糞便中任何血量之評定。梅歐得分將基於參與者最接近研究訪視之最近記錄的3天有效且連續的糞便日誌計算。研究機構(investigator site)將對日誌用法進行訓練，並將訓練參與者使用日誌。由參與者所輸入之日誌數據將在每次訪視時現場複查。 如果缺失糞便日誌數據，則平均值將取自接近研究訪視5天內(且如果是基線訪視，則為之前)所報告之3個最近可用天數以計算梅歐得分。梅歐得分計算的無效日係腸道準備的日期、內視鏡檢的日期、及在內視鏡檢程序之後1天的日期。 若在接近研究訪視5天內(且如果是基線訪視，則為之前)僅報告2個可用有效天數，則除非在5天內沒有報告日誌數據，否則平均值將取自有限可用數據。在此情況下，糞便頻率及直腸出血分項得分將被視為缺失。如果平均值係在＞0至＜1之間，則直腸出血分項得分將被四捨五入。 實施例5 發炎性腸道疾病調查表(Inflammatory Bowel Disease Questionnaire, IBDQ) IBDQ係經心理測量學驗證之PRO手段，用於量測患有IBD(包括UC)之參與者的疾病特異性生活品質。IBDQ包含32項，其被分組至4個領域(dimension)中：腸道功能、情緒狀態、全身症狀、及社會功能。4個領域得分如下： • 腸道症狀：10至70。 • 全身症狀：5至35。 • 情緒功能：12至84。 • 社會功能：5至35。 總IBDQ得分在32至224範圍內。對於總得分及各個領域，較高的得分指示較好的生活品質。至少170之得分對應於臨床緩解且增加至少16分被視為指示臨床有意義之改良。The present invention relates to a method for treating ulcerative colitis in an individual, which comprises administering a compound that inhibits certain JAK such as Tyk2 to an individual in need. The present invention further provides pharmaceutical compositions containing such inhibitors. The present invention provides a method for achieving clinical remission of moderate to severe ulcerative colitis in an individual, which comprises: (i) orally administering (1r,3r)-3-(cyanomethyl) to the individual for up to 8 weeks )-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and the individual achieves an endoscopic response. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In some embodiments, the amount in step (ii) is 200 or 400 mg QD. In certain embodiments, the present invention provides a method for achieving clinical remission of moderate to severe ulcerative colitis in an individual, comprising: (i) orally administering (1r,3r)-3 to the individual for up to 8 weeks -(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and the clinical remission is the fecal frequency sub-item score is less than or equal to 1, The score of rectal bleeding is 0, and the score of endoscopy is less than or equal to 1. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In certain embodiments, the amount in step (ii) is 200 or 400 mg QD. In certain other embodiments, the present invention provides a method for achieving clinical remission of moderate to severe ulcerative colitis in an individual, which comprises orally administering to the individual (1r,3r)-3-(cyanogen) for at least 8 weeks Methyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and the clinical remission is the fecal frequency sub-item score is less than or equal to 1, And rectal bleeding sub-item score is 0. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In certain embodiments, the present invention provides the method described below further comprising maintaining the clinical remission of the individual with moderate to severe ulcerative colitis, which comprises orally administering to the individual (1r, 3r)-3 for at least 52 weeks -(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein individual clinical remission is maintained for at least 52 weeks. In certain embodiments, this amount is 200 or 400 mg QD. In some other specific embodiments, the present invention provides a method for achieving a clinical response of an individual with moderate to severe ulcerative colitis, which comprises: (i) administering to the individual orally for up to 8 weeks (1r, 3r) -3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves a clinical response, and the clinical response is that the adjusted Mayo score decreases more than from baseline Or equal to 2 points and a reduction of greater than or equal to 30% from baseline, accompanied by (i) a decrease in rectal bleeding subscore greater than or equal to 1 or (ii) an absolute rectal bleeding subscore less than or equal to 1 (absolute rectal bleeding subscore) ). In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In certain embodiments, the amount in step (ii) is 200 or 400 mg QD. In some embodiments, the present invention provides a method for achieving a clinical response to moderate to severe ulcerative colitis in an individual, which comprises orally administering to the individual (1r,3r)-3-(cyanomethyl) for at least 8 weeks. Yl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves a clinical response, and the clinical response is that the adjusted Mayo score decreases more than from baseline Or equal to 2 points and a reduction of greater than or equal to 30% from baseline, accompanied by (i) a decrease in rectal bleeding score greater than or equal to 1 or (ii) an absolute rectal bleeding score less than or equal to 1. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In other specific embodiments, the present invention provides the method described below, which further comprises maintaining the clinical response of the individual with moderate to severe ulcerative colitis, which comprises administering to the individual orally for at least 52 weeks (1r, 3r)- 3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual's clinical response is maintained for at least 52 weeks. In certain embodiments, this amount is 200 or 400 mg QD. In certain embodiments, the present invention provides a method for achieving endoscope remission of moderate to severe ulcerative colitis in an individual, which comprises: (i) administering to the individual orally for at least 8 weeks (1r, 3r )-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves endoscopic remission, and the endoscopic remission is the endoscopy score The item score is 0. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In certain embodiments, the amount in step (ii) is 200 or 400 mg QD. In other specific embodiments, the present invention provides the method described below, which further comprises maintaining an endoscopic remission of moderate to severe ulcerative colitis in the individual, which comprises administering to the individual orally for at least 52 weeks (1r, 3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, in which individual endoscopic remission is maintained for at least 52 weeks. In certain embodiments, this amount is 200 or 400 mg QD. In certain embodiments, the present invention provides a method for achieving an improvement in endoscopic examination of an individual with moderate to severe ulcerative colitis, which comprises: (i) administering to the individual orally for at least 8 weeks (1r, 3r )-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an improvement in endoscopy, and the improvement in endoscopy is an endoscopy score The item score is less than or equal to 1. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In certain embodiments, the amount in step (ii) is 200 or 400 mg QD. In certain other embodiments, the present invention provides a method for achieving an improvement in endoscopic examination of an individual with moderate to severe ulcerative colitis, which comprises orally administering to the individual (1r, 3r)-3 for at least 8 weeks -(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an improvement in endoscopy, and the improvement in endoscopy is an endoscopy score The item score is less than or equal to 1. In a specific embodiment, the amount in step (i) is 100 mg QD. In other specific embodiments, the amount in step (i) is 200 mg QD. In some embodiments, the amount in step (i) is 300 mg QD. In some embodiments, the amount in step (i) is 400 mg QD. In some other embodiments, the amount in step (i) is 600 mg QD. In some specific embodiments, the present invention provides the method described below further comprising maintaining the endoscopic improvement of the individual with moderate to severe ulcerative colitis, which comprises administering to the individual orally for at least 52 weeks (1r, 3r) -3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, in which the improvement of individual endoscopy is maintained for at least 52 weeks. In certain embodiments, this amount is 200 or 400 mg QD. In certain other specific embodiments, the present invention provides a method for achieving an endoscopic reaction in an individual with moderate to severe ulcerative colitis, which comprises orally administering to the individual (1r, 3r)-3 for at least 8 weeks -(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an endoscopy reaction, and the endoscopy reaction is a Mayo endoscopy A score of 0 or 1 for the inspection sub-items. In certain embodiments, this amount is 100 mg QD. In other specific embodiments, this amount is 200 mg QD. In some embodiments, this amount is 300 mg QD. In certain embodiments, this amount is 400 mg QD. In certain other embodiments, the amount is 600 mg QD. In certain embodiments, the present invention provides the method described below, which further comprises maintaining an endoscopic response of the individual with moderate to severe ulcerative colitis, which comprises orally administering to the individual for at least 52 weeks (1r ,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, in which the individual's endoscopic reaction is maintained for at least 52 weeks. In certain embodiments, this amount is 200 or 400 mg QD. In further specific embodiments, the present invention provides the compound (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyridine Azolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, for preparation according to any of the methods described above for the treatment of ulcerative colitis The purpose of the medicine. In the therapeutic use of the treatment of a condition in a subject, the compound of the present invention or its pharmaceutical composition can be administered orally, parenterally, topically, rectal, transmucosally, or enterally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection to the affected area. Topical administration includes treatment of easily accessible skin or organs by topical application (eg, to the eyes or ears). It also includes transdermal delivery to produce systemic effects. Rectal administration includes the form of suppositories. The preferred route of administration is oral, topical, and parenteral. The pharmaceutical composition of the present invention can be manufactured by methods known in the art, for example, by conventional mixing, dissolution, granulation, sugar coating, grinding, emulsification, capsule filling, coating, freeze drying process, or spray drying The way. The pharmaceutical composition used according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and adjuvants), and these excipients and adjuvants help to treat the active compound It can be used as a medicinal preparation. The appropriate formulation depends on the chosen route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those with ordinary knowledge in the technical field to which the invention belongs, and are therefore included in the present invention. Such excipients and carriers are described in, for example, Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulation of the present invention can be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing. Therefore, pharmaceutical formulations can also be formulated for controlled release or for slow release. In addition, it should be understood that the initial dose administered can be increased beyond the above upper limit level in order to quickly reach the desired plasma concentration. On the other hand, the initial dose may be less than the optimal value, and the daily dose may be gradually increased during the course of treatment depending on the specific situation. If necessary, the daily dose can also be divided into multiple doses administered, for example, two to four times a day. [Chemical synthesis] The compound of the present invention can be prepared by any method known in the art. In particular, the compounds of the present invention can be prepared by referring to the procedures described in their disclosed prior art references. For those compounds that specifically inhibit Tyk2 (including (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazole And [1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile), the preparation method is disclosed in U.S. Patent No. 10,144,738, the content of which is incorporated herein in its entirety . Examples The following non-limiting examples are presented only to illustrate the present invention. Those with ordinary knowledge in the technical field to which the invention pertains will understand that there are many unillustrated equivalents and modifications, but they still form part of the teachings. Example 1 The method study for the treatment of ulcerative colitis consists of a 4-week screening period, an 8-week induction treatment period, a 52-week open-label extension treatment period, and a 4-week safety follow-up period. After the screening period, eligible participants will be randomly assigned to receive (1r,3r)-3-(cyanomethyl)-3-(4-(6- (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile 600 mg (QD), 300 mg QD, 100 mg QD, or matching placebo, and based on He has been exposed to UC biotherapy and stratified with oral corticosteroids at baseline. All participants who have completed 8 weeks of induction therapy without safety findings or do not meet the discontinuation criteria will be eligible to enter the 52-week open-label extended treatment period. Eligible participants will receive (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile 400 mg QD, and if necessary, de-escalation to 200 mg QD during the open-label treatment period . Example 2 Endoscopy Endoscopy (colonoscopy or flexible sigmoidoscopy) must be performed during screening, preferably after all other eligibility criteria have been verified and before baseline This should be done within 5 to 7 days (no more than 10 days) to allow the center-reading endoscopy sub-item scores to be obtained at the baseline visit for use in the calculation of the total Mayo score. The scores of the endoscopy sub-items of the Central Reader must be obtained during the baseline visit. The central reader's assessment will be used to derive the total Mayo score for research qualification. Stool frequency, rectal bleeding, and center-reading endoscopy sub-items based on the log data and endoscopy performed during the screening period and the Physician Global Assessment (PGA) obtained at baseline The score will be used to determine the pass. There must be an endoscopy report and a pathology report in the original document. Endoscopy is also carried out in the 8th and 60th week / during the early suspension of the visit, but if necessary, it can be carried out up to -7 days before the on-site visit. Bowel prep should be carried out in accordance with local procedures. The position of the endoscope will be based on the length of the instrument at various insertion levels and the morphological characteristics of the bowel as seen during screening endoscopy. The endoscopy report and any photos and/or video records taken during the process should be filed in the participant’s chart. The score of the endoscopy sub-item will be reported as the Mayo score based on the central reader, and the score of the Mayo endoscopy sub-item is 1, and whether there is friability will be indicated. Participants who meet any of the following 2 criteria are considered at risk of colorectal cancer and must undergo colonoscopy before randomization. The colonoscopy and pathology report must be included in the original file (if biopsy is obtained). • If the participant is ≥50 years of age, a colonoscopy within 10 years of the screening is required to exclude adenomatous polyps. Participants who are determined to have adenomatous polyps by screening endoscopy will not be eligible until they have completed a polypectomy and the pathology report is negative. • If the participant has had extensive (ie greater than the left side) colitis for more than 8 years or the disease is confined to the left side of the colon (ie, the distal splenic curve of the colon) for more than 10 years, regardless of age, they must be in the screening visit Colonoscopy within 1 year to check for dysplasia. Participants confirmed to have dysplasia or cancer through biopsy will be excluded. Example 3 Participants Stool Diary Study participants will use the electronic diary to record the following information at the beginning of the screening visit and on a daily basis throughout the study: • The number of "normal" stools per day (when there is no redness ( flare). This question will only be asked during the screening visit. • The "normal" number of stools per day before suffering from UC. This question will only be asked during the screening visit. • In the past 24 hours, how many bowel movements the individual has, including toileting that resulted in any of the following conditions: blood, mucous membranes, or feces along with bowel movements. • In the past 24 hours, when not in the toilet but with bowel movements, how many times did the individual experience leakage of excrement, blood, mucous membranes, or fluid from the anus? • The presence of blood in the stool (if any). • A description of blood in the stool (if any), only if it is noted as being present. The Subject Global Impression of Severity (PGIS) question will assess the severity of your ulcerative colitis in the past 24 hours. To encourage consistent log records, participants should start entering log data during the screening visit and continue throughout the study. Participants will be provided with instructions for completing the diary during the screening and will be reviewed during follow-up visits. Example 4 The Mayo Score of Ulcerative Colitis Activity The Mayo score is a tool designed to measure UC disease activity. The Mayo scoring system consists of four sub-items, each with a level of 0 to 3, and a higher score indicates more severe disease activity (see below and section 10.9.3). The total Mayo score is the sum of the scores of all 4 sub-items, ranging from 0 to 12 points. • Stool frequency (sub-item score 0 to 3). • Rectal bleeding (sub-item score 0 to 3). • Endoscopy findings (sub-item score 0 to 3). • Physician's overall assessment (sub-item score 0 to 3). The calculation of the Mayo score requires an assessment of the participant’s stool frequency and any blood volume in the stool. The Mayo score will be calculated based on the 3-day valid and continuous stool log of the participant closest to the study visit. The investigator site will train the log usage and train participants to use the log. The log data entered by the participants will be reviewed on-site during each visit. If the stool log data is missing, the average value will be taken from the 3 most recent available days reported within 5 days of the study visit (and if it is the baseline visit, then before) to calculate the Mayo score. The date of the invalid Japanese bowel preparation calculated by the Mayo score, the date of the endoscopy, and the date 1 day after the procedure of the endoscopy. If only 2 available valid days are reported within 5 days of the study visit (and if it is a baseline visit, then before), the average value will be taken from the limited available data unless log data is not reported within 5 days. In this case, stool frequency and rectal bleeding scores will be considered missing. If the average value is between >0 to <1, the rectal bleeding score will be rounded. Example 5 Inflammatory Bowel Disease Questionnaire (IBDQ) IBDQ is a PRO method validated by psychometrics to measure the disease-specific quality of life of participants with IBD (including UC). IBDQ contains 32 items, which are grouped into 4 dimensions: intestinal function, emotional state, systemic symptoms, and social function. The scores in the 4 areas are as follows: • Intestinal symptoms: 10 to 70. • Systemic symptoms: 5 to 35. • Emotional function: 12 to 84. • Social function: 5 to 35. The total IBDQ score ranges from 32 to 224. For the total score and each field, a higher score indicates a better quality of life. A score of at least 170 corresponds to clinical remission and an increase of at least 16 points is considered to indicate a clinically meaningful improvement.

Claims (14)

A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, is used in the manufacture of clinical relief of moderate to severe ulcerative colitis in individuals ( clinical remission), which comprises: (i) orally administer (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1) to the individual for up to 8 weeks -Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) orally administered to the individual for at least 52 weeks of (1r,3r)-3- (Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and wherein the individual achieves an endoscopic response. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, is used for the manufacture of clinical remissions of moderate to severe ulcerative colitis in individuals The use of the medicament includes: (i) Orally administer (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H) to the individual for up to 8 weeks -Pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) orally administered to the individual for at least 52 weeks of (1r,3r)-3- (Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and clinical remission is stool frequency subscore (stool frequency subscore) Is less than or equal to 1, the rectal bleeding subscore is 0, and the endoscopic subscore is less than or equal to 1. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, is used for the manufacture of clinical remissions of moderate to severe ulcerative colitis in individuals The use of a medicament comprises the oral administration of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-) to the individual for at least 8 weeks 4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves clinical remission, and the clinical remission is a stool frequency sub-item score of less than or equal to 1 , And the rectal bleeding sub-item score is 0. Such as the use of claim 3, which further comprises maintaining the clinical remission of moderate to severe ulcerative colitis in the individual, which comprises orally administering (1r,3r)-3-(cyanomethyl) to the individual for at least 52 weeks Yl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual has maintained clinical remission for at least 52 weeks. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, is used to produce a clinical response to moderate to severe ulcerative colitis in individuals ( clinical response), the method comprising: (i) orally administer (1r,3r)-3-(cyanomethyl)-3-(4-(6-() to the individual for up to 8 weeks 1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) orally administered to the individual for at least 52 weeks of (1r,3r)-3- (Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves a clinical response, and wherein the clinical response is that the adjusted Mayo score is from baseline A reduction of greater than or equal to 2 points and a reduction of greater than or equal to 30% from baseline, accompanied by (i) a decrease in rectal bleeding score greater than or equal to 1 or (ii) an absolute rectal bleeding score less than or equal to 1. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, used in the manufacture of a clinical response to moderate to severe ulcerative colitis in an individual The use of a medicament comprises the oral administration of (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-) to the individual for at least 8 weeks 4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves a clinical response, and wherein the clinical response is the adjusted Mayo score from baseline A reduction of greater than or equal to 2 points and a reduction of greater than or equal to 30% from baseline, accompanied by (i) a decrease in rectal bleeding score greater than or equal to 1 or (ii) an absolute rectal bleeding score less than or equal to 1. The use of claim 6, which further comprises maintaining the clinical response of the individual with moderate to severe ulcerative colitis, which comprises orally administering (1r,3r)-3-(cyanomethyl) to the individual for at least 52 weeks Yl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual's clinical response is maintained for at least 52 weeks. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, used to manufacture endoscopes for achieving moderate to severe ulcerative colitis in individuals The use of an agent for endoscopic remission, which includes: (i) orally administer (1r,3r)-3-(cyanomethyl)-3-(4-(6-) to the individual for at least 8 weeks (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) orally administered to the individual for at least 52 weeks of (1r,3r)-3- (Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves endoscopic remission, and the endoscopic remission is endoscopic The sub-item score is 0. Such as the use of claim 8, which further comprises maintaining the endoscope remission of moderate to severe ulcerative colitis in the individual, which comprises orally administering to the individual (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual’s endoscopic remission is maintained for at least 52 weeks. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, used to manufacture endoscopes for achieving moderate to severe ulcerative colitis in individuals The use of a medicament for endoscopic improvement, which comprises: (i) orally administer (1r,3r)-3-(cyanomethyl)-3-(4-(6-) to the individual for at least 8 weeks (1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; and, (ii) orally administered to the individual for at least 52 weeks of (1r,3r)-3- (Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an improvement in endoscopy, and the improvement in endoscopy is endoscopy The sub-item score is less than or equal to 1. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, used to manufacture endoscopes for achieving moderate to severe ulcerative colitis in individuals The use of the improved agent for testing, which comprises orally administering to the individual for at least 8 weeks (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H- Pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an improvement in endoscopy, and the improvement in endoscopy is endoscopy The sub-item score is less than or equal to 1. The use of claim 11, which further comprises maintaining the improvement of endoscopic examination of the individual with moderate to severe ulcerative colitis, which comprises orally administering to the individual (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual's endoscopic improvement is maintained for at least 52 weeks. A (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, used to manufacture endoscopes for achieving moderate to severe ulcerative colitis in individuals The use of the drug for detecting the reaction comprises orally administering (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-) to the individual for at least 8 weeks Pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent; thus the individual achieves an endoscopic reaction, and the endoscopic reaction is Mayo endoscopic Mayo endoscopy subscore is 0 or 1. Such as the use of claim 13, which further comprises maintaining an endoscopic reaction of the individual with moderate to severe ulcerative colitis, which comprises administering to the individual orally for at least 52 weeks (1r,3r)-3-( Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 100, 200, 300, 400, 600, or 1200 mg QD's (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] Pyridine

-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile free base equivalent, wherein the individual’s endoscopic reaction has been maintained for at least 52 weeks.