Heteroaryl compounds as inhibitors of TYK2 / JAK1, their compositions and applications

Abstract

The present disclosure provides phosphonate-containing heterocyclic compounds having TYK2 / JAK1 inhibitory activity, pharmaceutical compositions containing the same, and applications thereof. The present disclosure provides compounds of formula (I) as inhibitors of TYK2 / JAK1. These compounds can be used to prevent and / or treat TYK2 / JAK1-related diseases and / or conditions without significant inhibition of JAK2 activity. [Formula 1] JPEG2025525481000119.jpg87163

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Chinese Patent Application Nos. 202210853468.X, filed on July 8, 2022, and 202211575172.2, filed on December 8, 2022, all of which are incorporated herein by reference in their entirety.

[0002] The present invention is in the medical technology field and relates to compounds with selective TYK2 / JAK1 inhibitory activity. The present invention also relates to compositions containing the disclosed compounds, methods for making them, and their application in targeted therapies for the prevention and / or treatment of TYK2 / JAK1-related diseases, such as tumors, autoimmune diseases, neurodegenerative diseases, metabolic diseases, and genetic diseases. [Background technology]

[0003] Janus kinases, or JAKs, are non-receptor tyrosine kinases that bind to the intracellular portion of cell-surface cytokine receptors. Currently, there are four known human JAK family members: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2), each of which contains a kinase domain and a pseudokinase domain (Trends Pharmacol. Sci. 32 (2011), pp. 25-34). JAK1, JAK2, and TYK2 are expressed in various human tissues, while JAK3 is primarily expressed in various hematopoietic cells. A common feature of cell-surface cytokine receptors is that the receptor itself lacks kinase activity, but the intracellular portion of the receptor contains binding sites for the tyrosine kinase JAK. Thus, cytokine binding to the receptor results in JAK activation and phosphorylation of the JAK and associated receptor. Receptor phosphorylation then initiates the recruitment of STATs via the SH2 domain, which subsequently initiates the phosphorylation of signal transducers and activators of transcription (STAT) proteins. The phosphorylated STAT homodimers or heterodimers then translocate to the nucleus and bind to specific deoxyribonucleic acid (DNA) binding sites, regulating gene transcription and resulting in changes in cellular function (J. Med. Chem., 62 (2019), pp. 8953-8972).

[0004] Different pairs of JAK family members respond to signal transduction between different cytokines and their respective receptors. For example, TYK2, when paired with JAK2, regulates interleukin-12 (IL12)- and IL23-mediated signal transduction, whereas when paired with JAK1, it regulates interferon alpha (IFN-α)-mediated signal transduction. Because the JAK / STAT pathway is involved in inflammatory responses, it can be a target for treating diseases associated with immune disorders (J. Med. Chem., 57 (2014), pp. 5023-5038). TYK2 has particularly gained support in the research field as a potential target for treating autoimmune diseases. For example, mice lacking TYK2 survive and develop normally. However, deficiency of JAK1 (Cell, 93 (1998), pp. 373-383) or JAK2 (Cell, 93 (1998), pp. 397-409) in mice is lethal. Furthermore, JAK3-deficient mice exhibit severe B- and T-cell depletion (Science, 270 (1995), pp. 800-802). Furthermore, TYK2 has been shown to be protective in several autoimmune disease models (especially multiple sclerosis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, and psoriasis) (Brain, 134 (2011), pp. 693-703; Inflammation (London, UK) 7 (2010), pp. 41; Nat. Rev. Rheumatol. 12 (2016), pp. 25-36). TYK2 is also associated with several cancers, such as T-cell lineage acute lymphoblastic leukemia (Cancer Disc. 3 (2013), pp. 564-567).

[0005] The value of inhibiting pathways involving TYK2 in the treatment of autoimmune diseases has been clinically demonstrated by a variety of antibodies. The antibody ustekinumab, which targets the p40 subunit of both IL-12 and IL-23, is currently on the market for treating psoriasis, psoriatic arthritis, and Crohn's disease (Drugs, 71 (2011), pp. 1733-1753; N. Engl. J. Med., 375 (2016), pp. 1946-1960). This antibody recently demonstrated efficacy in patients with systemic lupus erythematosus (SLE) (Lancet, 392 (2018), pp. 1330-1339). The antibody guselkumab, which blocks IL-23 signaling by targeting the p19 subunit of IL-23 but not IL-12 signaling, has also been shown to be an effective treatment for psoriasis (J. Am. Acad. Dermatol., 76 (2017), pp. 405-417). Several studies have shown that interferon type 1 plays a pathogenic role in systemic lupus erythematosus (SLE), leading to the successful treatment of SLE with sifalimumab and anifrolumab in phase II clinical trials (Ann. Rheum. Dis., 75 (2016), pp. 1909-1916; Arthritis Rheumatol., 69 (2017), pp. 376-386).

[0006] Considering that TYK2 can be a therapeutic target, obtaining a highly selective TYK2 inhibitor can have a good therapeutic effect on the above diseases. Currently, there are selective TYK2 inhibitors BMS-986165 (J.Med.Chem., 62 (2019), pp. 8973-8995) (mainly targeting only TYK2, no inhibitory effect on JAK1) and JAK1 / TYK2 dual inhibitor PF-06700841 (J.Med.Chem., 61 (2018), pp. 8597-8612) (mainly targeting TYK2 and JAK1, but some studies have shown that it also inhibits JAK2, resulting in JAK2 IC. 50 / TYK2 IC 50The ratio of TYK2 to TYK2 / JAK1 is approximately 3.3 and is currently in clinical trials. Therefore, obtaining highly active and selective TYK2 or TYK2 / JAK1 inhibitors that could lead to the development of new drugs could lead to promising clinical applications. [ka] Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure provides heterocycles as selective TYK2 / JAK1 inhibitors, and compositions and applications thereof. These disclosed heterocycles, and compositions and applications thereof, can efficiently and selectively inhibit TYK2 / JAK1, thereby preventing or treating diseases and disorders including, for example, autoimmune or inflammatory diseases, cancer / tumors, allergies, transplant rejection, neurodegenerative diseases, asthma and other obstructive airway diseases.

[0008] One goal of the present disclosure is to provide selective TYK2 / JAK1 inhibitors, as well as compositions and applications thereof. [Means for solving the problem]

[0009] An aspect of the present disclosure is a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof: [ka] (In the formula, n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; X1 is N or CH; X2 is N or CH; X3 is N or CR 7 and Ring A is C 6~10 aryl or 5- to 10-membered heteroaryl; Ring B is C 6~10 aryl or 5- to 10-membered heteroaryl, or ring B is absent, and when ring B is absent, [ka] is directly linked to ring A, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, heteroaryl, -(CH2) p OR b , -(CH2) p SR b , -(CH2) p C(O)R b , -(CH2) p C(O)OR b , -(CH2) p OC(O)R b , -(CH2) p NR c R d , -(CH2) p C(O)NR c R d , -(CH2) p NR b C(O)R e , -(CH2) p NR b C(O)OR e , -S(O) q NR c R d or -S(O) q R e and C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with hydrogen, deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxide, C 1~3 Halo-alkoxides, C 2~6 Alkenyl, C 2~6 Alkynyl, substituted or unsubstituted C 3~6 substituted with one or more groups independently selected from the group consisting of cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 2 is hydrogen, C 1~4 Alkyl, -(CH2) p -phenyl or -(CH2) p -5 to 7-membered heterocycloalkyl, C 1~4 Alkyl is 0 to 1 R a and the phenyl is substituted with 0 to 3 R a and the 5- to 7-membered heterocycloalkyl contains 1 to 4 heteroatoms or heteroatomic groups in the ring, the heteroatoms or heteroatomic groups being independently NH, N, O, S(O), q , PH(O) r or P(O) r and heterocycloalkyl is 0 to 3 R a is replaced by Alternatively, R 1 and R 2 together with the nitrogen to which they are attached form a 3- to 14-membered heterocycloalkyl, which is unsubstituted or substituted with deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxide, C 1~6 Halo-alkoxides, C 2~6 Alkenyl and C 2~6 alkynyl; If present, each R 3are independently hydrogen, deuterium, halide, -OH, amino, -SH, -NO2, -CN, -P(O)R c R d , C 1~6 Alkyl, -C(O)NH2, C 1~6 Deuterated alkyl, -O(C 1~6 alkyl), -O(C 1~6 Deuterated alkyl), C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 6~10 aryl or 5- to 10-membered heteroaryl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, -O(C 1~6 alkyl), -O(C 1~6 Deuterated alkyl), C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are unsubstituted or include deuterium, halide, amino, -NO2, -CN, -OH, and C 1~3 substituted with one or more groups independently selected from the group consisting of alkyl; If present, each R 4 are independently hydrogen, deuterium, halide, -OH, amino, -CN, -CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl, -O(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 2~6 Alkenyl or C 2~6 Alkynyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, —NO2, —CN, and —OH; R 5 and R 6 Each of the 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl or C 3~6 is cycloalkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 3~6 The cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, —NO2, —CN, and —OH; Alternatively, R 5 and R 6 together with the phosphorus to which they are attached form a 5- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, —NO2, —CN, and —OH; If present, R 7 are independently hydrogen, deuterium, halide, -OH, amino, -CN, -CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl, -O(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 2~6 Alkenyl or C 2~6 Alkynyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, —NO2, —CN, and —OH; If present, R a , R b , R c , R d and R eeach is independently hydrogen, deuterium, halide, amino, -NO2, -CN, -OH, alkyl, deuterated alkyl, halo-alkyl, alkoxy, halo-alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, deuterated alkyl, halo-alkyl, alkoxy, halo-alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or are deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6 substituted with one or more groups independently selected from the group consisting of alkynyl, substituted or unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or adjacent or non-adjacent R a , R b , R c , R d and R e any two of form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with deuterium, halide, amino, -NO, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, substituted or unsubstituted C 3~6 substituted with one or more groups independently selected from the group consisting of cycloalkyl, substituted and unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; If present, each p is independently 0, 1, or 2; If present, each q is independently 1 or 2; If present, each r is 0 or 1, but However, B does not exist, [ka] is directly linked to ring A, the compound [ka] (provided that the

[0010] In some embodiments of a compound according to Formula (I), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, -C(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O) q NR c R d or -S(O) q R e and C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C1~6 Halo-Alkyl, C 1~6 Alkoxide, C 1~6 Halo-alkoxides, C 2~6 Alkenyl, C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 6~10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, and, if present, R a , R b , R c , R d and R e each independently represents hydrogen, deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 aryl or 5- to 10-membered heteroaryl, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted and unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 6~10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; or adjacent or non-adjacent R a , R b , R c , R d and R e Any two of these are C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 6~10 Forming an aryl or 5- to 10-membered heteroaryl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with deuterium, halide, amino, -NO2, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl, C 1~6 Halo-Alkyl, C 1~6 Alkoxy, C 1~6 Halo-alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C 6~10 substituted with one or more groups independently selected from the group consisting of aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; If present, q is independently 1 or 2.

[0011] In some embodiments of a compound according to Formula (I), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, Ring A is phenyl or 5- to 6-membered heteroaryl; Ring B is C 6~10aryl or 5- to 10-membered heteroaryl, preferably phenyl or 5- to 6-membered heteroaryl, and when present, each R 3 are independently halide, -CN, C 1~6 Alkyl, C 1~6 Deuterated alkyl, -O(C 1~6 alkyl), -O(C 1~6 Deuterated alkyl), C 3~6 Cycloalkyl or -C(O)NH2, preferably halide or -O(C 1~6 alkyl), R 5 is C 1~6 Alkyl or C 3~6 Cycloalkyl, preferably C 1~3 alkyl or cyclopropyl, R 6 is C 1~6 Alkyl or C 3~6 Cycloalkyl, preferably C 1~3 It is alkyl or cyclopropyl.

[0012] In some embodiments, the compound is of formula (II) or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof: [ka] (In the formula, X4 is N or CR 8 and X5 is N or CR 8 and X6 is N or CR 8 and If present, each R 8 are independently hydrogen, deuterium, halide, -OH, amino, -CN, -CF3, C 1~6 Alkyl, C 3~6 Cycloalkyl, -O(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 2~6 Alkenyl or C 2~6Alkynyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, —NO2, —CN, and —OH; n2, X2, ring B, R 1 , R 2 , R 4 , R 5 and R 6 are each defined as in formula (I).

[0013] In some embodiments of a compound according to Formula (I) or Formula (II), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, R 2 is defined as in formula (I), R 1 teeth, [ka] are independently selected from the group consisting of Each independently represents 0 to 3 R 9 is replaced by Preferably, R 1 teeth, [ka] Independently selected from the group consisting of Each independently represents 0 to 3 R 9 and, if present, each R 9 are independently deuterium, halide, amino, -NO2, -CN, -OH, C 1~3 Alkyl or C 1~3 It is an alkoxide.

[0014] In some embodiments of a compound according to Formula (I), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, R 1 and R 2 together with the nitrogens connected to them, [ka] each independently represents 0 to 3 R 10 is replaced by Preferably, R 1 and R 2 together with the nitrogens connected to them, [ka] and each of the 0 to 3 R 10 is replaced by If present, R 10 are independently deuterium, halide, amino, -NO2, -CN, -OH, C 1~3 Alkyl or C 1~3 It is an alkoxide.

[0015] In some embodiments, the compound is of formula (III) or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof: [ka] (In the formula, n2, ring B, R 1 , R 4 , X4, X5 and X6 are each defined as in formula (II).

[0016] In some embodiments of a compound according to Formula (III), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, [ka] teeth, [ka] each selected from the group consisting of 0 to 3 R 11 is replaced by Preferably, [ka] teeth, [ka] each selected from the group consisting of 0 to 3 R 11 is replaced by If present, each R 11 are independently deuterium, halide, amino, -CN, -OH, C 1~3 Alkyl or C 1~3 It is an alkoxy.

[0017] In some embodiments of a compound according to Formula (III), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, R 1 teeth, [ka] and each independently selected from the group consisting of 0 to 3 R 9 is substituted with, except that R 1 If is H, then R 1 is unsubstituted, Preferably, R 1 teeth, [ka] and each independently selected from the group consisting of 0 to 3 R 9 is replaced by If present, R 9 are independently deuterium, halide, amino, -NO2, -CN, -OH, C1~3 Alkyl or C 1~3 It is an alkoxide.

[0018] In some embodiments, the compound is according to formula (IV), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof. [ka] (In the formula, X2 is N or CH; X4 is N or CR 8 and X5 is N or CR 8 and X6 is N or CR 8 and If present, each R 8 are independently hydrogen, deuterium, halide, —OH, amino, or —CN; R 1 is hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, -C(O)R b , -C(O)OR b , -C(O)NR c R d or -S(O) q R e and C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with deuterium, halide, amino, -CN, -OH, C 1~6 Alkyl, deuterated C 1~6 Alkyl and C 1~6 substituted with one or more groups independently selected from the group consisting of alkoxides; R 4 is hydrogen, C 1~6 Alkyl, deuterated C 1~6 Alkyl, and C 3~6is cycloalkyl, C 1~6 Alkyl and C 3~6 The cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halide, amino, —CN, and —OH; R 5 and R 6 Each of the 1~6 Alkyl or C 3~6 is cycloalkyl, If present, R b , R c , R d and R e each independently represents hydrogen, halide, amino, —CN, —OH, C 1~6 Alkyl or C 3~6 is cycloalkyl, C 1~6 Alkyl and C 3~6 The cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halide, amino, —CN, and —OH; If present, q is 1 or 2).

[0019] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, X2 is N, X4 is N or CR 8 and X5 is N or CR 8 and X6 is N or CR 8 and If present, each R 8 are independently hydrogen or a halide, preferably hydrogen; R 1 is hydrogen, C 1~6 Alkyl, 5-10 membered heteroaryl, -C(O)R b , -C(O)OR b , -C(O)NR c R d or -S(O) q Re and C 1~6 The alkyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with halide, —CN, C 1~6 Alkyl, deuterated C 1~6 Alkyl and C 1~6 substituted with one or more groups independently selected from the group consisting of alkoxides; R 4 is hydrogen, C 1~6 Alkyl, deuterated C 1~6 Alkyl or C 3~6 is cycloalkyl, R 5 and R 6 Each of the 1~6 Alkyl or C 3~6 is cycloalkyl, If present, R b , R c , R d and R e each independently represents hydrogen, C 1~6 Alkyl or C 3~6 is cycloalkyl, C 1~6 Alkyl and C 3~6 The cycloalkyl is unsubstituted or substituted with one or more halides; If present, q is 2.

[0020] In some embodiments, the compound is according to formula (V), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof: [ka] (In the formula, X4 is N or CH; X5 is N or CR 8 and If present, each R 8 are independently hydrogen or fluorine, preferably hydrogen; R 1 is a 5- to 10-membered heteroaryl or -C(O)R band the 5- to 10-membered heteroaryl is unsubstituted or is a halide, —CN, C 1~3 Alkyl, deuterated C 1~3 Alkyl and C 1~3 substituted with one or more groups independently selected from the group consisting of alkoxides; R 4 are independently hydrogen, C 1~3 Alkyl, deuterated C 1~3 Alkyl and C 3~6 is cycloalkyl, R 5 and R 6 Each of the 1~3 Alkyl or C 3~6 is cycloalkyl, If present, R b independently, C 3~6 is cycloalkyl, C 3~6 Cycloalkyl is unsubstituted or substituted with one or more fluorines.

[0021] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof.

[0022] Another aspect of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the embodiments described hereinabove, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, and a pharmaceutically acceptable carrier.

[0023] Another aspect of the present disclosure provides compositions comprising a compound of any one of the hereinbefore described embodiments, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, or a pharmaceutical composition of any one of the hereinbefore described embodiments, and one or more additional therapeutic agents selected from the group consisting of anti-autoimmune / anti-inflammatory agents, anti-tumor / anti-cancer agents, anti-allergic agents, anti-transplant rejection agents, anti-neurodegenerative agents, anti-asthmatic agents and other anti-obstructive airway disease agents.

[0024] Another aspect of the present disclosure provides a method for treating a disease or disorder by inhibiting TYK2- and / or JAK1-mediated signaling in a subject suffering from the disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound of any one of the embodiments described hereinabove, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, or a pharmaceutical composition of any one of the embodiments described hereinabove, or a composition of any one of the embodiments described hereinabove.

[0025] In some embodiments of the above methods, the disease or disorder is an autoimmune or inflammatory disease, cancer or tumor, allergy, transplant rejection, neurodegenerative disease, asthma or other obstructive airway disease.

[0026] In some embodiments, the autoimmune or inflammatory disease is enteritis, skin disease, eye disease, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, Goodpasture's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmitis, myositis, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, chronic invasive hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polyarthritis Dermatomyositis, type I interferonopathies (including Aicardi-Goutiéres syndrome) and other systemic sclerosis caused by overexpression of type I interferons, Mendelian diseases, polyarteritis nodosa, multiple sclerosis, relapsing multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and bullous pemphigus, Cogan syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, diabetes mellitus or thyroiditis.

[0027] In some embodiments, the enteritis is Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis.

[0028] In some embodiments, the skin disease is atopic dermatitis, eczema, psoriasis, scleroderma, itching or other symptoms of itching, vitiligo, or alopecia.

[0029] In some embodiments, the ocular disease is keratoconjunctivitis, uveitis (including uveitis associated with Behcet's disease and lenticular-induced uveitis), keratitis, herpetic keratitis, keratoconus, muscular dystrophic epithelial keratitis inflammation, corneal leukopenia, anterior uveitis, scleritis, Mooren's ulcer, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca, bullous iridocyclitis, irisarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization.

[0030] In some embodiments, the diabetes is type 1 diabetes or diabetic complications.

[0031] In some embodiments, the cancer or tumor is gastrointestinal / gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell and squamous cell carcinoma), breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy, or diseases / tumors associated with vascular hyperplasia.

[0032] In some embodiments, the neurodegenerative disease is motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative diseases caused by trauma, injury, glutamate neurotoxicity or hypoxia, stroke, myocardial ischemia, renal ischemia, heart disease, cardiac hypertrophy, atherosclerosis, arteriosclerosis, organ hypoxia or ischemia / reperfusion injury of platelet aggregation.

[0033] In some embodiments, the allergy is allergic dermatitis (including allergic diseases in horses, e.g., allergies to bites), summer eczema, itchy horseshoes, muscle spasms, airway inflammation, recurrent airway obstruction, airway hyperresponsiveness, and chronic obstructive pulmonary disease in a subject.

[0034] In some embodiments, the asthma or other obstructive airways disease is chronic or excessive asthma, late-onset asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dust asthma.

[0035] In some embodiments, the transplant rejection is pancreatic islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (the organs and cells are bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limb, liver, lung, muscle, myoblasts, nerve, pancreas, skin, small intestine or trachea) or xenograft rejection.

[0036] The present disclosure also provides a formulation of a compound disclosed herein, including any embodiment, a pharmaceutical composition disclosed herein, including any embodiment, or a composition disclosed herein, including any embodiment, which is a tablet, capsule, injection, granule, powder, suppository, pill, gel, powder, oral liquid, inhalant, suspension, or dry suspension.

[0037] In some embodiments, including any one of the embodiments described thus far, the disclosed compounds that selectively inhibit TYK2 / JAK1 can be used as effective inhibitors of TYK2 / JAK1 and can be used to prevent or treat diseases and / or conditions caused by TYK2 / JAK1. In some embodiments, the disclosed compounds unexpectedly exhibit no or substantially no inhibition of JAK2.

[0038]

[0013] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, in which merely illustrative embodiments of the present disclosure have been shown and described. As will be recognized, the present disclosure is capable of other and different embodiments, and its several details are capable of changes in various obvious respects without departing from the entire scope of the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the JAK2 / JAK2 pathway with compounds A1-A7 according to Example 27.

[0040] [Figure 2] FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK2 / JAK2 pathway with compound A8 according to Example 27.

[0041] [Figure 3]FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK2 / JAK2 pathway with compound A9 according to Example 27.

[0042] [Figure 4] FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK2 / JAK2 pathway with compound A12 according to Example 27.

[0043] [Figure 5] FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK2 / JAK2 pathway with compound A17 according to Example 27.

[0044] [Figure 6] FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK2 / JAK2 pathway with compound A29 according to Example 27.

[0045] [Figure 7] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the JAK2 / JAK2 pathway with compounds A35, A38-A42 and A49-A50 according to Example 27.

[0046] [Figure 8] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the TYK2 / JAK2 pathway with compounds A1-A5 according to Example 27.

[0047] [Figure 9] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the TYK2 / JAK2 pathway with compound A8 according to Example 27.

[0048] [Figure 10] FIG. 1 depicts the results of Western blot experiments of the inhibition of the TYK2 / JAK2 pathway with compounds A4, A5, A9 and A12 according to Example 27.

[0049] [Figure 11]FIG. 1 depicts the results of a Western blot experiment of the inhibition of the TYK2 / JAK2 pathway with compounds A12, A17, A29, A35 and A38 according to Example 27.

[0050] [Figure 12] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the TYK2 / JAK2 pathway with compounds A39-A42 and A49-A50 according to Example 27.

[0051] [Figure 13] FIG. 1 depicts the results of Western blot experiments of inhibition of the JAK1 / JAK2 pathway with compounds A1, A5 and A6 according to Example 27.

[0052] [Figure 14] FIG. 1 depicts the results of a Western blot experiment of inhibition of the JAK1 / JAK2 pathway with compounds A4 and A5 according to Example 27.

[0053] [Figure 15] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the JAK1 / JAK2 pathway with compounds A2, A8-A9, A12, A17, and A29 according to Example 27.

[0054] [Figure 16] FIG. 1 depicts the results of a Western blot experiment of the inhibition of the JAK1 / JAK2 pathway with compounds A35, A38-A42 and A49-A50 according to Example 27.

[0055] Before proceeding with the detailed description, it is to be understood that the following detailed description is merely exemplary in nature and is not intended to limit the invention or its application and uses. Thus, while the present disclosure has been illustrated and described in terms of specific exemplary embodiments for convenience of explanation, it will be understood that it may be implemented in various other types of embodiments and equivalents, and in various other systems and environments. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0056] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0057] Detailed Description of the Invention While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0058] definition Compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it is understood that all optical isomers and mixtures thereof are included (unless otherwise specified). Furthermore, compounds with carbon-carbon double bonds can exist in Z- and E-forms, and all isomeric forms thereof are included in the present invention unless otherwise specified. When compounds exist in various tautomeric forms, the compounds described are not limited to a specific tautomer, but rather are intended to include all tautomers.

[0059] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" includes a plurality of such molecules, and the like.

[0060] As used herein, the terms "about" or "approximately" generally refer to within + / - 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a specified amount.

[0061] As used herein, the term "halogen" or "halide" generally refers to fluorine, chlorine, bromine, and iodine. As used herein, the term "haloalkyl" or "halo-alkyl" generally refers to an alkyl group substituted with one or more independently selected halogens (e.g., a "C1-C6 haloalkyl" group has 1 to 6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; mono-, di-, tri-, tetra-, or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl. As used herein, the term "haloalkoxy" or "halo-alkoxy" generally refers to an alkoxy group substituted with one or more independently selected halogens (e.g., a "C-C haloalkoxy" or "C-C halo-alkoxy" group has 1 to 6 carbon atoms and at least one halogen bonded to one of the carbon atoms). Examples of haloalkoxy groups include, but are not limited to, mono- or di-fluoromethoxy; mono- or di-chloromethoxy; mono-, di-, tri-, or tetra-fluoroethoxy; and mono-, di-, tri-, or tetra-chloroethoxy.

[0062] As used herein, the term "alkyl" generally refers to a straight or branched chain saturated aliphatic hydrocarbon. An alkyl group may contain 1 to 8 carbon atoms (C 1~8alkyl), 1 to 6 carbon atoms (C 1~6 In some embodiments, "C" refers to a group having 1 to 4 carbon atoms (C1-C4 alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. 1~6 "Alkyl" is preferably methyl, ethyl, n-propyl, isopropyl or tert-butyl. 1~3 Alkyl refers to straight- or branched-chain alkyl groups of 1 to 3 carbon atoms, including, for example, methyl, ethyl, propyl, and isopropyl. In some cases, the substituents on the alkyl group are specified. For example, "cyanoalkyl" refers to an alkyl group substituted with at least one cyano substituent.

[0063] As used herein, the term "alkenyl" generally refers to a straight- or branched-chain alkene group containing at least one unsaturated carbon-carbon double bond. Alkenyl groups include C 1 -C 2 -C 6 -C 6 -C 4 ... 2~8 Alkenyl group, C 2~6 Alkenyl groups and C 2~4 Alkenyl groups are included, for example, ethenyl, allyl and isopropenyl.

[0064] The term "alkynyl" as used herein generally refers to a straight- or branched-chain alkyne group having one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C alkynyl groups, which have 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. 2~8 Alkynyl group, C 2~6 Alkynyl groups and C 2~4Alkynyl groups are included, for example, ethynyl and propargyl.

[0065] The term "alkoxy" as used herein generally refers to an alkyl group as described above attached to another chemical moiety through an oxygen bridge. Alkoxy groups include alkyl groups of different lengths, for example, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 1~6 Alkoxy groups and C 1~4 As used herein, the term "OC" refers to an alkoxy group. 1~6 "Alkyl" generally refers to an alkoxy group containing an alkyl group (1 to 6 carbon atoms) attached to an oxygen atom. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.

[0066] As used herein, the term "cycloalkyl" generally refers to a group consisting of one or more saturated rings in which all ring members are carbon. For example, certain cycloalkyl groups include C 3~8 Cycloalkyl, where the cycloalkyl group contains one or more rings having 3 to 8 ring members, all of which are carbon, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Other examples of cycloalkyl groups include adamantyl. Cycloalkyl groups do not contain aromatic or heterocyclic rings. As used herein, the term "cycloalkenyl" generally refers to a group consisting of one or more unsaturated rings, all of which are carbon.

[0067] As used herein, the terms "heterocyclic" or "heterocycle" or "heterocyclyl" or "cycloheteroalkyl" generally refer to ring structures (monocyclic or polycyclic) containing 3 to 12 ring atoms (3- to 12-membered heterocycle), 3 to 8 ring atoms (3- to 8-membered heterocycle or 3- to 8-membered cycloheteroalkyl), 3 to 6 ring atoms (3- to 6-membered heterocycle or 3- to 6-membered cycloheteroalkyl), or 5 to 6 ring atoms (5- to 6-membered heterocycle or 5- to 6-membered cycloheteroalkyl), where at least one ring atom is carbon and at least one ring atom is a heteroatom selected from N, O, and S, or at least one heteroatom group is selected from C(=O), S(=O), and S(=O). Heterocyclic groups can be aromatic or non-aromatic. Piperidine and oxetane are non-limiting examples of non-aromatic heterocycles. Thiazole and pyridine are non-limiting examples of aromatic heterocycles. Other examples of heterocycles include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, and caprolactone. Similarly, the term "cycloheteroalkenyl" refers to a monocyclic or polycyclic ring structure containing carbon atom(s) and heteroatom(s) / heteroatom group(s), wherein the cycloheteroalkenyl contains at least one C=C double bond, at least one ring atom that is carbon, and at least one ring atom that is a heteroatom selected from N, O, and S, or a heteroatom group selected from C(=O), S(=O), and S(=O).

[0068] As used herein, the term "aryl" generally refers to an aryl group having 6 to 12 carbon atoms (C 6~12 aryl) or 6 to 10 (C 6~10"(aryl)" refers to an all-carbon monocyclic or fused-ring polycyclic group. Non-limiting examples of aryl groups are phenyl, naphthalenyl, tetrahydronaphthyl, indanyl, biphenyl, and anthracenyl. Aryl groups can be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR X R Y Contains R X and R Y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl, and combined 5- or 6-membered heteroalicyclic rings. Exemplary substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, aminoethyl, hydroxymethyl, methoxymethyl, 2-fluoroethyl, 2-methoxyethyl, and the like.

[0069] As used herein, the term "heteroaryl" generally refers to an aromatic group in which at least one aromatic ring contains at least one heteroatom selected from N, O, and S. Heteroaryl includes, for example, 5- to 12-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 7-membered monocyclic structure, or 7- to 12-membered bicyclic structure. The number of heteroatoms in a heteroaryl can be 1, 2, 3, 4, or more. Examples include, but are not limited to, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine-2(1H)-keto, pyridine-4(1H)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, imidazolyl, furanyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl. Heteroaryl groups can be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR X R Y Contains R X and R Y is as defined above.

[0070] As used herein, the term "amino" generally refers to primary amino groups (-NH), secondary amino groups (-NH-), and tertiary amino groups ( [ka] ) refers to

[0071] As used herein, the term "alkylamino" generally refers to a group having the general structure -NH-R1 or -N(R 1 )(R 2 ), and R 1 and R 2 refers to a secondary or tertiary amine independently selected from alkyl, cycloalkyl, and (cycloalkyl)alkyl groups. Such groups include, for example, mono- and di-(C 1~6 -NH(C alkyl) groups, respectively. 1~6 alkyl)" and "-N(C 1-6 alkyl), where each C 1~6 The alkyls may be the same or different. It will be apparent that the definition of "alkyl" used in the term "alkylamino" differs from the definition of "alkyl" used in all other alkyl-containing groups in that it encompasses cycloalkyl and (cycloalkyl)alkyl groups.

[0072] As used herein, the term "alkylthio" generally refers to an alkyl-substituted thio group, where the term alkyl is defined above.

[0073] As used herein, the terms "substituent" and "substituted" generally refer to a molecular moiety covalently bonded to an atom within the molecule of interest. The atom to which it is bonded can be carbon or nitrogen. The moiety can be alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. For example, ring substituents can be moieties such as halogen, alkyl, haloalkyl, or other groups covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of the ring. Substituents for aromatic groups are generally covalently bonded to a ring carbon or ring nitrogen atom. Linear chain substituents can be moieties such as halogen, alkyl, haloalkyl, or other groups covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a linear chain.

[0074] As used herein, the term "pharmaceutically acceptable" generally refers to the formation of a compound that is safe for administration to a subject. For example, a free base, salt form, solvate, hydrate, prodrug or derivative form of a compound described herein that has been approved for mammalian use by oral ingestion or any other route of administration by a regulatory agency or authority, such as the U.S. Food and Drug Administration (FDA), is pharmaceutically acceptable.

[0075] Included within the compounds of Formulas (I), (II), (III), (IV), and (V) are pharmaceutically acceptable salt forms of the free base compounds. As used herein, the term "pharmaceutically acceptable salts" generally refers to salts that are approved by regulatory agencies and are commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Salts are formed by ionic association, charge-charge interactions, covalent bonding, complexation, coordination, and the like. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. For example, the term "pharmaceutically acceptable salt" refers to a salt that is, within the bounds of good medical practice, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Acid salts include acetic acid, acetic acid, benzoic acid, cinnamic ...benzoic acid, cinnamic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, benzoic acid, cinnamic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic

[0076] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and other amine salts. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Examples include, but are not limited to, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is an ammonium, potassium, sodium, calcium, or magnesium salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, as appropriate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts. Bisalts (i.e., two counterions) and higher salts (e.g., three or more counterions) are included within the meaning of pharmaceutically acceptable salts.

[0077] As used herein, the term "ester" refers to organic compounds consisting of ester linkages, including monoesters, diesters, triesters, and polyesters.

[0078] As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Other solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and the like. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0079] As used herein, unless otherwise specified, a "prodrug" refers to a biologically active compound described herein that becomes active under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Discussions of prodrugs are found in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound of Formula (I), (II), (III), (IV), or (V) in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compounds of Formula (I), (II), (III), (IV), or (V) such that the modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxy, amino, or mercapto group, respectively, when the prodrug of the active compound of Formula (I), (II), (III), (IV), or (V) is administered to a mammalian subject.

[0080] The terms "isotopically labeled," "isotopically labeled," "isotopically labeled derivative," and "isotopically labeled" refer to unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound may contain, for example, tritium ( 3 H), iodine-125( 125I), carbon-14 ( 14 The compounds can also be radiolabeled with radioisotopes such as 2 H, 11 C. 13 C. 15 N, 17 O. 18 O. 18 F, 32 P, 35 S, 36 Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. Tritium isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) can facilitate preparation and detection. Furthermore, substitution with heavy isotopes such as deuterium (i.e., H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. All isotopic variations of the disclosed compounds, whether radioactive or not, are encompassed within the scope of the disclosure.

[0081] As used herein, the term "isomer" generally refers to different compounds having the same molecular formula, including all geometric isomers, tautomers, and stereoisomers. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. For example, "isomer" includes geometric double bond cis- and trans-isomers, also referred to as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)- and (l)-isomers, racemic mixtures thereof; and other mixtures thereof that fall within the scope of this disclosure, unless otherwise specified. As used herein, the term "tautomer" refers to a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa).

[0082] As used herein, the term "independently" means that at least two groups (or ring systems) present in a structure having the same or similar range of values may have the same or different meanings under certain circumstances. For example, if the substituents X and Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when the substituent X is hydrogen, the substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when the substituent Y is hydrogen, the substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0083] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the subsequently described event or circumstance.

[0084] In some embodiments, the compound(s) of Formula (I), (II), (III), (IV), or (V) are used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s) are, in one embodiment, combined with one or more pharmaceutically acceptable excipients, including carriers, diluents, or adjuvants, to form a suitable composition, as described in more detail herein.

[0085] As used herein, the term "excipient" generally refers to a pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), that is normally included for formulation and / or administration purposes.

[0086] The term "diluent" as used herein generally refers to an agent used as a filler to achieve the desired volume or weight of the composition.The diluent can be present in the pharmaceutical composition in the form of a single compound or a mixture of compounds in the granule.Non-limiting examples of diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0087] The term "adjuvant" as used herein generally refers to any substance or mixture of substances that, when used in conjunction with a compound disclosed herein, increases the effectiveness or potency of the compound disclosed herein against a target. However, when an adjuvant is used alone, no pharmacological effect is observed against the same target.

[0088] As used herein, the terms "treat," "treat," "treatment," and "therapy" generally refer to therapy, including, but not limited to, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic therapy generally prevents the onset of a disorder altogether or delays the onset of a preclinically evident stage of a disorder in an individual. Treatment includes the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active therapy, i.e., therapy dedicated to ameliorating a disease, pathological condition, or disorder, and also includes causal therapy, i.e., therapy directed at eliminating the cause of an associated disease, pathological condition, or disorder. In addition, this term includes palliative therapy, i.e., therapy aimed at alleviating symptoms rather than curing the disease, pathological condition, or disorder; preventive therapy, i.e., therapy aimed at minimizing or partially or completely suppressing the onset of an associated disease, pathological condition, or disorder; and supportive therapy, i.e., therapy used to complement another specific therapy aimed at ameliorating an associated disease, pathological condition, or disorder.

[0089] As used herein, the terms "prevent" or "preventing" refer to preventing, avoiding, avoiding, hindering, stopping, or impeding something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed unless specifically indicated otherwise.

[0090] The term "effective amount" or "therapeutically effective amount," as used herein, refers to a sufficient amount of an administered drug or compound to relieve to some extent one or more symptoms of the disease or condition being treated; achieve the goal of improving the severity and frequency of the disorder more than treatment with each drug alone, resulting in a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system; while avoiding side effects typically associated with alternative therapies. For example, an "effective amount" for therapeutic use is the amount of a composition as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies. In one embodiment, an effective amount is administered in a single dosage form or in multiple dosage forms.

[0091] Regardless of the selected route of administration, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those skilled in the art.

[0092] The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied, without toxicity to the patient, to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0093] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular hedgehog inhibitor employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and such factors as are well known in the medical arts.

[0094] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start doses of the compounds of the present invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0095] Generally, the appropriate daily dose of the compound of the present invention is the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective amount generally depends on the above-mentioned factors. In general, the intravenous, intracerebroventricular, and subcutaneous administration dose of the compound of the present invention to a patient ranges from about 0.0001 to about 100 mg per kg of body weight per day. The mode of administration can have a significant effect on the dosage. Higher doses can be used for local administration.

[0096] If desired, the effective daily dose of active compound can be administered as 2, 3, 4, 5, 6 or more sub-doses at appropriate intervals throughout the day, and optionally can be administered in unit dosage form.Those skilled in the art will easily understand that dosage level can vary as a function of specific compound, severity of symptoms and the sensitivity of the subject to side effects.Those skilled in the art can easily determine the dosage of a given compound disclosed herein by various means.

[0097] Pharmaceutical Compositions / Formulations One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), or (V), or a stereoisomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0098] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable preparation. Appropriate formulations depend on the selected route of administration. Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, HA and Lachman, L, EDS., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), which are incorporated herein by reference for their disclosures.

[0099] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I), (II), (III), (IV), or (V) with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0100] The pharmaceutical formulations described herein are administered to a subject by any suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combinations of immediate release and controlled release formulations.

[0101] All formulations for oral administration are in dosages suitable for such administration. Examples of such dosage units are tablets or capsules. In some embodiments, they contain about 1 to 2000 mg, advantageously about 1 to 500 mg, and typically about 5 to 150 mg of the active ingredient. The daily dose suitable for humans or other mammals varies greatly depending on the patient's condition and other factors, but can, again, be determined using routine methods and practices.

[0102] Traditional formulation techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, and the like.

[0103] Synthesis method The examples and preparations provided below illustrate and exemplify the compounds described herein and methods for preparing such compounds. In general, the compounds described herein can be prepared by processes known in the general chemical arts.

[0104] The compounds of the present invention can be prepared starting from commercially available materials using various synthetic routes, including those described below. The starting materials of the present invention are known, commercially available, or can be synthesized similarly to or according to methods known in the art. Many starting materials can be prepared according to known processes, and in particular, can be prepared using the processes described in the Examples. When synthesizing starting materials, functional groups are sometimes protected with appropriate protecting groups as necessary. Functional groups can be removed according to procedures known in the art.

[0105] The protection of functional groups by protecting groups, the protecting groups themselves, and reactions for their removal (commonly called "deprotection") can be found, for example, in standard reference works such as J.F.W.M. Comie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J. Meienhofer editors, Academic Press, London and New York (1981).

[0106] All synthetic procedures described herein can be carried out under known reaction conditions, advantageously those described herein, either in the absence or presence (usually) of solvents or diluents.

[0107] The present invention further encompasses "intermediate" compounds, including structures produced from the described synthetic procedures, whether isolated or not, prior to ultimately obtaining the desired compound. Structures resulting from performing steps from transient starting materials, structures resulting from deviations from the described methods at any stage, and structures forming from starting materials under reaction conditions are all "intermediates" encompassed by the present invention. Additionally, structures produced by using starting materials in the form of reactive derivatives or salts, or by compounds obtained by processes according to the present invention, and structures obtained by treating compounds of the present invention in situ are also within the scope of the present invention.

[0108] Novel starting materials and / or intermediates, as well as processes for their preparation, are also the subject of this invention. In selected embodiments, such starting materials are used and reaction conditions are selected to yield the desired compound(s).

[0109] The starting materials of the present invention are known, commercially available, or can be synthesized similarly to or according to methods known in the art. Many starting materials can be prepared according to known processes, in particular, by using the processes described in the Examples. When synthesizing starting materials, functional groups are sometimes protected with appropriate protecting groups as necessary. Protecting groups, their introduction and removal have been described above.

[0110] All reagents and solvents were commercially available unless otherwise noted. Commercially available reagents and solvents were used without purification unless otherwise noted. When necessary, some reagents and solvents were purified by standard techniques, such as distillation. For example, tetrahydrofuran can be purified by distillation from sodium. All thin-layer chromatography (TLC, GF254) analyses and column purifications (100-200 mesh) were performed on silica gel (Qingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd.) using petroleum ether (bp 60-90 °C) / ethyl acetate (v / v) as the eluent; and spots were revealed by UV visualization at 254 nm and I2 vapor or phosphomolybdic acid. All organic layers after extraction were dried over anhydrous Na2SO4 unless otherwise noted. All nuclear magnetic resonance spectra ( 1 H NMR was recorded on a Varian-400 spectrometer at 400 MHz using TMS as the internal standard. LC-MS was performed on an Agilent 1100 system equipped with an LC-MS D-trap recorder, a diode array detector (DAD) with detection wavelengths of 214 nm and 254 nm, and an ESI source. The HPLC column was an Agela Durashell C18 3.5 μm 4.6 × 50 mm column. A gradient of 0.1% NH4HCO3 aqueous solution to acetonitrile was run from 5 / 95 to 95 / 5 with the indicated run time (e.g., 5 min) at a flow rate of 1.8 mL / min.

[0111] The size and scale of the synthesis method vary depending on the amount of the desired final product. Specific reactants and amounts are described in the examples, but it is understood that those skilled in the art will know other alternative, equally viable, sets of reactants that will yield the same compound. Thus, when common oxidizing agents, reducing agents, and solvents of various natures (aprotic, nonpolar, polar, etc.) are utilized, equivalents are known in the art and are contemplated herein for use in the present method.

[0112] Many of the following steps illustrate various workups after the reaction is complete. Workup typically involves quenching the reaction to eliminate residual catalytic activity and starting reagents. This is typically followed by the addition of an organic solvent and separation of the aqueous and organic layers. The product is typically obtained from the organic layer, while unused reactants, spurious by-products, and unwanted chemicals are typically captured in the aqueous layer and discarded. In standard organic synthesis procedures found throughout the literature, workup typically involves drying the product by exposure to a drying agent such as anhydrous Na2SO4, removing excess water and aqueous by-products that remain partially dissolved in the organic layer, and concentrating the remaining organic layer. Concentration of the dissolved product can be achieved by known means, such as evaporation under pressure or evaporation at elevated temperature and pressure. Such concentration can be achieved using standard laboratory equipment, such as rotary evaporation. This can optionally be followed by one or more purification steps, including, but not limited to, flash column chromatography, filtration through various media, and / or other preparative methods known in the art, and / or crystallization / recrystallization. (See, e.g., Addison Ault, "Techniques and Experiments for Organic Chemistry," 6th Ed., University Science Books, Sausalito, Calif., 1998, Ann B. McGuire, Ed., pp. 45-59).

[0113] Abbreviation

[0114] DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene. DMF means N,N-dimethylformamide. EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. HOBT is hydroxybenzotriazole. IPA is isopropyl alcohol. NMI is 1-methylimidazole or N-methylimidazole. NMP is N-methyl-2-pyrrolidone. Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0). Pd(dppf)Cl2 is 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(OAc)2 is palladium(II) acetate. TEA or Et3N is triethylamine. THF is tetrahydrofuran. DCM means dichloromethane. Xantphos is (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane). MTBE is methyl tert-butyl ether. NaOAc is sodium acetate. LiHMDS is lithium bis(trimethylsilyl)amide. DPPA is diphenylphosphoryl azide. t-BuOH is tert-butyl alcohol. (BPIN)2 is bis(pinacolato)diboron. EtOAc or EA means ethyl acetate. DCE means 1,2-dichloroethane. NaH is sodium hydride. PE is petroleum ether. TLC means thin layer chromatography. HPLC means high performance liquid chromatography. LC-MS means liquid chromatography-mass spectrometry. NMR means nuclear magnetic resonance.

[0115] General synthetic route The following Methods AA-AR are embodiments of several general synthetic routes to compounds of Formula (I), (II), (III), (IV), or (V). Detailed reaction conditions for each method can be found in the provided examples, see below.

[0116] Method AA:

[0117] Method AA [ka]

[0118] Bromination of ethyl 1H-pyrazole-4-carboxylate with bromine followed by decarboxylation with 50% H2SO4 gave 3,5-dibromo-1H-pyrazole (steps a, b). After alkylation under basic conditions (step c), the intermediate was coupled with an alkyl phosphorus oxide to give the desired product (step d).

[0119] Method AB [ka]

[0120] Reduction of the nitro group with iron powder followed by cross-coupling reaction gave the corresponding compounds (steps a, b).

[0121] method ac [ka]

[0122] The desired product was obtained via Suzuki coupling reaction (step a).

[0123] Method AD [ka]

[0124] The final compound is S N Obtained via Ar reaction (step a).

[0125] Method AE [ka]

[0126] Nitration of 4-bromopyridin-3-ol with HNO3 and methylation of the hydroxyl group with iodomethane could give the corresponding intermediate (step a). Treatment with iron powder gave the pyridin-2-amine derivative (step b).

[0127] Method AF [ka]

[0128] The final compound was obtained via Suzuki coupling reaction (step a).

[0129] Method AG [ka]

[0130] The final compound was obtained via Suzuki coupling reaction (step a).

[0131] Method AH [ka]

[0132] The desired compounds were obtained via copper-mediated coupling followed by Buchwald-Hartwig reaction (steps a, b).

[0133] Method AI [ka]

[0134] The Regitz diazo transfer reaction of diethyl 3-oxopentanedioate was carried out with arylsulfonyl azides (step a). Treatment with triphenylphosphine followed by cyclization afforded the pyridazine derivatives (steps b, c). Chlorination of the hydroxyl group with phosphorus oxychloride followed by ester hydrolysis afforded the final compounds (steps d, e).

[0135] Method AJ [ka]

[0136] Various benzene or heterocyclic dibromide derivatives were coupled with alkyl phosphorus oxides to give the desired products (step a).

[0137] Method AK [ka]

[0138] The desired compound was obtained via Suzuki and Buchwald-Hartwig reactions (steps a, b).

[0139] Method AL [ka]

[0140] The final compound was obtained via a Buchwald-Hartwig reaction, with the cyclopropanecarbonyl being hydrolyzed during this process.

[0141] method AM [ka]

[0142] Curtius rearrangement of 5-bromothiophene-2-carboxylic acid with DPPA and t-BuOH gave tert-butyl (5-bromothiophen-2-yl)carbamate (step a), which underwent Miyaura-Suzuki coupling between pyrazole and thiophene to give the corresponding intermediate (steps b, c). Deprotection with EA / HCl afforded the desired compound (step d).

[0143] method an [ka]

[0144] Activation of the carboxylic acid using oxalyl chloride promoted an addition-elimination process to form the corresponding amide (step a). N The Ar reaction was carried out under basic conditions (step b). Palladium-catalyzed Buchwald-Hartwig (step c) or S N Ar reaction gave the desired compound (step d).

[0145] Method AO [ka]

[0146] Palladium-catalyzed coupling of 4-bromo-1H-pyrazole and dicyclopropylphosphine oxide gave dicyclopropyl(1H-pyrazol-4-yl)phosphine oxide (step a), which was coupled with 2-bromo-6-nitrophenol to give the corresponding intermediate (step b). Methylation with CHCl, followed by nitro reduction with zinc powder, gave (1-(3-amino-2-methoxyphenyl)-1H-pyrazol-4-yl)dicyclopropylphosphine oxide (step d). N Ar reaction under acidic conditions followed by Buchwald-Hartwig reaction gave the desired compounds (steps e, f).

[0147] Method AP [ka]

[0148] Protection of N-pyrazole with MOMCl (step a), followed by coupling reaction between 3,5-dibromo-1-(methoxymethyl)-1H-pyrazole and dicyclopropylphosphine oxide gave the corresponding intermediate (step b), which was reacted with 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline via Suzuki reaction (step c). N Ar reaction under acidic conditions followed by Buchwald-Hartwig reaction gave the desired compounds (steps d, e).

[0149] Method AQ [ka]

[0150] Coupling of the starting material with an alkylphosphorus oxide gave the desired compound (step a).

[0151] Method AR [ka]

[0152] Coupling reaction with the starting material 1-bromo-2-fluoro-3-nitrobenzene (step a) followed by displacement of the fluorine at C2 of the aryl ring with sodium methoxide gave the corresponding intermediate (step b). Reduction of the nitro group with iron powder followed by S N Ar and Buchwald-Hartwig reaction gave the desired products (steps c, d, e). [Example]

[0153] The general reaction progress was monitored by analytical thin-layer chromatography performed on silica gel HSGF254 precoated plates. The organic solution was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The final compound was purified by column chromatography on silica gel 100-200 mesh. 1 H NMR was obtained on a 300 MHz (Varian) spectrometer. 13 C NMR was obtained on a 151 MHz or 101 MHz (Varian) spectrometer. Chemical shifts are given in ppm using tetramethylsilane as an internal standard. Mass spectra were obtained using an Agilent 1100 LC / MSD Trap SL version mass spectrometer. HRMS analyses were recorded on an Agilent 6540 UHD Accurate-Mass Q-TOF LC / MS.

[0154] Example 1, Methods AA, AB, AC, AI, AN

[0155] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A1) [ka]

[0156] Step a. Ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate: To a solution of ethyl 1H-pyrazole-4-carboxylate (3.0 g, 21.3 mmol) in ethanol / water (18 mL / 27 mL), NaOAc (6.9 g, 95.0 mmol) and bromide (8.4 g, 53.0 mmol) were added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of saturated aqueous NaSO (60 mL). The aqueous layer was extracted with dichloromethane (60 mL × 3). The organic layers were combined, dried over NaSO, and concentrated to give the desired compound (6.1 g, 96%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.37 - 4.19 (m, 2H), 1.42 - 1.23 (m, 3H). LC-MS: 296.9 [M+H] + .

[0157] Step b. 3,5-Dibromo-1H-pyrazole: Ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (3.0 g, 10.0 mmol) was dissolved in 50% H2SO4 (30 mL). The solution was stirred at 160 °C for 2 h. After cooling to room temperature, saturated aqueous NaHCO3 (100 mL) was added to neutralize the acid. The aqueous layer was extracted with ethyl acetate (20 mL × 4). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the final compound (1.4 g, 62%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): δ 13.92 (s, 1H), 6.58 (s, 1H). LC-MS: 225.0 [M+H] + .

[0158] Step c. 3,5-Dibromo-1-methyl-1H-pyrazole: To a solution of 3,5-dibromo-1H-pyrazole (500 mg, 2.2 mmol) in acetonitrile (10 mL) was added K2CO3 (607 mg, 4.4 mmol) and iodomethane (369 mg, 2.6 mmol). The mixture was stirred at 80 °C overnight. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the final compound (350 mg, 66%) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 6.29 (s, 1H), 3.84 (s, 3H). LC-MS: 239.0 [M+H] + .

[0159] Step d. (3-Bromo-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 3,5-dibromo-1-methyl-1H-pyrazole (1.5 g, 6.3 mmol) in DMF (5 mL) was added KPO (1.7 g, 12.6 mmol), dicyclopropylphosphine oxide (1.5 g, 11.5 mmol), Pd(OAc) (135 mg, 0.6 mmol), and Xantphos (347 mg, 0.6 mmol). The mixture was stirred at 110 °C under a N atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the final compound (470 mg, 26%) as a pale yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 6.59 (d, J = 1.2 Hz, 1H), 4.14 (s, 3H), 1.04-0.93 (m, 10H). LC-MS: 289.0 [M+H] + .

[0160] Step e. 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: To a solution of 3-bromo-2-methoxyaniline (6.1 g, 30 mmol) in 1,4-dioxane (60 mL) was added (Bpin) (11.4 g, 45 mmol), KOAc (8.8 g, 90 mmol), and Pd(dppf)Cl (1.3 g, 1.8 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 4 / 1) to give the final compound (7.0 g, 93%) as a yellow oil. 1 H NMR (300 MHz, CDCl3): δ 7.11 (d, J = 6.9Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 4.86 (s, 2H), 3.81 (s, 3H), 1.36 (s, 12H). LC-MS: 250.1 [M+H] + .

[0161] Step f. (3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10.4 g, 41.7 mmol) and (3-bromo-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (8.0 g, 27.8 mmol) in 1,4-dioxane / water (30 mL / 3 mL) was added Pd(dppf)Cl (2.0 g, 2.8 mmol) and KCO (7.7 g, 55.6 mmol). The mixture was stirred at 110 °C under a N atmosphere overnight. The solvent was removed and the residue was purified by silica gel chromatography column (PE / EA=5 / 1) to give the final compound (8.1 g, 59%) as a white solid. 1H-NMR (300 MHz, CDCl3): δ 7.20-7.30 (m, 1H), 7.15-7.08 (m, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.23 (s, 3H), 3.88 (s, 2H), 3.64 (s, 3H), 1.15-0.75 (m, 10H). LC-MS: 331.9 [M+H] + .

[0162] Step g. Diethyl 2-diazo-3-oxopentanedioate: To a solution of diethyl 3-oxopentanedioate (7.0 g, 34.6 mmol) in acetonitrile (100 mL) was added EtN (3.8 g, 38.1 mmol) and 4-acetamidobenzenesulfonyl azide (8.7 g, 36.9 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solvent was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl ether (200 mL), and the solution was filtered again. The filtrate was concentrated to give the crude product (7.4 g, 94%) as a yellow solid.

[0163] Step h. Diethyl 3-oxo-2-((triphenyl-15-phosphanylidene)hydrazono)pentanedioate: To a solution of diethyl 2-diazo-3-oxopentanedioate (7.4 g, 32.5 mmol) in ethyl ether (250 mL) was added PPh3 (9.6 g, 36.5 mmol). The mixture was stirred at room temperature for 48 h. The solvent was concentrated to give the crude product (17.0 g, 94%) as a yellow oil.

[0164] Step i. Ethyl 4,6-dihydroxypyridazine-3-carboxylate: Diethyl 3-oxo-2-((triphenyl-15-phosphanylidene)hydrazono)pentanedioate (17.0 g, 34.7 mmol) was dissolved in acetic acid / water (80 mL / 8 mL). The mixture was refluxed for 12 hours. The solvent was removed and the residue was rinsed with ethyl acetate (50 mL) to give the desired product (3.0 g, 47%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 12.30 (s, 1H), 10.62 (s, 1H), 6.33 (s, 1H), 4.53 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). LC-MS: 185.1 [M+H] + .

[0165] Step j. Ethyl 4,6-dichloropyridazine-3-carboxylate: Ethyl 4,6-dihydroxypyridazine-3-carboxylate (21 g, 114.1 mmol) was dissolved in POCl3 (250 mL). The mixture was stirred at 115 °C overnight. The solvent was removed, and saturated aqueous NaCl (200 mL) was added. The aqueous layer was extracted with ethyl acetate (200 mL × 3). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the desired product (10.6 g, 42%) as a brown oil.

[0166] Step k. 4,6-Dichloropyridazine-3-carboxylic acid: To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate in tetrahydrofuran (100 mL) was added 1N LiOH (92 mL, 92 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and 1.5N HCl was added to adjust the pH to 2. The aqueous layer was extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product (10.6 g, 90%) as a yellow solid.

[0167] Step l. 4,6-Dichloropyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxylic acid (2.0 g, 10.4 mmol) in dichloromethane (20 mL) was added oxalyl dichloride (1.3 mL, 15.6 mmol) and DMF (1 drop) at 0° C. The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was dissolved in dichloromethane (20 mL). Ammonium hydroxide (2 mL) was added to the solution. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by silica gel chromatography (DCM) to give the final compound (1.8 g, 90%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H).

[0168] Step m. 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (69.6 mg, 0.4 mmol) and (3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (100 mg, 0.3 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1 N LiHMDS (0.8 mL, 0.8 mmol) under N atmosphere. The mixture was stirred at room temperature for 3 h. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (50 mg, 29%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.78 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.23 (s, 2H), 4.13 (s, 3H), 3.63 (s, 3H), 1.42 - 1.28 (m, 2H), 0.99 - 0.87 (m, 4H), 0.84 - 0.64 (m, 4H).

[0169] Step n. 6-(cyclopropanecarboxamide)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A1): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (16 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (8.33 mg, 0.09 mmol), Pd(dba) (9.16 mg, 0.01 mmol), Xantphos (5.79 mg, 0.01 mmol), and KPO (3.9 g, 12.0 mmol). The mixture was stirred in a microwave oven at 120° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the crude product, which was rinsed with EtO to give the desired product (7 mg, 40%) as a white solid.

[0170] Example 2, Methods AA, AB, AC, AN

[0171] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)nicotinamide (A2) [ka]

[0172] Step a. 4,6-Dichloronicotinamide: To a solution of 4,6-dichloronicotinic acid (500 mg, 2.6 mmol) in dichloromethane (20 mL) was added oxalyl dichloride (434 mg, 3.4 mmol) and DMF (1 drop) at 0° C. The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was dissolved in dichloromethane (20 mL). 7M ammonia in methanol (1.1 mL, 7.7 mmol) was added to the solution. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by silica gel chromatography (DCM) to give the final compound (240 mg, 48%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.11 (s, 1H), 7.88 (s, 2H).

[0173] Step b. 6-Chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)nicotinamide: To a solution of 4,6-dichloronicotinamide (37 mg, 0.19 mmol) and (3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (66 mg, 0.20 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (0.44 mL, 0.44 mmol) under N atmosphere. The mixture was stirred at room temperature for 3 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (53 mg, 57%) as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 10.86 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 7.39 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 6.93 (s, 1H), 4.12 (s, 3H), 3.61 (s, 3H), 1.45-1.26 (m, 2H), 0.99-0.75 (m, 8H).

[0174] Step c. 6-(cyclopropanecarboxamide)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)nicotinamide (A2): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)nicotinamide (53 mg, 0.11 mmol) in 1,4-dioxane (25 mL) was added cyclopropanecarboxamide (28 mg, 0.33 mmol), Pd(dba) (9 mg, 0.01 mmol), Xantphos (5 mg, 0.01 mmol), and CsCO (72 mg, 0.22 mmol). The mixture was stirred in a microwave at 130 °C under a N atmosphere for 2 h. The solvent was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (10 mg, 17%) as a yellow solid.

[0175] Example 3, Methods AA, AD, AF, AI, AN

[0176] Preparation of 6-(cyclopropanecarboxamido)-4-((6-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-methoxypyrimidin-4-yl)amino)pyridazine-3-carboxamide (A3) [ka]

[0177] Step a. (3-(6-Amino-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (500 mg, 1.7 mmol) in 1,4-dioxane (20 mL) was added (Bpin) (635 mg, 1.5 mmol), KOAc (500 mg, 5.1 mmol), and Pd(dppf)Cl (124 mg, 0.17 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. To the above mixture was added water (1 mL), K2CO3 (469 mg, 3.4 mmol), Pd(dppf)Cl2 (124 mg, 0.17 mmol), and 6-chloro-5-methoxypyrimidin-4-amine (270 mg, 1.7 mmol). The mixture was stirred at 100 °C for 10 hours. The solvent was removed, and the residue was purified by silica gel chromatography column (DCM / MeOH / NH3.HO = 50 / 2 / 1) to give the desired product (530 mg, 93%) as a black solid.

[0178] Step b. 6-chloro-4-((6-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-methoxypyrimidin-4-yl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (128 mg, 0.67 mmol) and (3-(6-amino-5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (150 mg, 30.45 mmol) in anhydrous tetrahydrofuran (8 mL) was added NaH (108 mg, 2.25 mmol) under N atmosphere. The mixture was stirred at room temperature for 24 h. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (50 mg, 23%) as a yellow oil. 1 H-NMR (300 MHz, DMSO-d6): δ 12.94 (s, 1H), 9.25 (s, 1H), 8.99 (s, 1H), 8.75 (s, 1H), 8.35 (s, 1H), 7.45 (s, 1H), 4.20 (s, 3H), 3.92 (s, 3H), 1.53-1.30 (m, 2H), 0.97-0.73 (m, 8H). LC-MS: m / z 488.7 [M+H] + .

[0179] Step c. 6-(cyclopropanecarboxamide)-4-((6-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-methoxypyrimidin-4-yl)amino)pyridazine-3-carboxamide (A3): To a solution of 6-chloro-4-((6-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-methoxypyrimidin-4-yl)amino)pyridazine-3-carboxamide (50 mg, 0.10 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (25 mg, 0.30 mmol), Pd(dba) (9 mg, 0.01 mmol), Xantphos (5 mg, 0.01 mmol), and CsCO (65 mg, 0.20 mmol). The mixture was stirred in a microwave oven at 130° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (4 mg, 17%) as a yellow solid.

[0180] Example 4, Methods AA, AB, AC, AI, AN

[0181] Preparation of 4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-6-(pyridin-2-ylamino)pyridazine-3-carboxamide (A4) [ka]

[0182] Step a. 4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-6-(pyridin-2-ylamino)pyridazine-3-carboxamide (A4): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (100 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was added pyridin-2-amine (60 mg, 0.3 mmol), Pd(dba) (18 mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), and CsCO (128 mg, 0.4 mmol). The mixture was stirred in a microwave oven at 130° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (7 mg, 6%) as a yellow solid.

[0183] A similar procedure as described in Example 4 was carried out to give compounds A5, A9, A12, A15, A17, A20, A21, A22, A23, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43 and A47.

[0184] Example 5, Methods AA, AB, AC, AI, AN

[0185] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(diethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A6) [ka]

[0186] Step a. (3-Bromo-1-methyl-1H-pyrazol-5-yl)diethylphosphine oxide: To a solution of 3,5-dibromo-1-methyl-1H-pyrazole (500 mg, 2.1 mmol) in DMF (10 mL) was added KPO (1.30 g, 6.3 mmol), diethylphosphine oxide (339 mg, 3.2 mmol), Pd(OAc) (135 mg, 0.6 mmol), and Xantphos (116 mg, 0.2 mmol). The mixture was stirred at 130 °C under a N atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (240 mg, 43%) as a pale yellow oil. LC-MS: m / z 265.0 [M+H] + .

[0187] Step b. (3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)diethylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (311 mg, 1.25 mmol) and (3-bromo-1-methyl-1H-pyrazol-5-yl)diethylphosphine oxide (220 mg, 0.83 mmol) in 1,4-dioxane / water (30 mL / 3 mL) was added Pd(dppf)Cl (59 mg, 0.08 mmol) and KCO (229 mg, 1.6 mmol). The mixture was stirred at 110 °C under a N atmosphere overnight. The solvent was removed and the residue was purified by silica gel chromatography column (DCM / MeOH=100 / 3) to give the compound (240 mg, 94%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 7.22 (d, J = 6.9 Hz, 1H), 7.02-6.93 (m, 1H), 6.88 (s, 1H), 6.74 (d, J = 7.2 Hz, 1H), 4.28 (s, 3H), 3.93 (s, 2H), 3.62 (s, 3H), 2.11-1.95 (m, 4H), 1.30-1.20 (m, 6H).

[0188] Step c. 6-chloro-4-((3-(5-(diethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (155 mg, 0.8 mmol) and (3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)diethylphosphine oxide (165 mg, 0.5 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (1.4 mL, 1.4 mmol) under N atmosphere. The mixture was stirred at room temperature for 3 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (120 mg, 32%) as a yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 10.76 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.29-7.21 (m, 2H), 7.07-6.97 (m, 1H), 6.95-6.86 (m, 1H), 5.80 (s, 1H), 4.29 (s, 3H), 3.60 (s, 3H), 2.11-1.93 (m, 4H), 1.25-1.12 (m, 6H). LC-MS: m / z 462.7 [M+H] + .

[0189] Step d. 6-(cyclopropanecarboxamide)-4-((3-(5-(diethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A6): To a solution of 6-chloro-4-((3-(5-(diethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (130 mg, 0.3 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (72 mg, 0.8 mmol), Pd(dba) (27 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), and CsCO (65 mg, 0.20 mmol). The mixture was stirred in a microwave oven at 130° C. under a N atmosphere for 1.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (14 mg, 10%) as a yellow solid.

[0190] A similar procedure as described in Example 5 was carried out to give compounds A8, A10, A26, A29, A30, A31 and A33.

[0191] Example 6, Methods AB, AK, AI, AN

[0192] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dimethylphosphoryl)pyrimidin-2-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A7) [ka]

[0193] Step a. 3-(5-Bromopyrimidin-2-yl)-2-methoxyaniline: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.3 g, 5.1 mmol) and 2,5-dibromopyrimidine (800 mg, 3.4 mmol) in 1,4-dioxane / water (30 mL / 3 mL) was added Pd(dppf)Cl (250 mg, 0.34 mmol) and KCO (938 mg, 6.8 mmol). The mixture was stirred at 95 °C under a N atmosphere overnight. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 2 / 1) to give the compound (645 mg, 68%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 8.90 (s, 2H), 7.22-7.16 (m, 1H), 7.08-6.97 (m, 1H), 6.91-6.85 (m, 1H), 3.96 (s, 2H), 3.68 (s, 3H). LC-MS: m / z 280.0 [M+H] + .

[0194] Step b. (2-(3-Amino-2-methoxyphenyl)pyrimidin-5-yl)dimethylphosphine oxide: To a solution of 3-(5-bromopyrimidin-2-yl)-2-methoxyaniline (645 mg, 2.3 mmol) in 1,4-dioxane (10 mL) was added KCO (635 mg, 4.6 mmol), dimethylphosphine oxide (269 mg, 3.5 mmol), Pd(OAc) (52 mg, 0.23 mmol), and Xantphos (133 mg, 0.23 mmol). The mixture was stirred at 120 °C under a N atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (200 mg, 31%) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.15 (s, 1H), 9.13 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.11-7.02 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.01 (s, 2H), 3.74 (s, 3H), 1.87 (d, J = 13.2 Hz, 6H). LC-MS: m / z 278.1 [M+H] + .

[0195] Step c. 6-chloro-4-((3-(5-(dimethylphosphoryl)pyrimidin-2-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (95 mg, 0.5 mmol) and (2-(3-amino-2-methoxyphenyl)pyrimidin-5-yl)dimethylphosphine oxide (70 mg, 0.25 mmol) in anhydrous tetrahydrofuran (3 mL) was added 1N LiHMDS (0.75 mL, 0.75 mmol) under N atmosphere. The mixture was stirred at room temperature for 2 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=15 / 1) to give the final compound (25 mg, 23%) as a yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 10.75 (s, 1H), 9.16 (s, 2H), 8.09 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.42-7.26 (m, 2H), 7.00 (s, 1H), 3.78 (s, 3H), 1.89 (d, J = 10.2 Hz, 6H).

[0196] Step d. 6-(cyclopropanecarboxamide)-4-((3-(5-(dimethylphosphoryl)pyrimidin-2-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A7): To a solution of 6-chloro-4-((3-(5-(dimethylphosphoryl)pyrimidin-2-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (24 mg, 0.05 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (14 mg, 0.16 mmol), Pd(dba) (5 mg, 0.005 mmol), Xantphos (3 mg, 0.005 mmol), and CsCO (32 mg, 0.10 mmol). The mixture was stirred in a microwave at 130 °C under a N atmosphere for 1.5 h. The solvent was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (12 mg, 50%) as a yellow solid.

[0197] A similar procedure as described in Example 6 was carried out to give compounds A14 and A16.

[0198] Example 7, Methods AA, AB, AC, AI, AN

[0199] Preparation of 4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-6-(pyrrolidin-1-yl)pyridazine-3-carboxamide (A11) [ka]

[0200] Step a. 4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-6-(pyrrolidin-1-yl)pyridazine-3-carboxamide (A11): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (50 mg, 0.1 mmol) in DMF (2 mL) was added pyrrolidine (28 mg, 0.4 mmol) and KCO (41 mg, 0.3 mmol). The mixture was stirred at 110 °C in a microwave for 2.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over NaSO and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (22 mg, 17%) as a white solid.

[0201] A similar procedure as described in Example 7 was carried out to give compounds A27, A28 and A32.

[0202] Example 8, Methods AA, AE, AG, AI, AL

[0203] Preparation of 6-amino-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (A13) [ka]

[0204] Step a. 6-chloro-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (276 mg, 1.4 mmol) and (3-(2-amino-3-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (320 mg, 0.96 mmol) in anhydrous tetrahydrofuran (10 mL) was added 1N LiHMDS (2.9 mL, 2.9 mmol) under N atmosphere. The mixture was stirred at room temperature for 24 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=15 / 1) to give the final compound (116 mg, 25%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 12.62 (s, 1H), 9.24 (s, 1H), 8.89 (s, 1H), 8.33-8.04 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 7.39 (s, 1H), 4.17 (s, 3H), 3.79 (s, 3H), 1.52-1.22 (m, 2H), 1.06-0.72 (m, 8H).

[0205] Step b. 6-amino-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (A13): To a solution of 6-chloro-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (30 mg, 0.06 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (15 mg, 0.18 mmol), Pd(dba) (5 mg, 0.006 mmol), Xantphos (4 mg, 0.006 mmol), and CsCO (40 mg, 0.12 mmol). The mixture was stirred in a microwave oven at 130° C. under a N atmosphere for 1.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the by-product (4 mg, 14%) as a yellow solid.

[0206] Example 9, Methods AA, AE, AG, AI, AN

[0207] Preparation of 6-(cyclopropanecarboxamido)-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (A18) [ka]

[0208] Step a. 6-(cyclopropanecarboxamide)-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (A18): To a solution of 6-chloro-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (20 mg, 0.04 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (10 mg, 0.12 mmol), Pd(dba) (4 mg, 0.004 mmol), Xantphos (4 mg, 0.006 mmol), and KPO (17 mg, 0.08 mmol). The mixture was stirred in a microwave at 120° C. under N atmosphere for 1 hour. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give the desired product (8 mg, 14%) as a yellow solid.

[0209] Example 10, Methods AA, AB, AC, AN

[0210] Preparation of 2-(cyclopropanecarboxamido)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyrimidine-5-carboxamide (A19) [ka]

[0211] Step a. 2-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyrimidine-5-carboxamide: To a solution of 2,4-dichloropyrimidine-5-carboxamide (122 mg, 0.3 mmol) and (3-(2-amino-3-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (210 mg, 0.3 mmol) in DMA (8 mL) was added TEA (128 mg, 1.2 mmol). The mixture was stirred at room temperature overnight. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the final compound (130 mg, 42%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 12.08 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.39-8.34 (m, 1H), 7.95 (s, 1H), 7.64-7.52 (m, 1H), 7.30-7.18 (m, 2H), 4.13 (s, 3H), 3.67 (s, 3H), 1.44-1.30 (m, 2H), 0.97-0.71 (m, 8H). LC-MS: m / z 486.7 [M+H] + .

[0212] Step b. 2-(cyclopropanecarboxamide)-4-((3-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyrimidine-5-carboxamide (A19): To a solution of 6-chloro-4-((4-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (125 mg, 0.30 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (65 mg, 0.80 mmol), Pd(dba) (27 mg, 0.030 mmol), Xantphos (20 mg, 0.030 mmol), and CsCO (195 mg, 0.60 mmol). The mixture was stirred in a microwave oven at 130° C. under a N atmosphere for 1.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (5 mg, 4%) as a yellow solid.

[0213] Example 11, Methods AA, AB, AC, AI, AN

[0214] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dicyclopropylphosphoryl)-1-(methyl-d3)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A24) [ka]

[0215] Step a. 3,5-Dibromo-1-(methyl-d3)-1H-pyrazole: To a solution of 3,5-dibromo-1H-pyrazole (500 mg, 2.2 mmol) in acetonitrile (10 mL) was added K2CO3 (613 mg, 4.4 mmol) and iodomethane-d3 (0.17 mL, 2.7 mmol). The mixture was stirred at 80 °C for 2 h. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the final compound (443 mg, 82%). 1 H-NMR (300 MHz, CDCl3): δ 6.28 (s, 1H).

[0216] Step b. (3-Bromo-1-(methyl-d3)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 3,5-dibromo-1-(methyl-d3)-1H-pyrazole (3.2 g, 13 mmol) in 1,4-dioxane (5 mL), K3PO4 (5.6 g, 26 mmol), dicyclopropylphosphine oxide (3.4 g, 26 mmol), Pd(OAc)2 (295 mg, 1.3 mmol), and Xantphos (761 mg, 1.3 mmol) were added. The mixture was stirred at 110 °C under a N2 atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (1.8 g, 47%) as a pale yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 6.59 (d, J = 1.2 Hz, 1H), 4.14 (s, 3H), 1.04-0.93 (m, 10H). 1 H-NMR (300 MHz, CDCl3): δ 6.59 (s, 1H), 1.09-0.86 (m, 10H). LC-MS: m / z 291.8 [M+H] + .

[0217] Step c. (3-(3-amino-2-methoxyphenyl)-1-(methyl-d3)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.8 g, 7.2 mmol) and (3-bromo-1-(methyl-d3)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (1.4 g, 4.8 mmol) in 1,4-dioxane / water (30 mL / 3 mL) was added Pd(dppf)Cl2 (351 mg, 0.50 mmol) and K2CO3 (1.3 g, 9.6 mmol). The mixture was stirred at 110 °C under a N2 atmosphere overnight. The solvent was removed and the residue was purified by silica gel chromatography column (DCM / MeOH=100 / 3) to give the compound (1.4 g, 87%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 7.22 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 6.97 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 3.89 (s, 2H), 3.64 (s, 3H), 1.16-0.88 (m, 10H). LC-MS: m / z 334.9 [M+H] + .

[0218] Step d. 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-(methyl-d3)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (776 mg, 4.0 mmol) and (3-(3-amino-2-methoxyphenyl)-1-(methyl-d3)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (900 mg, 2.7 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (11 mL, 11 mmol) under N2 atmosphere. The mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (800 mg, 61%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 11.15 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.33-7.14 (m, 3H), 3.62 (s, 3H), 1.43-1.28 (m, 2H), 1.02-0.69 (m, 8H). LC-MS: m / z 489.7 [M+H] + .

[0219] Step e. 6-(Cyclopropanecarboxamide)-4-((3-(5-(dicyclopropylphosphoryl)-1-(methyl-d)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A24): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1-(methyl-d)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (80 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (42 mg, 0.49 mmol), Pd(dba) (15 mg, 0.020 mmol), Xantphos (10 mg, 0.020 mmol), and KPO (69 mg, 0.33 mmol). The mixture was stirred in a microwave oven at 120° C. under a N atmosphere for 1.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (10 mg, 11%) as a brown solid.

[0220] The same procedure as described in Example 11 was carried out to give compounds A49, A50, A59 and A65-A67.

[0221] Example 12, Methods AA, AM, AI, AN

[0222] Preparation of 6-(cyclopropanecarboxamido)-4-((5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)amino)pyridazine-3-carboxamide (A25) [ka]

[0223] Step a. tert-Butyl (5-bromothiophen-2-yl)carbamate: To a solution of 5-bromothiophene-2-carboxylic acid (300 mg, 1.5 mmol) in anhydrous t-BuOH (15 mL) was added TEA (303 mg, 3.0 mmol) and DPPA (467 mg, 1.7 mmol) under a N atmosphere. The mixture was stirred at 70 °C for 24 h. Water (10 mL) was added to the mixture, and it was extracted with EA (10 mL × 3). The combined organic layers were dried over Na SO and concentrated. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to give the final compound (280 mg, 67%) as a white solid. 1 H-NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 6.75 (d, J = 3.9 Hz, 1H), 6.23 (d, J = 3.9 Hz, 1H), 2.17 (s, 9H). LC-MS: m / z 299.7 [M+Na] + .

[0224] Step b. tert-Butyl (5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)carbamate: To a solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (500 mg, 1.7 mmol) in 1,4-dioxane (20 mL) was added (Bpin) (660 mg, 1.5 mmol), KOAc (500 mg, 5.1 mmol), Pd(dppf)Cl (124 mg, 0.17 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. To the above mixture, water (2 mL), K2CO3 (469 mg, 3.4 mmol), Pd(dppf)Cl2 (124 mg, 0.17 mmol), and tert-butyl (5-bromothiophen-2-yl)carbamate (692 mg, 2.5 mmol) were added. The mixture was stirred at 100 °C for 12 hours. The solvent was removed, and the residue was purified by silica gel chromatography column (DCM / MeOH = 30 / 1) to give the desired product (450 mg, 65%) as a black solid. 1H-NMR (300 MHz, CDCl3): δ 7.51 (s, 1H), 7.06 (d, J = 3.0 Hz, 1H), 6.69 (s, 1H), 6.47 (d, J = 3.9 Hz, 1H), 4.14 (s, 3H), 1.23 (s, 9H), 1.06-0.93 (m, 10H). LC-MS: m / z 407.8 [M+H] + .

[0225] Step c. (3-(5-aminothiophen-2-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of tert-butyl (5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)carbamate (100 mg, 0.24 mmol) in DCE (5 mL) was added TFA (136 mg, 1.2 mmol). The mixture was stirred at room temperature for 4 hours. The solvent was concentrated in vacuo and diluted with saturated aqueous NaHCO (10 mL). The mixture was extracted with DCM (10 mL × 3), and the combined organic layers were dried over NaSO. The organic layer was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the desired product (30 mg, 41%) as a brown oil. 1 H-NMR (300 MHz, CDCl3): δ 7.52 (s, 1H), 6.92-6.87 (m, 1H), 6.15-6.11 (m, 1H), 4.14 (s, 3H), 3.87 (s, 2H), 1.12-0.85 (m, 10H). LC-MS: m / z 307.8 [M+H] + .

[0226] Step d. 6-chloro-4-((5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (126 mg, 0.66 mmol) and (3-(5-aminothiophen-2-yl)-1-methyl-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (136 mg, 0.44 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (1.3 mL, 1.3 mmol) under N atmosphere. The mixture was stirred at room temperature for 3 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (95 mg, 47%) as a yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 10.48 (s, 1H), 8.07 (s, 1H), 7.22-7.17 (m, 1H), 7.10 (s, 1H), 6.86-6.83 (m, 1H), 6.78 (s, 1H), 5.73 (s, 1H), 4.19 (s, 3H), 1.33-1.23 (m, 2H), 1.12-0.96 (m, 8H). LC-MS: m / z 462.7 [M+H] + .

[0227] Step e. 6-(cyclopropanecarboxamide)-4-((5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)amino)pyridazine-3-carboxamide (A25): To a solution of 6-chloro-4-((5-(5-(dicyclopropylphosphoryl)-1-methyl-1H-pyrazol-3-yl)thiophen-2-yl)amino)pyridazine-3-carboxamide (50 mg, 0.10 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (27 mg, 0.30 mmol), Pd(dba) (9 mg, 0.010 mmol), Xantphos (5 mg, 0.010 mmol l), and KPO (42 mg, 0.20 mmol). The mixture was stirred in a microwave oven at 120° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (15 mg, 29%) as a yellow solid.

[0228] Example 13, Method AO

[0229] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(4-(dicyclopropylphosphoryl)-1H-pyrazol-1-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A44) [ka]

[0230] Step a. Dicyclopropyl(1H-pyrazol-4-yl)phosphine oxide: To a solution of 4-bromo-1H-pyrazole (1.5 g, 10 mmol) in 1,4-dioxane (5 mL), KPO (3.2 g, 15 mmol), dicyclopropylphosphine oxide (2.7 g, 20 mmol), Pd(OAc) (229 mg, 1.0 mmol), and Xantphos (590 mg, 1.0 mmol) were added. The mixture was stirred at 110 °C under a N atmosphere for 0.5 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (465 mg, 24%) as a pale yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 7.82 (s, 2H), 1.01-0.85 (m, 10H). LC-MS: m / z 197.0 [M+H] + .

[0231] Step b. Dicyclopropyl(1-(2-hydroxy-3-nitrophenyl)-1H-pyrazol-4-yl)phosphine oxide: To a solution of dicyclopropyl(1H-pyrazol-4-yl)phosphine oxide (515 mg, 2.6 mmol), 2-bromo-6-nitrophenol (382 mg, 1.8 mmol) in DMF (5 mL) was added CuO (250 mg, 1.8 mmol) and CsCO (1.1 g, 3.5 mmol). The mixture was stirred in a microwave reactor at 135 °C for 2 h. The mixture was filtered and concentrated in vacuo. The residue was used in the next step without further purification. LC-MS: m / z 333.8 [M+H] + .

[0232] Step c. Dicyclopropyl(1-(2-methoxy-3-nitrophenyl)-1H-pyrazol-4-yl)phosphine oxide: To a solution of dicyclopropyl(1-(2-hydroxy-3-nitrophenyl)-1H-pyrazol-4-yl)phosphine oxide in DMF (10 mL) was added K2CO3 (363 mg, 2.6 mmol) and iodomethane (373 mg, 2.6 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound as a yellow oil (655 mg, 72%). 1 H-NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.01 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 3.67 (s, 3H), 1.08-0.87 (m, 10H). LC-MS: m / z 347.8 [M+H] + .

[0233] Step d. (1-(3-amino-2-methoxyphenyl)-1H-pyrazol-4-yl)dicyclopropylphosphine oxide: To a solution of dicyclopropyl(1-(2-methoxy-3-nitrophenyl)-1H-pyrazol-4-yl)phosphine oxide (650 mg, 1.9 mmol) in a mixed solvent of EtOH and water (30 mL / 10 mL), zinc powder (487 mg, 7.5 mmol) and NHCl (202 mg, 3.7 mmol) were added. The mixture was stirred at 50 °C for 2 h and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the desired product (400 mg, 67%) as a red oil. 1H-NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 7.94 (s, 1H), 7.03-6.94 (m, 2H), 6.76 (t, J = 4.2 Hz, 1H), 4.01 (s, 2H), 3.47 (s, 3H), 1.05-0.82 (m, 10H). LC-MS: m / z 317.9 [M+H] + .

[0234] Step e. 6-chloro-4-((3-(4-(dicyclopropylphosphoryl)-1H-pyrazol-1-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of (1-(3-amino-2-methoxyphenyl)-1H-pyrazol-4-yl)dicyclopropylphosphine oxide (300 mg, 0.95 mmol) and 4,6-dichloropyridazine-3-carboxamide (218 mg, 1.1 mmol) in EtOH (3 mL) was added a catalytic amount of conc. HCl (1 drop). The mixture was stirred in a microwave reactor at 120° C. for 2.5 hours. The solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the desired product (180 mg, 40%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 11.22 (s, 1H), 8.78 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.54 (d, LC-MS: m / z 472.7 [M+H] + .

[0235] Step f. 6-(cyclopropanecarboxamide)-4-((3-(4-(dicyclopropylphosphoryl)-1H-pyrazol-1-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A44): To a solution of 6-chloro-4-((3-(4-(dicyclopropylphosphoryl)-1H-pyrazol-1-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (120 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (65 mg, 0.76 mmol), Pd(dba) (23 mg, 0.030 mmol), Xantphos (15 mg, 0.030 mmol), and KPO (108 mg, 0.51 mmol). The mixture was stirred in a microwave oven at 110° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the crude product, which was rinsed with EtO to give the desired product (25 mg, 19%) as a yellow solid.

[0236] Example 14, Methods AB, AC, AH, AI, AN

[0237] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-5-(dimethylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A45) [ka]

[0238] Step a. 3,5-Dibromo-1-cyclopropyl-1H-pyrazole: To a solution of 3,5-dibromo-1H-pyrazole (1.7 g, 7.6 mmol) in DCE (30 mL) was added cyclopropylboronic acid (1.3 g, 15.1 mmol), bipyridine (1.2 g, 7.6 mmol), Cu(OAc) and NaCO. The mixture was stirred at 75 °C in open air overnight. The mixture was diluted with saturated aqueous NHCl (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL) and dried over NaSO. The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel chromatography (PE / EA = 20 / 1) to give the desired product (756 mg, 38%) as a yellow solid. 1 H-NMR (300 MHz, CDCl3): δ 6.29 (s, 1H), 3.50-3.36 (m, 1H), 1.27-1.17 (m, 2H), 1.12-1.03 (m, 2H). LC-MS: m / z 264.8 [M+H] +

[0239] Step b. (3-Bromo-1-cyclopropyl-1H-pyrazol-5-yl)dimethylphosphine oxide: To a solution of 3,5-dibromo-1-cyclopropyl-1H-pyrazole (756 mg, 2.8 mmol) in 1,4-dioxane (5 mL), KPO (720 mg, 3.4 mmol), dimethylphosphine oxide (334 mg, 4.3 mmol), Pd(OAc) (51 mg, 0.23 mmol), and Xantphos (133 mg, 0.23 mmol) were added. The mixture was stirred at 130 °C under a N atmosphere for 1 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 75 / 1) to give the final compound (175 mg, 23%) as a pale yellow solid. 1H-NMR (300 MHz, CDCl3): δ 6.43 (s, 1H), 4.31-4.13 (m, 1H), 1.86 (d, J = 13.5 Hz, 6H), 1.43-1.34 (m, 2H), 1.15-1.01 (m, 2H). LC-MS: m / z 263.0 [M+H] + .

[0240] Step c. (3-(3-Amino-2-methoxyphenyl)-1-cyclopropyl-1H-pyrazol-5-yl)dimethylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (249 mg, 1.0 mmol) and (3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)dimethylphosphine oxide (176 mg, 0.67 mmol) in 1,4-dioxane / water (10 mL / 1 mL) was added Pd(dppf)Cl (49 mg, 0.070 mmol) and KCO (185 mg, 1.3 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. The solvent was removed and the residue was purified by silica gel chromatography column (DCM / MeOH=100 / 3) to give the compound (140 mg, 68%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 7.18 (d, J = 7.8 Hz, 1H), 6.99-6.90 (m, 2H), 6.72 (d, J = 7.5 Hz, 1H), 4.36-4.18 (m, 1H), 3.87 (s, 2H), 3.63 (s, 3H), 1.89 (d, J = 13.5 Hz, 6H), 1.53-1.43 (m, 2H), 1.15-1.03 (m, 2H). LC-MS: m / z 306.1 [M+H] +

[0241] Step d. 6-chloro-4-((3-(1-cyclopropyl-5-(dimethylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (255 mg, 1.3 mmol) and (3-(3-amino-2-methoxyphenyl)-1-cyclopropyl-1H-pyrazol-5-yl)dimethylphosphine oxide (270 mg, 0.90 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (3.6 mL, 3.6 mmol) under N atmosphere. The mixture was stirred at room temperature for 8 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (280 mg, 68%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 11.13 (s, 1H), 8.76 (s, 1H), 8.11 (s, 1H), 7.73-7.67 (m, 1H), 7.53-7.49 (m, 1H), 7.29-7.23 (m, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 4.34-4.26 (m, 1H), 3.62 (s, 3H), 1.86 (d, J = 13.8 Hz, 6H), 1.32-1.28 (m, 2H), 1.10-1.06 (m, 2H).LC-MS: m / z 460.7 [M+H] + .

[0242] Step e. 6-(cyclopropanecarboxamide)-4-((3-(1-cyclopropyl-5-(dimethylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A45): To a solution of 6-chloro-4-((3-(1-cyclopropyl-5-(dimethylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (120 mg, 0.26 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (68 mg, 0.80 mmol), Pd(dba) (28 mg, 0.030 mmol), Xantphos (32 mg, 0.056 mmol), and KPO (112 mg, 0.52 mmol). The mixture was stirred in a microwave oven at 120° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=12 / 1) to give the crude product, which was rinsed with EtO to give the desired product (31 mg, 24%) as a white solid.

[0243] A similar procedure as described in Example 14 was carried out to give compounds A46, A52, A53 and A54.

[0244] Example 15, Methods AB, AP

[0245] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dicyclopropylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A48) [ka]

[0246] Step a. 3,5-Dibromo-1-(methoxymethyl)-1H-pyrazole: To a solution of 3,5-dibromo-1H-pyrazole (500 mg, 2.2 mmol) in anhydrous THF (15 mL), 60% NaH (195 mg, 4.9 mmol) was added, and the mixture was stirred at 0 °C for 1 h. After adding MOMCl (267 mg, 3.3 mmol), the mixture was stirred at 0 °C for 2 h, followed by stirring at room temperature overnight. The reaction was quenched with ice water (20 mL), and the mixture was extracted with EA (20 mL × 3). The combined organic layers were dried over Na SO and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give the final compound (550 mg, 93%) as a colorless oil. 1 H-NMR (300 MHz, CDCl3): δ 6.37 (s, 1H), 5.39 (s, 2H), 3.37 (s, 3H). LC-MS: m / z 268.7 [M+H] + .

[0247] Step b. (3-Bromo-1-(methoxymethyl)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 3,5-dibromo-1-(methoxymethyl)-1H-pyrazole (550 mg, 2.0 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (424 mg, 3.1 mmol), dicyclopropylphosphine oxide (400 mg, 3.1 mmol), Pd(OAc)2 (44.8 mg, 0.20 mmol), and Xantphos (116 mg, 0.20 mmol). The mixture was stirred at 110 °C under a N2 atmosphere for 5 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the crude product as a black solid. LC-MS: m / z 318.8 [M+H] + .

[0248] Step c. (3-(3-amino-2-methoxyphenyl)-1-(methoxymethyl)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.4 mmol) and (3-bromo-1-(methoxymethyl)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (300 mg, 0.94 mmol) in 1,4-dioxane / water (10 mL / 1 mL) was added Pd(dppf)Cl (66 mg, 0.090 mmol) and KCO (248 mg, 1.8 mmol). The mixture was stirred at 100 °C under a N atmosphere for 6 h. The solvent was removed and the residue was purified by silica gel chromatography column (DCM / MeOH=50 / 1) to give the crude product as a black oil. LC-MS: m / z 361.9 [M+H] +

[0249] Step d. 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of (3-(3-amino-2-methoxyphenyl)-1-(methoxymethyl)-1H-pyrazol-5-yl)dicyclopropylphosphine oxide (140 mg, 0.39 mmol) and 4,6-dichloropyridazine-3-carboxamide (89.4 mg, 0.46 mmol) in EtOH (8 mL) was added a catalytic amount of conc. HCl (1 drop). The mixture was stirred in a microwave reactor at 120° C. for 1 h. The solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the desired product (68 mg, 37%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 13.80 (s, 1H), 11.17 (s, 1H), 8.77 (s, 1H), 8.12 (s, 1H), 7.68-7.47 (m, 2H), 7.41-7.25 (m, 1H), 7.28-7.20 (m, 1H), 7.18-7.05 (m, 1H), 3.60 (s, 3H), 1.03-0.64 (m, 10H). LC-MS: m / z 472.7 [M+H] + .

[0250] Step e. 6-(cyclopropanecarboxamide)-4-((3-(5-(dicyclopropylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (A48): To a solution of 6-chloro-4-((3-(5-(dicyclopropylphosphoryl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (60 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (33 mg, 0.38 mmol), Pd(dba) (12 mg, 0.013 mmol), Xantphos (8.0 mg, 0.013 mmol), and KPO (55 mg, 0.26 mmol). The mixture was stirred in a microwave oven at 120° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give the crude product, which was rinsed with EtO to give the desired product (10 mg, 15%) as a yellow solid.

[0251] Example 16, Methods AA, AB, AC, AI, AN

[0252] Preparation of 4-((3-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A51) [ka]

[0253] Step a. 3-Bromo-5-fluoro-2-methoxyaniline: To a solution of 1-bromo-5-fluoro-2-methoxy-3-nitrobenzene (650 mg, 1.9 mmol) in a mixed solvent of EtOH and saturated aqueous NH4Cl (25 mL / 5 mL), iron powder (3.6 g, 66 mmol) was added. The mixture was stirred at 70 °C for 2 hours and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (PE / EA = 4 / 1) to give the desired product (1.3 g, 92%) as a brown oil. 1 H-NMR (300 MHz, CDCl3): δ 6.62 (dd, J = 8.4, 2.7 Hz, 1H), 7.40 (dd, J = 8.7, 3.9 Hz, 1H), 3.98 (s, 2H), 3.79 (s, 3H). LC-MS: m / z 220.0 [M+H] + .

[0254] Step b. 5-Fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: To a solution of 3-bromo-5-fluoro-2-methoxyaniline (704 mg, 3.2 mmol) in 1,4-dioxane (60 mL) was added (Bpin) (1.6 g, 6.4 mmol), KOAc (940 mg, 9.6 mmol), and Pd(dppf)Cl (243 mg, 0.33 mmol). The mixture was stirred at 105 °C under a N atmosphere overnight. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 4 / 1) to give the final compound (560 mg, 50%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 6.95-6.87 (m, 2H), 6.47-6.38 (m, 1H), 4.26 (s, 3H), 3.99 (s, 2H), 3.60 (s, 3H), 1.85 (d, J = 13.5 Hz, 6H).

[0255] Step c. (3-(3-amino-5-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide: To a solution of 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (243 mg, 0.42 mmol) and (3-bromo-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (150 mg, 0.63 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) was added Pd(dppf)Cl (43 mg, 0.063 mmol) and KCO (174 mg, 1.3 mmol). The mixture was stirred at 110 °C under a N atmosphere overnight. The solvent was removed and the residue was purified by silica gel chromatography column (DCM / MeOH=30 / 1) to give the final compound (150 mg, 50%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 6.95-6.87 (m, 2H), 6.46-6.39 (m, 1H), 4.27 (s, 3H), 3.98 (s, 2H), 3.60 (s, 3H), 1.80 (d, J = 13.6 Hz, 6H). LC-MS: m / z 298.1 [M+H] + .

[0256] Step d. 6-chloro-4-((3-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (423 mg, 2.3 mmol) and (3-(3-amino-5-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (450 mg, 1.5 mmol) in anhydrous tetrahydrofuran (6 mL) was added 1N LiHMDS (4.7 mL, 4.7 mmol) under N atmosphere. The mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl (5 mL) was added, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (190 mg, 25%) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d6): δ 11.31 (s, 1H), 8.81 (s, 1H), 8.15 (s, 1H), 7.49 (d, J = 11.4 Hz, 1H), 7.46-7.34 (m, 2H), 7.12 (s, 1H), 4.17 (s, 3H), 3.62 (s, 3H), 1.82 (d, J = 13.8 Hz, 6H). LC-MS: m / z 452.7 [M+H] + .

[0257] Step e. 4-((3-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A51): To a solution of 6-chloro-4-((3-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carboxamide (170 mg, 0.34 mmol) in 1,4-dioxane (2 mL) was added 4-methylpyridin-2-amine (122 mg, 1.1 mmol), Pd(dba) (34 mg, 0.037 mmol), dppf (42 mg, 0.074 mmol), and KPO (166 mg, 0.78 mmol). The mixture was stirred in a microwave oven at 110° C. under a N atmosphere for 2.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=12 / 1) to give the crude product, which was rinsed with EtO to give the desired product (83 mg, 46%) as a yellow solid.

[0258] A similar procedure as described in Example 16 was carried out to give compound A56.

[0259] Example 17, Methods AA, AE, AG, AI, AN

[0260] Preparation of 4-((4-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A55) [ka]

[0261] Step a. (3-(2-Amino-3-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide: To a solution of 4-bromo-3-methoxypyridin-2-amine (185 mg, 0.92 mmol) in 1,4-dioxane (20 mL) was added (Bpin) (460 mg, 1.8 mmol), KOAc (230 mg, 2.3 mmol), and Pd(dppf)Cl (66 mg, 0.090 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. To the above mixture, water (1 mL), K2CO3 (230 mg, 1.7 mmol), Pd(dppf)Cl2 (48 mg, 0.070 mmol), and (3-bromo-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (156 mg, 0.66 mmol) were added. The mixture was stirred at 100 °C for 6 hours. The solvent was removed, and the residue was purified by silica gel chromatography column (DCM / MeOH = 50 / 1) to give the desired product (60 mg, 32%) as a yellow solid. LC-MS: m / z 281.1 [M+H] + .

[0262] Step b. 6-chloro-4-((4-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (357 mg, 1.9 mmol) and (3-(2-amino-3-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (350 mg, 1.2 mmol) in anhydrous tetrahydrofuran (8 mL) was added NaH (250 mg, 6.2 mmol) under N atmosphere. The mixture was stirred at room temperature for 24 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (60 mg, 11%) as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 12.26 (s, 1H), 9.39 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.11 (s, 1H), 5.77 (s, 1H), 4.32 (s, 3H), 3.81 (s, 3H), 1.88 (d, J = 13.5 Hz, 6H). LC-MS: m / z 435.7 [M+H] +

[0263] Step c. 4-((4-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A55): To a solution of 6-chloro-4-((4-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-3-methoxypyridin-2-yl)amino)pyridazine-3-carboxamide (50 mg, 0.11 mmol) in 1,4-dioxane (2 mL) was added 4-methylpyridin-2-amine (36 mg, 0.33 mmol), Pd(dba) (10 mg, 0.011 mmol), dppf (12 mg, 0.022 mmol), and KPO (70 mg, 0.33 mmol). The mixture was stirred in a microwave oven at 110° C. under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=15 / 1) to give the crude product, which was rinsed with EtO to give the desired product (27 mg, 49%) as a white solid.

[0264] A similar procedure as described in Example 17 was carried out to give compound A60.

[0265] Example 18, Methods AA, AF, AI, AN

[0266] Preparation of 4-((5-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-4-methoxypyridin-3-yl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A57) [ka]

[0267] Step a. (3-(5-Amino-4-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide: To a solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (1.0 g, 4.2 mmol) in 1,4-dioxane (20 mL) was added (Bpin) (1.6 g, 6.3 mmol), KOAc (1.2 g, 13 mmol), and Pd(dppf)Cl (307 mg, 0.42 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. Water (2 mL), K2CO3 (1.8 g, 13 mmol), Pd(dppf)Cl2 (154 mg, 0.21 mmol), and 5-bromo-4-methoxypyridin-3-amine (685 mg, 3.4 mmol) were added to the solution. The mixture was stirred at 100 °C for 8 hours. The solvent was removed, and the residue was purified by silica gel chromatography (DCM / MeOH = 12 / 1) to give the desired product (1.1 g, 92%) as a black oil. 1 H-NMR (300 MHz, CDCl3): δ 8.37 (s, 1H), 8.10 (s, 1H), 6.84 (s, 1H), 4.29 (s, 3H), 3.69 (s, 3H), 1.87 (d, J = 13.8 Hz, 6H). LC-MS: m / z 280.9 [M+H] + .

[0268] Step b. 6-chloro-4-((5-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-4-methoxypyridin-3-yl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (165 mg, 0.43 mmol) and (3-(5-amino-4-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-yl)dimethylphosphine oxide (200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (8 mL) was added 1N LiHMDS (2.1 mL, 2.1 mmol) under N atmosphere. The mixture was stirred at room temperature for 24 hours. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=20 / 1) to give the final compound (140 mg, 89%) as a yellow oil. 1 H-NMR (300 MHz, DMSO-d6): δ 10.91 (s, 1H), 8.86 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 7.08 (s, 1H), 7.06 (s, 1H), 4.18 (s, 3H), 3.75 (s, 3H), 1.83 (d, J = 13.8 Hz, 6H). LC-MS: m / z 435.7 [M+H] + .

[0269] Step c. 4-((5-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-4-methoxypyridin-3-yl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (A57): To a solution of 6-chloro-4-((5-(5-(dimethylphosphoryl)-1-methyl-1H-pyrazol-3-yl)-4-methoxypyridin-3-yl)amino)pyridazine-3-carboxamide (135 mg, 0.31 mmol) in 1,4-dioxane (2 mL) was added 4-methylpyridin-2-amine (101 mg, 0.93 mmol), Pd(dba) (29 mg, 0.030 mmol), dppf (34 mg, 0.060 mmol), and KPO (198 mg, 0.93 mmol). The mixture was stirred in a microwave oven at 115° C. under a N atmosphere for 2.5 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with EtO to give the desired product (60 mg, 38%) as a gray solid.

[0270] A similar procedure as described in Example 18 was carried out to give compound A58.

[0271] Example 19, Methods AB, AC, AJ, AN

[0272] Preparation of 6-(cyclopropanecarboxamido)-4-((4'-(dimethylphosphoryl)-2-methoxy-[1,1'-biphenyl]-3-yl)amino)nicotinamide (A61) [ka]

[0273] Step a. (4-Bromophenyl)dimethylphosphine oxide: To a solution of 1,4-dibromobenzene (585 mg, 2.5 mmol) in 1,4-dioxane (10 mL), K2CO3 (518 mg, 3.8 mmol), dimethylphosphine oxide (234 mg, 3.0 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), and Xantphos (115 mg, 0.20 mmol) were added. The mixture was stirred at 125 °C under a N2 atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (120 mg, 21%) as a yellow oil. LC-MS: m / z 233.0 [M+H] + .

[0274] Step b. (3'-Amino-2'-methoxy-[1,1'-biphenyl]-4-yl)dimethylphosphine oxide: To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (107 mg, 0.43 mmol) and (4-bromophenyl)dimethylphosphine oxide (90 mg, 0.39 mmol) in 1,4-dioxane / water (10 mL / 1 mL) was added Pd(dppf)Cl (28 mg, 0.039 mmol) and KCO (107 mg, 0.78 mmol). The mixture was stirred at 100 °C under a N atmosphere overnight. The solvent was removed, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the compound (65 mg, 61%) as a brown solid. 1 H-NMR (300 MHz, CDCl3): δ 7.88-7.62 (m, 4H), 7.07-6.92 (m, 1H), 6.85-6.66 (m, 2H), 3.95 (br, s, 2H), 3.40 (s, 3H), 1.87 (d, J = 13.8 Hz, 6H).LC-MS: m / z 276.1 [M+H] + .

[0275] Step c. 6-Chloro-4-((4'-(dimethylphosphoryl)-2-methoxy-[1,1'-biphenyl]-3-yl)amino)nicotinamide: To a solution of 4,6-dichloronicotinamide (104 mg, 0.54 mmol) and (3'-amino-2'-methoxy-[1,1'-biphenyl]-4-yl)dimethylphosphine oxide (100 mg, 0.36 mmol) in anhydrous tetrahydrofuran (3 mL), 1 N LiHMDS (1.4 mL, 1.4 mmol) was added under N atmosphere. The mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl (5 mL) was added, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to give the final compound (94 mg, 61%) as a yellow oil.

[0276] Step d. 6-(cyclopropanecarboxamide)-4-((4'-(dimethylphosphoryl)-2-methoxy-[1,1'-biphenyl]-3-yl)amino)nicotinamide (A61): To a solution of 6-chloro-4-((4'-(dimethylphosphoryl)-2-methoxy-[1,1'-biphenyl]-3-yl)amino)nicotinamide (94 mg, 0.22 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (56 mg, 0.66 mmol), Pd(dba) (21 mg, 0.020 mmol), Xantphos (13 mg, 0.020 mmol), and KPO (92 mg, 0.43 mmol). The mixture was stirred in a microwave at 135 °C under a N atmosphere for 1.5 h. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=15 / 1) to give the crude product, which was rinsed with Et 2 O to give the desired product (17 mg, 18%) as a yellow solid.

[0277] A similar procedure as described in Example 19 was carried out to give compound A62.

[0278] Example 20, Methods AB, AK, AN

[0279] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(5-(dimethylphosphoryl)pyrazin-2-yl)-2-methoxyphenyl)amino)nicotinamide (A63) [ka]

[0280] Step a. 3-(5-Bromopyrazin-2-yl)-2-methoxyaniline: To a solution of 2,5-dibromopyrazine (1.0 g, 4.2 mmol) and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1 g, 4.2 mmol) in 1,4-dioxane / water (100 mL / 5 mL) was added Pd(dppf)Cl (0.31 g, 0.42 mmol) and KCO (1.2 g, 8.4 mmol). The mixture was stirred at 90 °C under a N atmosphere overnight. The solvent was removed, and the residue was purified by silica gel chromatography (PE / EA = 2 / 1) to give the compound (470 mg, 40%) as a yellow oil. 1 H-NMR (300 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.84 (s, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H), 5.14 (s, 2H), 3.45 (s, 3H). LC-MS: m / z 280.0 [M+H] + .

[0281] Step b. (5-(3-Amino-2-methoxyphenyl)pyrazin-2-yl)dimethylphosphine oxide: To a solution of 3-(5-bromopyrazin-2-yl)-2-methoxyaniline (200 mg, 0.71 mmol) in 1,4-dioxane (10 mL) was added KCO (160 mg, 1.1 mmol), dimethylphosphine oxide (84 mg, 1.1 mmol), Pd(OAc) (20 mg, 0.072 mmol), and Xantphos (42 mg, 0.072 mmol). The mixture was stirred at 125 °C under a N atmosphere for 1 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (194 mg, 97%) as a cyan solid. 1 H-NMR (300 MHz, DMSO-d6): δ 9.17 (s, 1H), 9.12 (s, 1H), 7.04-6.96 (m, 1H), 6.92 (d, J = 6.9 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 5.18 (s, 2H), 3.57 (s, 3H), 1.77 (d, J = 13.8 Hz, 6H). LC-MS: m / z 278.1 [M+H] + .

[0282] Step c. 6-Chloro-4-((3-(5-(dimethylphosphoryl)pyrazin-2-yl)-2-methoxyphenyl)amino)nicotinamide: To a solution of 4,6-dichloronicotinamide (176 mg, 0.92 mmol) and (5-(3-amino-2-methoxyphenyl)pyrazin-2-yl)dimethylphosphine oxide (170 mg, 0.61 mmol) in anhydrous tetrahydrofuran (7 mL), 1 N LiHMDS (2.4 mL, 2.4 mmol) was added under N atmosphere. The mixture was stirred at room temperature for 2 h. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to give the final compound (50 mg, 19%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H), 8.42-8.33 (m, 1H), 7.85-7.78 (m, 1H), 7.64-7.60 (m, 2H), 7.39 (t, J = 8.4 Hz, 1H), 6.94 (s, 1H), 3.54 (s, 3H), 1.79 (d, J = 13.8 Hz, 6H). LC-MS: m / z 431.7 [M+H] + .

[0283] Step d. 6-(cyclopropanecarboxamide)-4-((3-(5-(dimethylphosphoryl)pyrazin-2-yl)-2-methoxyphenyl)amino)nicotinamide (A63): To a solution of 6-chloro-4-((3-(5-(dimethylphosphoryl)pyrazin-2-yl)-2-methoxyphenyl)amino)nicotinamide (48 mg, 0.11 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (28 mg, 0.33 mmol), Pd(dba) (6.0 mg, 0.010 mmol), Xantphos (10 mg, 0.010 mmol), and KPO (47 mg, 0.22 mmol). The mixture was stirred in a microwave at 120 °C under a N atmosphere for 2 h. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with Et2O to give the desired product (10 mg, 19%) as a yellow solid.

[0284] A similar procedure as described in Example 20 was carried out to give compound A64.

[0285] Example 21, Methods AQ, AN

[0286] Preparation of 4-((4-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (B1) [ka]

[0287] Step a. (4-Amino-3-methoxyphenyl)dicyclopropylphosphine oxide: To a solution of 4-bromo-2-methoxyaniline (3.3 g, 16 mmol) in 1,4-dioxane (10 mL) was added KCO (3.4 g, 25 mmol), dicyclopropylphosphine oxide (4.3 g, 33 mmol), Pd(OAc) (370 mg, 1.7 mmol), and Xantphos (953 mg, 1.7 mmol). The mixture was stirred at 120 °C under a N atmosphere for 2 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 100 / 3) to give the final compound (2.2 g, 54%) as a brown solid. 1 H-NMR (300 MHz, CDCl3): δ 7.22 (d, J = 11.4 Hz, 1H), 7.16 (d, J = 10.5 Hz, 1H), 6.74 (s, 1H), 4.10 (s, 2H), 3.90 (s, 3H), 1.04-0.72 (m, 10H). LC-MS: m / z 251.9 [M+H] + .

[0288] Step b. 6-Chloro-4-((4-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (1.4 g, 7.2 mmol) and (4-amino-3-methoxyphenyl)dicyclopropylphosphine oxide (1.5 g, 6.0 mmol) in EtOH (40 mL) was added a catalytic amount of conc. HCl (1 drop). The mixture was stirred in a microwave reactor at 120° C. for 2.5 hours. The solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the desired product (770 mg, 32%) as a white solid. 1H-NMR (300 MHz, CDCl3): δ 10.75 (s, 1H), 8.07 (s, 1H), 7.54-7.37 (m, 3H), 7.10 (s, 1H), 5.70 (s, 1H), 3.95 (s, 3H), 1.12-0.81 (m, 10H). LC-MS: m / z 406.8 [M+H] + .

[0289] Step c. 4-((4-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)-6-((4-methylpyridin-2-yl)amino)pyridazine-3-carboxamide (B1): To a solution of 6-chloro-4-((4-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (70 mg, 0.14 mmol) in 1,4-dioxane (2 mL) was added 4-methylpyridin-2-amine (49 mg, 0.0.42 mmol), Pd(dba) (15 mg, 0.014 mmol), Xantphos (9 mg, 0.014 mmol), and CsCO (91 mg, 0.28 mmol). The mixture was stirred in a microwave at 130 °C under a N atmosphere for 1.5 h. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=10 / 1) to give the crude product, which was rinsed with Et2O to give the desired product (10 mg, 24%) as a yellow solid.

[0290] A similar procedure as described in Example 21 was carried out to give compounds B2, B4, B5, B6, B7 and B8.

[0291] Example 22, Method AQ, AN

[0292] Preparation of 6-(cyclopropanecarboxamido)-4-((4-(diethylphosphoryl)-2-methoxyphenyl)amino)nicotinamide (B3) [ka]

[0293] Step a. (4-Amino-3-methoxyphenyl)diethylphosphine oxide: To a solution of 4-bromo-2-methoxyaniline (700 mg, 3.5 mmol) in 1,4-dioxane (20 mL) was added KCO (731 mg, 5.3 mmol), diethylphosphine oxide (742 mg, 7.0 mmol), Pd(OAc) (79 mg, 0.35 mmol), and Xantphos (203 mg, 0.35 mmol). The mixture was stirred at 115 °C under a N atmosphere for 12 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1) to give the final compound (400 mg, 51%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 7.19 (d, J = 11.1 Hz, 1H), 6.99-6.88 (m, 1H), 6.78-6.69 (m, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 2.00-1.81 (m, 4H), 1.24-1.02 (m, 6H). LC-MS: m / z 227.9 [M+H] + .

[0294] Step b. 6-Chloro-4-((4-(diethylphosphoryl)-2-methoxyphenyl)amino)nicotinamide: To a solution of 4,6-dichloronicotinamide (189 mg, 0.99 mmol) and (4-amino-3-methoxyphenyl)diethylphosphine oxide (150 mg, 0.66 mmol) in anhydrous tetrahydrofuran (7 mL), 1 N LiHMDS (2.7 mL, 2.7 mmol) was added under N atmosphere. The mixture was stirred at room temperature for 2 h. Saturated aqueous NH4Cl (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH = 20 / 1) to give the final compound (150 mg, 60%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.79 (s, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H), 7.62-7.54 (m, 1H), 7.40-7.29 (m, 2H), 7.03 (s, 1H), 3.89 (s, 3H), 2.02-1.83 (m, 4H), 1.05-0.85 (m, 6H). LC-MS: m / z 381.8 [M+H] + .

[0295] Step c. 6-(Cyclopropanecarboxamide)-4-((4-(diethylphosphoryl)-2-methoxyphenyl)amino)nicotinamide (B3): To a solution of 6-chloro-4-((4-(diethylphosphoryl)-2-methoxyphenyl)amino)nicotinamide (100 mg, 0.26 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (67 mg, 0.79 mmol), Pd(dba) (24 mg, 0.026 mmol), Xantphos (15 mg, 0.026 mmol), and CsCO (170 mg, 0.52 mmol). The mixture was stirred in a microwave at 130 °C under a N atmosphere for 3 h. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=30 / 1) to give the crude product, which was rinsed with Et2O to give the desired product (14 mg, 12%) as a yellow solid.

[0296] A similar procedure as described in Example 22 was carried out to give compound B9.

[0297] Example 23, Method AR

[0298] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (B10) [ka]

[0299] Step a. Dicyclopropyl(2-fluoro-3-nitrophenyl)phosphine oxide: To a solution of 1-bromo-2-fluoro-3-nitrobenzene (1.8 g, 8.2 mmol) in 1,4-dioxane (20 mL) was added KPO (2.6 g, 12 mmol), dicyclopropylphosphine oxide (2.1 g, 16 mmol), Pd(OAc) (184 mg, 0.80 mmol), and Xantphos (475 mg, 0.80 mmol). The mixture was stirred in a microwave reactor at 120 °C under a N atmosphere for 0.5 h. The solvent was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the final compound (600 mg, 27%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 8.28-8.04 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H), 1.30-0.70 (m, 10H). LC-MS: m / z 269.9 [M+H] + .

[0300] Step b. Dicyclopropyl(2-methoxy-3-nitrophenyl)phosphine oxide: To a solution of dicyclopropyl(2-fluoro-3-nitrophenyl)phosphine oxide (600 mg, 2.2 mmol) in MeOH (10 mL) was added NaOCH3 (181 mg, 3.3 mmol). The mixture was stirred at room temperature for 4 hours. The solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH = 30 / 1) to give the final compound (370 mg, 59%) as a yellow oil. 1 H-NMR (300 MHz, CDCl3): δ 8.09-8.07 (m, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 3.96 (s, 3H), 1.30-0.70 (m, 10H). LC-MS: m / z 281.9 [M+H] + .

[0301] Step c. (3-Amino-2-methoxyphenyl)dicyclopropylphosphine oxide: To a solution of dicyclopropyl(2-methoxy-3-nitrophenyl)phosphine oxide (300 mg, 1.1 mmol) in a mixed solvent of EtOH and water (15 mL / 5 mL), iron powder (240 mg, 4.4 mmol) and NHCl (115 mg, 2.2 mmol) were added. The mixture was stirred at 80 °C for 3 h and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give the desired product (160 mg, 60%) as a brown oil. 1 H-NMR (300 MHz, CDCl3): δ 7.19 (d, J = 12.0 Hz, 1H), 7.02 (t, J = 6.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 2H), 1.26-0.74 (m, 10H). LC-MS: m / z 251.9 [M+H] + .

[0302] Step d. 6-Chloro-4-((3-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide: To a solution of 4,6-dichloropyridazine-3-carboxamide (147 mg, 0.80 mmol) and (3-amino-2-methoxyphenyl)dicyclopropylphosphine oxide (160 mg, 0.60 mmol) in EtOH (2 mL) was added a catalytic amount of conc. HCl (1 drop). The mixture was stirred in a microwave reactor at 120 °C for 2.5 h. The solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the desired product (120 mg, 46%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.78 (s, 1H), 8.13 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 10.2 Hz, 1H), 7.34 (t, J = LC-MS: m / z 406.8 [M+H] + .

[0303] Step e. 6-(cyclopropanecarboxamide)-4-((3-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (B10): To a solution of 6-chloro-4-((3-(dicyclopropylphosphoryl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (60 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxamide (38 mg, 0.44 mmol), Pd(dba) (14 mg, 0.010 mmol), Xantphos (9 mg, 0.010 mmol), and KPO (63 mg, 0.30 mmol). The mixture was stirred in a microwave at 115 °C under a N atmosphere for 2 hours. The solvent was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography column (DCM / MeOH=10 / 1) to give the crude product, which was rinsed with Et2O to give the desired product (1.3 mg, 2%) as a yellow solid.

[0304] Table 1 shows a selection of compounds prepared according to the methods described above, with the method numbers indicated in the third column of the table.

[0305] Table 1. Selected compounds of the present invention (A1-A67, B1-B10) [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0306] Example 24, Luciferase Assay

[0307] Testing Procedure: 1. L929 ISRE cells (5000 cells / well) were seeded onto 96-well plates and incubated overnight at room temperature; 2. Cells were pretreated by adding test compounds at different concentrations (10 nM, 50 nM, 100 nM, 200 nM or 1000 nM) for 2 h; 3. IFN-α (100 ng / mL) was added to stimulate the cells for 6 h; 4. The upper medium was removed, PBS (100 μL) was added, washed, and then the PBS was removed; 5. PLB lysis solution (50 μL) was added to each well, and the wells were shaken for 15 min; 6. PLB lysate (30 μL) was transferred to a new 96-well white board, LAR II reagent (LAR II) was added, and then the OD value at 450 nm was read immediately using a plate washer; 7. Stop & Glo reagent (30 μL) was added, and then the OD value was read at 450 nm using a plate washer. 8. The final result was the OD value of step 6 / OD value of step 7.

[0308] Table 2. Inhibitory activity of compounds against IFNα-induced TYK2 / JAK1-mediated STAT activation [Table 2-1] [Table 2-2] The symbol " / " indicates that no inhibition was detected; BMS986165 is a reference for comparison.

[0309] According to Table 2, compounds A1-A8, A11-A14, A17-A19, A21, A23-A24, A26, A29-A31, A33-A35, A38-A42, A48-A51, A55-A56, A58-A59, A63, and A65-A67 exhibited inhibitory activity against IFNα-induced TYK2 / JAK1-mediated STAT activation. Furthermore, by comparing the inhibitory effects of five groups of compounds A1, B5 and B10, A4 and B4, A6 and B6, A12 and B1, and A17 and B7, it can be tentatively summarized that the A-series compounds containing a B ring (e.g., a pyrazole ring) have higher inhibitory activity than the B-series compounds that do not contain a B ring in their general structure (see, for example, Formulas (I)-(IV)).

[0310] Example 25. Enzyme-linked immunosorbent assay (ELISA)

[0311] Testing Procedure: 1. Soak the plate: add 300 μL 1× washing solution and let it sit for 30 seconds. After discarding the washing solution, dry the micro-pore plate on absorbent paper. 2. Add standards: Add 100 μL of 2x standard to standard wells. Add 100 μL standard diluent (serum / plasma samples) or medium (cell culture supernatant samples) to blank wells. 3. Add sample: Serum / Plasma: Add 50 μL 1× Assay Buffer and 50 μL sample to sample well. Cell Culture Supernatant: Add 100 μL cell culture supernatant to sample well. 4. Add detection antibody: Add 50 μL diluted detection antibody (diluted 1:100) to each well. Ensure steps 4, 5, and 6 are added continuously without interruption. The sampling process was completed within 15 minutes. 5. Incubation: Seal the plate using sealing plate film. Shake at 300 rpm and incubate at room temperature for 2 hours. 6. Wash: Discard the liquid, add 300 μL of washing solution, and wash the plate six times. After each wash, blot dry on absorbent paper. To obtain the desired experimental performance, residual liquid must be completely removed. 7. Add enzyme: Add 100 μL diluted horseradish peroxidase-labeled streptavidin to each well (diluted 1:100). 8. Incubation: Seal the plate with new sealing film. Shake at 300 rpm and incubate at room temperature for 45 minutes. 9. Wash: Repeat step 8. 10. Add the colorimetric substrate: Add 100 μL of the colorimetric substrate TMB to each well, keep away from light, and incubate at room temperature for 5 to 30 minutes. 11. Add stop solution: Add 100 μL stop solution to each well. The color should change from blue to yellow. If the color appears green or changes unevenly, gently tap the plate frame to mix the wells thoroughly. 12. Assay reading: Within 30 minutes, measure the OD at the absorption maximum wavelength of 450 nm and the reference wavelength of 570 nm or 630 nm using a microplate reader with dual wavelength detection. The calibrated OD value is the value measured at 450 nm minus the value measured at 570 nm or 630 nm.

[0312] Table 3. ELISA results for test compounds [Table 3]

[0313] As shown in Table 3, compound A1 effectively inhibited IFNα-induced CXCL-10 in PBMCs, thereby indicating its ability to inhibit the JAK1 / TYK2 signaling pathway. The inhibitory effect of A1 was better than that of BMS986165.

[0314] Example 26. Competitive Binding Assay

[0315] Testing Procedure:

[0316] For most assays, kinase-tagged T7 phage stocks were prepared in E. coli hosts derived from the BL21 strain. E. coli were grown to logarithmic phase, infected with T7 phage, and incubated at 32°C with shaking until lysis. The lysate was centrifuged and filtered to remove cellular debris. The remaining kinase was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Ligand-bound beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding. Binding reactions were assembled by combining kinase, ligand-conjugated affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6mM DTT). Test compounds were prepared as 111x stocks in 100% DMSO. Dissociation constants (Kd) were determined using an 11-point, 3-fold compound dilution series with three DMSO controls. For Kd measurements, all compounds were dispensed into 100% DMSO by acoustic transfer (non-contact dispensing). Compounds were then diluted directly into the assay, resulting in a final DMSO concentration of 0.9%. All reactions were performed in polypropylene 384-well plates, each in a final volume of 0.02 ml. The assay plate was incubated at room temperature with shaking for 1 hour, and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5µM non-biotinylated affinity ligand) and incubated for 30 minutes with shaking at room temperature. Kinase concentrations in the eluate were measured by qPCR.

[0317] Eleven-point, 3-fold serial dilutions of each test compound were prepared in 100% DMSO at 100x the final test concentration, followed by dilution to 1x in the assay (final DMSO concentration = 1%). The majority Kd was determined using a compound highest concentration of 30,000 nM. If the initial Kd determined was < 0.5 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower highest concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be > 30,000 nM.

[0318] Binding constants (Kd) were calculated from standard dose-response curves using the Hill equation.

number

[0319] The slope of the hill was set to -1.

[0320] Curves were fitted using nonlinear least-squares fitting with the Levenberg-Marquardt algorithm.

[0321] Table 4. Competitive binding affinities of compounds for TYK2 JH2, JAK1 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1 [Table 4]

[0322] As shown in Table 4, compound A1 exhibited strong affinity for TYK2 JH2 and JAK1 JH2 and weak affinity for JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1. Compound A1 is 10,000-fold more selective for binding to JAK1 JH2 and TYK2 JH2 than to JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1.

[0323] Example 27, Selectivity Evaluation

[0324] Aim 1: To test the inhibitory activity against the JAK2 / JAK2 pathway

[0325] Testing Procedure:

[0326] HEL cells were digested with trypsin, resuspended in 1640 medium, and counted. The compounds to be measured were added to a 6-well plate (1 million per well) for 2 hours, and then thrombopoietin (TPO) (final concentration: 100 ng / mL) was added to stimulate the cells for 30 minutes. The cells were harvested and lysed with protein lysate. Protein was quantitatively tested using a bicinchoninic acid (BCA) kit. Finally, p-STAT3 / STAT3 and the internal standard protein β-actin were detected by Western blot.

[0327] As shown in Figures 1-7, compounds A1-A9, A12, A17, A29, A35, A38-A42, and A49-A50 had no effect on TPO-induced downstream STAT3 phosphorylation, similar to BMS986165. This observation indicated that these compounds did not have inhibitory activity against the JAK2 / JAK2 pathway. Therefore, compounds A1-A9, A12, A17, A29, A35, A38-A42, and A49-A50 did not have inhibitory activity against JAK2. The pan-JAK inhibitor ruxolitinib (Rux in Figures 2-6) can inhibit the JAK2 / JAK2 pathway. JAK2 can pair with itself and is essential for platelet production, erythropoiesis, myelopoiesis, and keratinocyte production. Therefore, inhibition of JAK2 activity can cause serious adverse effects, such as thrombocytopenia and anemia.The compounds of the present invention do not have JAK2 inhibitory activity, and can avoid these adverse effects caused by inhibition of JAK2.

[0328] Aim 2: To test the inhibitory activity against the TYK2 / JAK2 pathway

[0329] Testing Procedure:

[0330] Mouse spleens were isolated and crushed into single cells with curved forceps. The splenic single cells were centrifuged (400g) for 5 minutes, red blood cells were lysed with ammonium chloride-potassium (ACK) solution, neutralized in 1640 medium, centrifuged (400g) for 5 minutes, and then resuspended in 1640 medium. The splenic single-cell suspension was counted and transferred to a 6-well plate for incubation (5 million / well). The compound to be tested was added. After 2 hours, IL-12 (50ng / mL) was added and the cells were stimulated for 1 hour. The cells were collected and lysed with protein lysate. Protein was quantitatively tested using a BCA kit. Finally, p-STAT4 / STAT4 and the internal standard protein β-actin were detected by Western blot.

[0331] As shown in Figures 8-12, compounds A1-A5, A8-A9, A12, A17, A29, A35, A38-A42, and A49-A50 efficiently inhibited IL-12-induced downstream STAT4 phosphorylation, indicating that the compounds could inhibit the TYK2 / JAK2 pathway and that the inhibitory activity was better than that of BMS986165. Combining the results in Figures 1-7, compounds A1-A5, A8, A9, A12, A17, A29, A35, A38-A42, A49, and A50 did not inhibit JAK2, indicating that their inhibitory activity against the TYK2 / JAK2 pathway was mainly due to the selective inhibition of TYK2. Overall, the activity of A1–A5, A8–A9, A12, A17, A29, A35, A38–A42, and A49–A50 against TYK2 was superior to that of BMS986165.

[0332] Aim 3: To test the inhibitory activity of the JAK1 / JAK2 pathway

[0333] Testing Procedure:

[0334] HT-29 cells were digested with trypsin, suspended in Dulbecco's modified Eagle's medium (DMEM), and counted. The tested compounds were added to a 6-well plate (400,000 / well). After 2 hours, IFN-γ (100 ng / mL) was added to stimulate the cells for 30 minutes. The cells were harvested and lysed with protein lysate. Protein was quantitatively tested using a BCA kit. Finally, p-STAT1 / STAT1 and the internal standard protein β-actin were detected by Western blot.

[0335] As shown in Figures 13 to 16, it was indicated that compound BMS986165 had no effect on IFN-γ-induced downstream STAT1 phosphorylation and no inhibitory effect on the JAK1 / JAK2 pathway, whereas compounds A1 to A2, A4 to A6, A8 to A9, A12, A17, A29, A35, A38 to A42, A49 to A50 and ruxolitinib inhibited the JAK1 / JAK2 pathway in a concentration-dependent manner. Combining the results in Figures 1-7, it was shown that compounds A1-A2, A4-A6, A8-A9, A12, A17, A29, A35, A38-A42, and A49-A50 had no inhibitory activity against JAK2, and the inhibitory effects of A1-A2, A4-A6, A8-A9, A12, A17, A29, A35, A38-A42, and A49-A50 on the JAK1 / JAK2 pathway were due to their inhibition of JAK1. As a result, A1-A2, A4-A6, A8-A9, A12, A17, A29, A35, A38-A42, and A49-A50 had more biological functions than BMS986165. Due to their unique selective inhibitory profiles, the compounds of the present disclosure may be more effective treatments for autoimmune diseases.

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled derivatives or isomers thereof. 【Chemistry 1】 (In the formula, n １ is 0, 1, 2, 3 or 4, n ２ is 0, 1, 2, 3 or 4, X １ is N or CH, X ２ is N or CH, X ３ is N or CR ７ And, Ring A is C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl. Ring B is C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl, or ring B is absent, and if ring B is absent, 【Chemistry 2】 It is directly connected to ring A, R １ is hydrogen, C １～６ alkyl, C １～６ deuterated alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, heteroaryl, -(CH ２ ) ｐ OR ｂ -(CH ２ ) ｐ SR ｂ -(CH ２ ) ｐ C(O)R ｂ -(CH ２ ) ｐ C(O)OR ｂ -(CH ２ ) ｐ OC(O)R ｂ -(CH ２ ) ｐ NR ｃ R ｄ -(CH ２ ) ｐ C(O)NR ｃ R ｄ -(CH ２ ) ｐ NR ｂ C(O)R ｅ -(CH ２ ) ｐ NR ｂ C(O)OR ｅ -S(O) ｑ NR ｃ R ｄ or -S(O) ｑ R ｅ and C １～６ alkyl, C １～６ deuterated alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl and heteroaryl are unsubstituted or hydrogen, deuterium, halide, amino, -NO ２ , -CN, -OH, C １～６ alkyl, deuterated C １～６ alkyl, C １～６ halo-alkyl, C １～６ Alkoxide, C １～３ Halo alkoxide, C ２～６ Alkenil, C ２～６ Alkynyl, substituted or unsubstituted C ３～６ It is substituted with one or more groups independently selected from the group consisting of cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R ２ is hydrogen, C １～４ Alkyl, -(CH ２ ) ｐ -phenyl or -(CH ２ ) ｐ -5 to 7 member heterocycloalkyl, C １～４ Alkyl groups have 0 to 1 R ａ It is substituted with phenyl, and 0 to 3 R ａ The substituted group is a 5-7 membered heterocycloalkyl group containing 1-4 heteroatoms or heteroatomic groups in the ring, and the heteroatoms or heteroatomic groups are independently NH, N, O, S(O) ｑ , PH(O) ｒ or P(O) ｒ The heterocycloalkyl group has 0 to 3 R ａ It has been replaced with, Alternatively, R １ and R ２ However, together with the nitrogen atoms bonded to them, they form 3- to 14-membered heterocycloalkyl groups, and these 3- to 14-membered heterocycloalkyl groups are unsubstituted, or contain deuterium, halides, amino acids, or -NOx. ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxide, C １～６ Halo alkoxide, C ２～６ Alkenyl and C ２～６ It is substituted with one or more groups independently selected from the group consisting of alkynyl groups, When present, each R ３ is independently hydrogen, deuterium, halide, -OH, amino, -SH, -NO ２ , -CN, -P(O)R ｃ R ｄ , C １～６ alkyl, -C(O)NH ２ , C １～６ deuterated alkyl, -O(C １～６ alkyl), -O(C １～６ deuterated alkyl), C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, C ３～６ heterocycloalkyl, C ６～１０ aryl or 5- to 10-membered heteroaryl, and C １～６ alkyl, C １～６ deuterated alkyl, -O(C １～６ alkyl), -O(C １～６ deuterated alkyl), C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, C ３～６ heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted with one or more groups independently selected from the group consisting of deuterium, halide, amino, -NO ２ , -CN, -OH and C １～３ alkyl, If present, each R ４ These are independently hydrogen, deuterium, halides, -OH, amino, -CN, and -CF ３ , C １～６ Alkyl, C ３～６ Cycloalkyl, -O(C １～６ Alkyl), -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , C ２～６ Alkenyl or C ２～６ It is alkinyl, C １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is unsubstituted, or contains deuterium, halide, amino, or -NO ２ It is substituted with one or more groups independently selected from the group consisting of -CN and -OH, R ５ and R ６ Each of them independently, C １～６ Alkyl, C １～６ Alkyl deuterated, C ２～６ Alkenil, C ２～６ Alkinyl or C ３～６ It is a cycloalkyl, C １～６ Alkyl, C １～６ Alkyl deuterated, C ２～６ Alkenil, C ２～６ Alkinyl and C ３～６ The cycloalkyl group is unsubstituted, or contains deuterium, halides, amino acids, or -NO. ２ It is substituted with one or more groups independently selected from the group consisting of -CN and -OH. Or R ５ and R ６ These, together with the phosphorus bonded to them, form a 5-6 member heterocycloalkyl group, and the 5-6 member heterocycloalkyl group is unsubstituted, or contains deuterium, halide, amino, or -NO ２ It is substituted with one or more groups independently selected from the group consisting of -CN and -OH. If present, R ７ These are independently hydrogen, deuterium, halides, -OH, amino, -CN, and -CF ３ , C １～６ Alkyl, C ３～６ Cycloalkyl, -O(C １～６ Alkyl), -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , C ２～６ Alkenyl or C ２～６ It is alkinyl, C １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is unsubstituted, or contains deuterium, halide, amino, or -NO ２ It is substituted with one or more groups independently selected from the group consisting of -CN and -OH, If present, R ａ , R ｂ , R ｃ , R ｄ and R ｅ Each of these independently consists of hydrogen, deuterium, halide, amino, and -NO. ２ -CN, -OH, alkyl, deuterated alkyl, halo-alkyl, alkoxy, halo-alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, halo-alkyl, alkoxy, halo-alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted, or deuterium, halogen, amino, -NO ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Substituted with one or more groups independently selected from the group consisting of alkynyl, substituted or unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or adjacent or non-adjacent R ａ , R ｂ , R ｃ , R ｄ and R ｅ Any two of these form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are unsubstituted, or contain deuterium, halides, aminos, or -NO ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkynyl, substituted or unsubstituted C ３～６ It is substituted with one or more groups independently selected from the group consisting of cycloalkyl, substituted and unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; If present, each p is independently 0, 1, or 2. If present, each q is independently 1 or 2. If present, each r is either 0 or 1, However, B does not exist, 【Transformation 3】 However, if it is directly linked to ring A, the compound 【Chemistry 4】 (Provided that it is not the case.)

2. R １ However, hydrogen, C １～６ Alkyl, C １～６ Alkyl deuterated, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , -S(O) ｑ NR ｃ R ｄ or -S(O) ｑ R ｅ C １～６ Alkyl, C １～６ Alkyl deuterated, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ The aryl and 5-10 membered heteroaryls are unsubstituted, or contain deuterium, halides, aminos, or -NO ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxide, C １～６ Halo alkoxide, C ２～６ Alkenil, C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Cycloalkyl, substituted or unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C ６～１０ It is substituted with one or more groups independently selected from the group consisting of aryls and substituted or unsubstituted 5- to 10-membered heteroaryls. If present, R ａ , R ｂ , R ｃ , R ｄ and R ｅ Each of these independently produces hydrogen, deuterium, halides, amino acids, and -NO. ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ It is an aryl or 5-10 member heteroaryl, C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ The aryl and 5-10 membered heteroaryls are unsubstituted, or contain deuterium, halides, aminos, or -NO ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Cycloalkyl, substituted and unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C ６～１０ Substituted with one or more groups independently selected from the group consisting of aryls and substituted or unsubstituted 5- to 10-membered heteroaryls; or adjacent or non-adjacent R ａ , R ｂ , R ｃ , R ｄ and R ｅ Any two of C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C ６～１０ Forms an aryl or 5-10 member heteroaryl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C ６～１０ The aryl and 5-10 membered heteroaryls are unsubstituted, or contain deuterium, halides, aminos, or -NO ２ , -CN, -OH,C １～６ Alkyl, deuterated C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Cycloalkyl, substituted or unsubstituted 3-6 member heterocycloalkyl, substituted or unsubstituted C ６～１０ It is substituted with one or more groups independently selected from the group consisting of aryls and substituted or unsubstituted 5- to 10-membered heteroaryls. If present, the compound according to claim 1, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, wherein q is independently 1 or 2.

3. Ring A is phenyl or a 5-6 member heteroaryl, Ring B is C ６～１０ The aryl or 5-10 membered heteroaryl, preferably phenyl or 5-6 membered heteroaryl, If present, each R ３ However, independently, halides, -CN, C １～６ Alkyl, C １～６ Alkyl deuterated, -O(C) １～６ Alkyl), -O (C １～６ Alkyl deuterated), C ３～６ Cycloalkyl or -C(O)NH ２ Preferably a halide or -O(C) １～６ It is alkyl, R ５ However, C １～６ Alkyl or C ３～６ Cycloalkyl, preferably C １～３ Alkyl or cyclopropyl, R ６ However, C １～６ Alkyl or C ３～６ Cycloalkyl, preferably C １～３ The compound according to claim 1, which is alkyl or cyclopropyl, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof.

4. The compound according to claim 1, wherein the compound is of formula (II), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof. 【Transformation 5】 (In the formula, X ４ is N or CR ８ And, X ５ is N or CR ８ And, X ６ is N or CR ８ And, If present, each R ８ However, independently, hydrogen, deuterium, halide, -OH, amino, -CN, -CF ３ , C １～６ Alkyl, C ３～６ Cycloalkyl, -O(C １～６ Alkyl), -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , C ２～６ Alkenyl or C ２～６ It is alkinyl, C １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is unsubstituted, or contains deuterium, halide, amino, or -NO ２ It is substituted with one or more groups independently selected from the group consisting of -CN and -OH, n ２ , X ２ , ring B, R １ , R ２ , R ４ , R ５ and R ６ However, as described in claim 1).

5. R ２ However, as described in claim 1, R １ However, 【Transformation 6】 Selected from the group consisting of, Each has 0 to 3 R's ９ It is replaced by, however, R １ If H, then R １ Assuming that is a non-substitution, If present, each R ９ However, independently, deuterium, halides, amino acids, and -NO ２ , -CN, -OH,C １～３ Alkyl or C １～３ The compound described in claim 1, which is an alkoxide, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof.

6. R ２ However, as described in claim 1, R １ but, 【Transformation 7】 A group consisting of is selected, and each has 0 to 3 R ９ The compound according to claim 5, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, which is substituted with .

7. R １ and R ２ However, together with the nitrogen attached to them, 【Transformation 8】 A heterocycloalkyl group is formed by selecting from the group consisting of the following, and each independently has 0 to 3 R １０ It has been replaced with, If present, R １０ However, independently, deuterium, halides, amino acids, and -NO ２ , -CN, -OH,C １～３ Alkyl or C １～３ The compound described in claim 1, which is an alkoxide, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof.

8. R １ and R ２ However, together with the nitrogen attached to them, 【Chemistry 9】 A heterocycloalkyl group selected from the group consisting of the following is formed, and each has 0 to 3 R １０ The compound according to claim 7, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, which is substituted with.

9. The compound according to claim 4, wherein the compound is of formula (III), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof. 【Chemistry 10】 (In the formula, n ２ , ring B, R １ , R ４ , X ４ , X ５ and X ６ However, as described in claim 4). 【Request Item 10】 【Chemistry 11】 but, 【Chemistry 12】 Selected from the group consisting of, Each of them is 0 to 3 R １１ It has been replaced with, If present, each R １１ However, independently, deuterium, halide, amino, -CN, -OH, C １～３ Alkyl or C １～３ The compound according to claim 9, which is an alkoxy, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof. 【Request Item 11】 【Chemistry 13】 but, 【Chemistry 14】 A group consisting of is selected, and each is 0 to 3 R １１ The compound according to claim 10, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, which is substituted with.

12. R １ but, 【Chemistry 15】 Independently selected from the group consisting of, each of which has 0 to 3 R ９ It is replaced by, however, R １ If H, then R １ Assuming that is a non-substitution, If present, R ９ However, independently, deuterium, halides, amino acids, and -NO ２ , -CN, -OH,C １～３ Alkyl or C １～３ The compound according to claim 9, which is an alkoxide, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof.

13. R １ but, 【Chemistry 16】 Independently selected from the group consisting of, each of which has 0 to 3 R ９ The compound according to claim 12, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, which is substituted with.

14. The compound according to claim 1, wherein the compound is of formula (IV), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof. 【Chemistry 17】 (In the formula, X ２ However, it is N or CH, X ４ However, N or CR ８ And, X ５ However, N or CR ８ And, X ６ However, N or CR ８ And, If present, each R ８ However, independently, they are hydrogen, deuterium, halide, -OH, amino, or -CN. R １ However, hydrogen, C １～６ Alkyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ or -S(O) ｑ R ｅ C １～６ Alkyl, C ３～６ Cycloalkyl, 3-6 member heterocycloalkyl, C ６～１０ The aryl and 5-10 membered heteroaryls are unsubstituted, or contain deuterium, halides, aminos, -CN, -OH, and C. １～６ Alkyl, deuterated C １～６ Alkyl and C １～６ It is substituted with one or more groups independently selected from the group consisting of alkoxides, R ４ However, hydrogen, C １～６ Alkyl, deuterated C １～６ Alkyl and C ３～６ It is a cycloalkyl, C １～６ Alkyl and C ３～６ The cycloalkyl group is either unsubstituted or substituted with one or more groups independently selected from the group consisting of halides, aminos, -CN, and -OH. R ５ and R ６ Each of them independently, C １～６ Alkyl or C ３～６ It is a cycloalkyl, If present, R ｂ , R ｃ , R ｄ and R ｅ Each of these independently consists of hydrogen, a halide, an amino, -CN, -OH, and C. １～６ Alkyl or C ３～６ It is a cycloalkyl, C １～６ Alkyl and C ３～６ The cycloalkyl group is either unsubstituted or substituted with one or more groups independently selected from the group consisting of halides, aminos, -CN, and -OH. If present, q is 1 or 2).

15. X ２ N is, X ４ However, N or CR ８ And, X ５ However, N or CR ８ And, X ６ However, N or CR ８ And, If present, each R ８ However, independently, hydrogen or a halide, preferably hydrogen, R １ However, hydrogen, C １～６ Alkyl, 5-10 member heteroaryl, -C(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ or -S(O) ｑ R ｅ C １～６ Alkyl and 5-10 member heteroaryls are unsubstituted or halides, -CN,C １～６ Alkyl, deuterated C １～６ Alkyl and C １～６ It is substituted with one or more groups independently selected from the group consisting of alkoxides, R ４ However, hydrogen, C １～６ Alkyl, deuterated C １～６ Alkyl or C ３～６ It is a cycloalkyl, R ５ and R ６ Each of them independently, C １～６ Alkyl or C ３～６ It is a cycloalkyl, If present, R ｂ , R ｃ , R ｄ and R ｅ Each of them independently produces hydrogen and C １～６ Alkyl or C ３～６ It is a cycloalkyl, C １～６ Alkyl and C ３～６ The cycloalkyl group is either unsubstituted or substituted with one or more halides. The compound according to claim 14, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, if present, having q as 2.

16. The compound according to claim 1, wherein the compound is of formula (V), or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof. [Chemistry 18] (In the formula, X ４ is N or CH, X ５ is N or CR ８ And, If present, each R ８ However, independently, hydrogen or fluorine, preferably hydrogen, R １ However, 5-10 member heteroaryl or -C(O)R ｂ The 5-10 member heteroaryl group is unsubstituted, or a halide, -CN, C １～３ Alkyl, deuterated C １～３ Alkyl and C １～３ It is substituted with one or more groups independently selected from the group consisting of alkoxides, R ４ However, independently, hydrogen, C １～３ Alkyl, deuterated C １～３ Alkyl and C ３～６ It is a cycloalkyl, R ５ and R ６ Each of them independently, C １～３ Alkyl or C ３～６ It is a cycloalkyl, If present, R ｂ However, independently, C ３～６ It is a cycloalkyl, C ３～６ The cycloalkyl group is either unsubstituted or substituted with one or more fluorines. 【Request Item 17】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 A compound, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, or isomer thereof, selected from the group consisting of the above.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, and a pharmaceutically acceptable carrier.

19. (i) A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, and (ii) One or more additional therapeutic agents selected from the group consisting of anti-autoimmune / anti-inflammatory agents, antitumor / anticancer agents, anti-allergic agents, anti-transplant rejection agents, anti-neurodegenerative agents, anti-asthmatic agents, and other anti-obstructive airway disease agents. A composition containing the following:

20. A composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative or isomer thereof, for treating a subject suffering from a disease or disorder by inhibiting TYK2 and / or JAK1-mediated signaling, wherein the disease or disorder is an autoimmune or inflammatory disease, cancer or tumor, allergy, transplant rejection, neurodegenerative disease, asthma or other obstructive airway disease, and the autoimmune or inflammatory disease is enteritis, skin disease, eye disease, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, Goodpasture syndrome, or autoimmune thrombocytopenia. This includes diseases such as sympathetic ophthalmitis, myositis, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, chronic infiltrative hepatitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, ulcerative colitis, membranous glomerulosis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polyarthritis dermatomyositis, type I interferonosis (including Aicardi-Goutieres syndrome) and other systemic sclerosis caused by overexpression of type I interferon, Mendelian genetic diseases, polyarteritis nodosa, multiple sclerosis, relapsing multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and bullous pemphigus, Cogan syndrome, ankylosing spondylitis, Wegeneer's granulomatosis, autoimmune alopecia, diabetes mellitus, or thyroiditis. The enteritis is Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis. The skin disease in question is atopic dermatitis, eczema, psoriasis, scleroderma, itching or other symptoms of itching, vitiligo, or alopecia. The eye disease is keratoconjunctivitis, uveitis (including uveitis associated with Behcet's disease and uveitis caused by the lens), keratitis, herpetic keratitis, keratoconus, muscular dystrophy superficial keratitis, corneal leukopenia, anterior uveitis, scleritis, Mooren's ulcer, Graves' ophthalmopathy, Vogt-Koyanagi-Hara syndrome, keratoconjunctivitis sicca, bullous iridocyclitis, iridosarcoidosis, endocrine eye disorder, sympathetic ophthalmitis, allergic conjunctivitis, or ocular neovascularization. The diabetes in question is type 1 diabetes or diabetic complications. The cancer or tumor is a disease / tumor associated with gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell and squamous cell carcinoma), breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma (including multiple myeloma), myeloproliferative disorder, proliferative diabetic retinopathy, or vascular hyperplasia. The neurodegenerative disease is motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by cerebral ischemia, trauma, injury, glutamate neurotoxicity or hypoxia, stroke, myocardial ischemia, renal ischemia, heart disease, cardiac hypertrophy, atherosclerosis, arteriosclerosis, organ hypoxia or ischemia / reperfusion injury of platelet aggregation, The allergy is allergic dermatitis in the subject (including allergic diseases in horses, e.g., allergies to bites), summer eczema, horseshoe itchiness, muscle spasms, airway inflammation, recurrent airway obstruction, airway hyperresponsiveness, and chronic obstructive pulmonary disease. The asthma or other obstructive airway disease is chronic or severe asthma, delayed-onset asthma, bronchitis, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, or dust asthma. A composition in which the transplant rejection is islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (where the organ and cells are bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea) or xenograft rejection.

21. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 17, wherein the preparation is a tablet, capsule, injectable, granule, powder, suppository, pill, gel, powder, oral solution, inhalant, suspension, or dry suspension.

Images