JAK inhibitor analogue, preparation and application thereof

Abstract

The present disclosure provides JAK inhibitor analogs, and compositions and methods thereof for treating diseases or conditions, such as inflammatory bowel disease and ulcerative colitis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 331,463, filed on April 15, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure provides JAK inhibitor analogs, and compositions and methods for use thereof in treating diseases or disorders, such as inflammatory bowel disease and ulcerative colitis. Background Art

[0004] Inflammatory bowel disease (IBD) affects more than 6.8 million patients worldwide, and 1 to 2 million in the United States. Ulcerative colitis (UC) accounts for 2 / 3 of IBD cases, while Crohn's disease accounts for the remaining one-third of IBD cases. UC typically begins in the rectum and extends proximally to the colon, where inflammation is limited to the innermost layer of the intestine (mucosa), leading to ulcers and bloody diarrhea. In addition, depending on the severity and duration of the disease, patients with UC have a risk of developing colon cancer of up to 18%.

[0005] Current treatment options have various limitations. Anti-inflammatory treatments using controlled-release formulations of 5-aminosalicylate and corticosteroids have only limited effectiveness in alleviating symptoms. Anti-TNF antibody therapy is effective but requires lifelong injections. Immune system suppressants such as azathioprine and cyclosporine have limited effectiveness and exhibit severe side effects after long-term use.

[0006] Inhibition of Janus kinases (JAK1, JAK2, JAK3, and TYK2) has recently been proposed as a therapeutic approach for the treatment of UC. Several orally bioavailable small molecule JAK inhibitors, such as tofacitinib, have been developed and approved for the treatment of IBD and rheumatoid arthritis. However, tofacitinib, like all other JAK inhibitors, carries black box warnings for serious side effects, including: a high incidence of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke), arterial and venous thrombosis and pulmonary embolism, malignancies (lymphoma and lung cancer), and an increased risk of serious infections leading to death. Summary of the invention

[0007] In one aspect, disclosed herein is a Janus kinase (JAK) inhibitor analog, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor analog has the following structure:

[0008] ALB

[0009] in:

[0010] A is the JAK inhibitor part;

[0011] L is a cleavable linker; and

[0012] B is a prodrug moiety.

[0013] In some embodiments, the JAK inhibitor portion is derived from abrocitinib, baricitinib, cerdulatinib, delgocitinib, deucravacitinib, fedratinib, filgotinib, gandotinib, lestaurtinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitor portion includes a benzimidazole portion, a pyrrolopyrimidine portion, or a biarylpyrimidine portion.

[0014] In some embodiments, the cleavable linker comprises at least one selectively cleavable group or bond. In some embodiments, the selectively cleavable group or bond is enzymatically cleavable. In some embodiments, the cleavable linker comprises an azo group.

[0015] In some embodiments, L comprises Where E 1 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R 1a ; and R 1a is hydrogen or C1-C6 alkyl. 1 C4-C 10 Arylene or C4-C 10Heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, or -COO-R 1a .

[0016] In some embodiments, L comprises:

[0017] In some embodiments, L further comprises a combination of one or more groups selected from: -CH2-, -O-, -NR 1b -, arylene and heteroarylene, and R 1b is hydrogen or C1-C6 alkyl. In some embodiments, L further comprises:

[0018] In some embodiments, B comprises Where G is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl; and J is a bond or a linker comprising a combination of one or more groups selected from the group consisting of: -C(R 1c )2-, -CH=CH-, -C≡C-, -O-, -NR 1c -、-S-、-C(O)-、-C(NR 1c )-, -S(O)- and -S(O)2-, where each R 1c In some embodiments, J is a linker comprising a combination of one or more groups selected from the group consisting of: -C(R 1c )2-、-NR 1c - and -C(O)-, where each R 1c is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, J comprises In some embodiments, J is a bond.

[0019] In some embodiments, B comprises

[0020] In some embodiments, the JAK inhibitor analog is a compound of formula (I):

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein:

[0023] Z is NR a , where R a is H or C1-C6 alkyl;

[0024] R 1 Alkyl or SO2-R 2 , where R 2 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R b )2, and each R b are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring;

[0025] X is O, SO2 or CH2;

[0026] Y is NH, O or CH2;

[0027] W is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 Heteroarylene, wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl;

[0028] J' is a bond or a linker comprising a combination of one or more groups selected from: -C(R c )2-, -CH=CH-, -C≡C-, -O-, -NR c -、-S-、-C(O)-、-C(NR c )-, -S(O)- and -S(O)2-, where each R c independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0029] n is 1, 2, 3, 4, 5 or 6; and

[0030] L' is a cleavable linker.

[0031] In some embodiments, J' is a linker comprising a combination of one or more groups selected from: -C(R c)2-、-NR c - and -C(O)-, where each R c is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, J' comprises In some embodiments, J' is a bond.

[0032] In some embodiments, the JAK inhibitor analog is a compound of Formula (Ia):

[0033]

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, Z is NH. In some embodiments, R 1 -SO2-N(R b )2. In some embodiments, one R d is hydrogen, and the other is C1-C6 alkyl. In some embodiments, X and Y are O. In some embodiments, n is 1, 2 or 3.

[0036] In some embodiments, L' comprises E 2 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R d ; and R d is hydrogen or C1-C6 alkyl. 2 C4-C 10 Arylene or C4-C 10 Heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, or -COO-R d .

[0037] In some embodiments, L' comprises

[0038] In some embodiments, L' further comprises a combination of one or more groups selected from: -CH2-, -O-, -NR e -, arylene and heteroarylene.

[0039] In some embodiments, L' further comprises

[0040] In some embodiments, the compound is:

[0041]

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a JAK inhibitor analog disclosed herein (eg, a compound of formula ALB or a compound of formula (I) or (Ia)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0045] In another aspect, disclosed herein is a method for treating or preventing a disease or condition, comprising administering to a subject in need thereof an effective amount of a JAK inhibitor analog disclosed herein (e.g., a compound of formula ALB or a compound of formula (I) or (Ia)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a JAK inhibitor analog disclosed herein or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the disease or condition is cancer, an autoimmune disease, or an inflammatory disease. In some embodiments, the disease or condition is a gastrointestinal inflammatory disease or condition. In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, inflammatory bowel disease is ulcerative colitis or Crohn's disease. In some embodiments, the disease or condition is cancer. In some embodiments, the subject has cancer, has had cancer, is susceptible to cancer, or has a family history of cancer. In some embodiments, the JAK inhibitor analog or a pharmaceutically acceptable salt thereof or a composition is administered orally.

[0047] In another aspect, disclosed herein is a compound of formula (II):

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein:

[0050] Q is

[0051] Z' is NR c , where R c is H or C1-C6 alkyl;

[0052] R 3 Alkyl or SO2-R4 , where R 4 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R d )2, and each R d are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R d Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring;

[0053] R 5 is hydrogen, -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3; and

[0054] R 6 It is -OCH3 or -OCH2CH2-OCH3.

[0055] In some embodiments, Z' is NH. In some embodiments, R 3 SO2-N(R d )2. In some embodiments, one R d is hydrogen, and one R d is a C1-C6 alkyl group. In some embodiments, Q is And R 5 is -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3. In some embodiments, Q is R 5 is hydrogen, and R 6 is -OCH3 or -OCH2CH2-OCH3. In some embodiments, Q is R 5 is -CH2-OCH3, and R 6 is -OCH3 or -OCH2CH2-OCH3. In some embodiments, Q is R 5 is CH2-(OCH2CH2)-OCH3, and R 6 It is -OCH3- or -OCH2CH2-OCH3.

[0056] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0057] In another aspect, disclosed herein is a method for treating or preventing a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0058] Other aspects and embodiments of the present disclosure will be apparent from the following detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1A is a schematic representation of the pharmacokinetics of an exemplary GI locally activated JAK inhibitor. Figure 1B is a schematic diagram of the design of an exemplary GI locally activated JAK inhibitor. Figure 1C The co-crystal structure of JAK2 and fedratinib is shown (PDB6VNE).

[0060] Figure 2 Shown are the structures of MMT3-72 and its five metabolites: MMT3-72-M1, MMT3-72-M2, MMT3-72-M3, MMT3-72-M4, and MMT3-72-M5.

[0061] Figure 3 Figure 3 shows the inhibition of different isoforms of JAK by MMT3-72 and the active metabolite MMT3-72-M2. Inhibition of JAK activity by MMT3-72 and MMT3-72-M2 (0.01–10,000 nM) was measured using the Kinase-Glo Max assay against purified enzymes JAK1, JAK2, JAK3, and TYK2. IC values ​​for compounds inhibiting different JAK isoforms were calculated using Prism 8. 50 .

[0062] Figures 4A-4C Graph showing the concentrations of MMT3-72 and MMT3-72-M2 in GI content, GI tissues, and plasma. Figure 4A Graphs showing MMT3-72 concentrations in plasma, colon tissue, small intestinal tissue, colon content, and small intestinal content at 0.5 h, 2 h, 4 h, 12 h, and 24 h. Figure 4B Graph showing the concentration of MMT3-72-M2 in plasma, colonic tissue, and small intestinal tissue at 0.5 h, 2 h, 4 h, 12 h, and 24 h. The dashed lines show the IC values ​​of MMT3-72-M2 for inhibiting JAK1, JAK2, JAK3, and TYK2, respectively. 50 . Figure 4C Graph showing the concentration of MMT3-72-M2 in colonic content, small intestinal content, and gastric content at 0.5 h, 2 h, 4 h, 12 h, and 24 h.

[0063] Figures 5A-5H A graph comparing the in vivo efficacy of MMT3-72 and tofacitinib for the treatment of UC. Figure 5A Graph showing improvement in UC DAI score after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). Figure 5BGraph showing recovery of colon length in DSS-induced colitis after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). Figure 5C Graph showing the percentage of mice with severe colitis with massive bleeding on day 5 after MMT3-72 and tofacitinib (1, 5 mg / kg) treatment. Figure 5D Graph showing the percentage of mice with moderate colitis on day 5 after MMT3-72 and tofacitinib (1, 5 mg / kg) treatment.

[0064] Figure 5E is a graph showing the improvement of UC DAI score after MMT3-72 and tofacitinib (10 mg / kg) treatment. Fig. 5F Graph showing recovery of colon length after MMT3-72 and tofacitinib (10 mg / kg) treatment. Figure 5G Figure 2 is a graph showing the percentage of mice that developed severe colitis with massive bleeding on day 5 after MMT3-72 and tofacitinib (10 mg / kg) treatment. Figure 5H Graph showing the percentage of mice developing moderate colitis on day 5 following MMT3-72 and tofacitinib (10 mg / kg) treatment.

[0065] Figure 6 It is an image of H&E staining of colon tissue after MMT3-72 and tofacitinib treatment in the DSS-induced colitis model. The control is H&E staining of colon tissue of healthy mice. DSS-induced colitis shows epithelial destruction and immune cell infiltration in colon tissue. In the DSS-induced colitis model, MMT3-72 (5, 10 mg) treatment reduced epithelial destruction and immune cell infiltration in colon tissue compared to tofacitinib (5, 10 mg / kg).

[0066] Figure 7 The structures of MMT3-56, MMT3-84, MMT3-83, MMT3-85, MMT3-73, MMT3-89, MMT3-79, and MMT3-90 are shown.

[0067] Fig. 8A and 8B It is a JAK-related cell line HEL cell ( Fig. 8A ) and SET-2 cells ( Figure 8B ) in Figure 2. DETAILED DESCRIPTION

[0068] JAK inhibitor analogs and compositions thereof are described herein. Exemplary GI locally active JAK inhibitor analogs maximize exposure of the drug to intestinal tissues, resulting in superior efficacy in the treatment of UC, while reducing systemic drug exposure, thereby mitigating the adverse side effects of JAK inhibitors.

[0069] The inactivated synthetic compound MMT3-72 shows minimal inhibitory activity against JAK (JAK1, JAK2, JAK3 and TYK2) and has low absorption potential for systemic circulation. However, after activation, MMT3-72-M2 is released, mainly in the colon, and shows potent inhibitory activity against JAK1 / 2 and TYK2. MMT3-72 accumulates in the GI lumen, but not in GI tissue or plasma, while the released active metabolite MMT3-72-M2 accumulates in the colon lumen and colon tissue, with minimal exposure in plasma. MMT3-72 (PO, 5, 10 mg / kg) achieved efficacy superior to tofacitinib in dextran sulfate sodium (DSS)-induced colitis in mice.

[0070] The section headings as used in this section and the entire disclosure herein are for organizational purposes only and are not intended to be limiting.

[0071] 1. Definition

[0072] As used herein, the terms "comprising," "including," "having," "has," "may," "containing," and variations thereof are intended to be open transitional phrases, terms, or words that do not exclude the possibility of additional actions or structures. Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentially of" the embodiments or elements set forth herein, whether or not explicitly stated.

[0073] For the recitation of numerical ranges herein, each intermediate value with the same degree of precision is expressly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range of 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are expressly contemplated.

[0074] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms shall be clear; however, if there is any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. In addition, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0075] As used herein, the terms "joint", "linking group" and "linking key" are used interchangeably and refer to the connecting portion of the main chain connecting two groups and having any suitable length. In some cases, the joint has a main chain of 20 atoms or less in length. The joint or linking key can be a covalent bond connecting two groups or a chain of any suitable length (e.g., a length between 1 and 20 atoms), such as a length of about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20 carbon atoms, wherein the joint can be linear, branched, cyclic or a single atom. The joint may include, but is not limited to, polyethylene glycol, modified polyethylene glycol; ethers, thioethers, tertiary amines, alkyls (which may be linear or branched, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl) etc.). The linker backbone may include a cyclic group, such as an aryl, heterocyclic or cycloalkyl group, wherein 2 or more atoms (eg, 2, 3 or 4 atoms) of the cyclic group are contained in the backbone. The linker may be cleavable or non-cleavable.

[0076] As used herein, the term "moiety" is used to refer to a portion of an entity or molecule, in some cases having a specific function, structure, or structural characteristic.

[0077] As used herein, the terms "providing," "administering," and "introducing" are used interchangeably herein and refer to placing the composition of the present disclosure into a subject by a method or route that results in at least partial localization of the composition to a desired site. The composition can be administered by any appropriate route that results in delivery to a desired location in a subject.

[0078] A "subject" or "patient" can be human or non-human, and can include, for example, animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Likewise, patients can include adults or adolescents (e.g., children). In addition, a patient can refer to any living organism, preferably a mammal (e.g., human and non-human), that can benefit from the administration of the compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals include rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In one embodiment, the mammal is a human.

[0079] As used herein, "treat," "treating," and the like means to slow, stop, or reverse the progression of a disease or condition when a compound or composition described herein is provided to an appropriate control subject. The term also means to reverse the progression of such a disease or condition to the extent that the symptoms are eliminated or greatly alleviated. Thus, "treating" means applying or administering a composition described herein to a subject, wherein the subject suffers from a disease or symptom of a disease, with the purpose of curing, healing, alleviating, relieving, altering, remedying, improving, ameliorging, or affecting the disease or symptom of a disease.

[0080] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic table, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional parts and reactivity are described in the following: Sorrell, Organic Chemistry, 2nd edition, University Science Books, Sausalito, 2006; Smith, March's Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7th edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rd edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987; The entire contents of each of them are incorporated herein by reference.

[0081] As used herein, the term "alkyl" means a straight or branched saturated hydrocarbon chain. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0082] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0083] As used herein, the term "alkoxyalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced by an alkoxy group as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, methoxymethyl.

[0084] As used herein, the term "amino" refers to a -NH2 group. As used herein, the term "alkylamino" refers to a group -NHR, wherein R is an alkyl group as defined herein. As used herein, the term "dialkylamino" refers to a group -NR2, wherein each R is independently an alkyl group as defined herein.

[0085] As used herein, the term "aminoalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced by an amino group.

[0086] As used herein, the term "aryl" refers to a monocyclic, bicyclic or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms ("C6-C 14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl", ie, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "aryl", for example naphthyl, such as 1-naphthyl and 2-naphthyl).

[0087] As used herein, the term "arylene" refers to a divalent aromatic group.

[0088] As used herein, the term "azo group" refers to a group having the general formula RN=N-R', wherein R and R' may independently be aryl or alkyl.

[0089] As used herein, the term "benzimidazole" refers to a bicyclic heteroaryl group having the formula:

[0090]

[0091] As used herein, the term "biarylpyrimidine" refers to a group having the following structure:

[0092]

[0093] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl group may be monocyclic, bicyclic, bridged, fused or spirocyclic. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl and bicyclo[5.2.0]nonyl.

[0094] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group.

[0095] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatom group such as -NH-, -O-, -S-, -S(O)-, -S(O)2-, -OP(O)(O)2-, -NH-, -O-, -S-, -S(O)2 ... - )O-, etc. For example, 1, 2, 3, 4, 5, 6 or more carbon atoms can be independently replaced by the same or different heteroatom groups. The heteroalkyl group can also include one or more carbonyl moieties (i.e., wherein the carbon atoms of the alkyl group are oxidized to -C(O)- groups).

[0096] As used herein, the term "heteroalkylene" refers to a divalent heteroalkyl group.

[0097] As used herein, the term "heteroaryl" refers to an aromatic group having a single ring (monocyclic) or multiple rings (bicyclic or tricyclic) with one or more ring heteroatoms independently selected from O, N and S. An aromatic monocyclic ring is a five-membered or six-membered ring containing at least one heteroatom independently selected from O, N and S (e.g., 1, 2, 3 or 4 heteroatoms independently selected from O, N and S). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. An example of a bicyclic heteroaryl is a monocyclic heteroaryl ring fused to a monocyclic aryl as defined herein or a monocyclic heteroaryl as defined herein. An example of a tricyclic heteroaryl is a monocyclic heteroaryl ring fused to two rings independently selected from a monocyclic aryl as defined herein or a monocyclic heteroaryl as defined herein. Representative examples of monocyclic heteroaryl groups include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, 1,2,4-triazinyl, and 1,3,5-triazinyl. The representative example of bicyclic heteroaryl includes but is not limited to benzimidazolyl, benzodioxolyl, benzofuranyl, benzoxadiazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, chromenyl, imidazopyridine, imidazothiazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, naphthyridinyl, purinyl, pyridoimidazolyl, quinazolinyl, quinolyl, quinoxalinyl, thiazolopyridyl, thiazolopyridyl, thiazolopyrimidinyl, thienopyrrolyl and thienothienyl. The representative example of tricyclic heteroaryl includes but is not limited to dibenzofuranyl and dibenzothienyl. Monocyclic, bicyclic and tricyclic heteroaryl are connected to the parent molecular part by any carbon atom or any nitrogen atom contained in the ring.

[0098] As used herein, the term "heteroarylene" refers to a divalent heteroaryl group.

[0099] As used herein, the term "heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. A heterocyclyl may be a monocyclic ring system ("monocyclic heterocyclyl"), or a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated, or may be partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring or the heterocyclyl ring, or includes ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl can be described as, for example, 3-7 membered heterocyclyls, wherein the term "member" refers to non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxiranyl, and thiol. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridone (e.g., 1-methylpyridine-2-one), and thienyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinone (2-methylpyridazine-3-one), pyrimidone (e.g., 1-methylpyrimidin-2-one, 3-methylpyrimidin-4-one), dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxoctanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 5-membered heterocyclic groups fused to a heterocyclic ring (also referred to herein as 5,5-bicyclic heterocyclic rings) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclic groups fused to a heterocyclic ring (also referred to herein as 4,6-membered heterocyclic rings) include, but are not limited to, diazaspirononyl (e.g., 2,7-diazaspiro[3.5]nonyl). Exemplary 6-membered heterocyclyls fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyls fused to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctyl (e.g., (1,5)-8-azabicyclo[3.2.1]octyl). Exemplary 6-membered heterocyclyls fused to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononyl (e.g., 9-azabicyclo[3.3.1]nonyl).

[0100] As used herein, the term "heterocyclylene" refers to a divalent heterocyclic group.

[0101] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0102] As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom (eg, one hydrogen atom) is replaced with a hydroxy group.

[0103] As used herein, the term "pyrrolopyrimidine" refers to a bicyclic heteroaryl group (ie, a 7H-pyrrolo[2,3-d]pyrimidine group) having the formula:

[0104]

[0105] As used herein, the term "substituent" refers to a group that replaces an atom of the indicated group.

[0106] When a group or moiety can be substituted, the term "substituted" indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogen atoms on the group indicated in the expression using "substituted" can be replaced with a series of listed indicated groups or with suitable substituents known to those skilled in the art (e.g., one or more of the groups listed below), provided that the normal valence of the designated atom is not exceeded. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazine, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamido, thiol, thiol, thioketone, thioloxy, or a combination thereof.

[0107] As used herein, in chemical structures, indicates:

[0108]

[0109] Indicates the point where one part joins another.

[0110] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkylalkenyl) is indicated by the prefix "C x -C y ” indicates an alkyl group containing from 1 to 3 carbon atoms, wherein x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. Thus, for example, “C1-C3 alkyl” refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0111] For the compounds described herein, radicals and substituents may be chosen with regard to the allowed valences of atoms and substituents such that selection and substitution results in stable compounds, e.g., which do not spontaneously transform such as by rearrangement, cyclization, elimination, or the like.

[0112] Where substituent groups are designated by conventional chemical formulas written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- is intended to encompass -OCH2-, and -C(O)NH- is intended to encompass -NHC(O)-.

[0113] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are illustrative only and are not intended to be limiting.

[0114] 2. Janus kinase (JAK) inhibitor analogs

[0115] In one aspect, the present invention provides a Janus kinase (JAK) inhibitor analog or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor analog has the following structure:

[0116] ALB

[0117] in:

[0118] A is the JAK inhibitor part;

[0119] L is a cleavable linker; and

[0120] B is a prodrug moiety.

[0121] The JAK family plays a role in cytokine-dependent regulation of cell proliferation and function involved in immune responses. Inhibitors of JAK family members have therapeutic efficacy in the treatment of cancer, autoimmune and inflammatory diseases. Currently, there are four known members of the mammalian JAK family: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as protein tyrosine kinase 2). The size of JAK proteins ranges from 120 to 140 kDa and contains seven conserved JAK homology (JH) domains; one of which is a functional catalytic kinase domain and the other is a pseudokinase domain that may play a regulatory function and / or serve as a docking site for signal transducers and activators of transcription (STAT).

[0122] As used herein, "JAK inhibitor moiety" refers to a moiety that inhibits at least one activity of a JAK kinase. In some embodiments, the JAK inhibitor moiety includes a benzimidazole moiety, a pyrrolopyrimidine moiety, or a biarylpyrimidine moiety. For example, JAK inhibitor compounds having a biarylpyrimidine moiety are disclosed in WO 2007 / 053452, which is incorporated herein by reference.

[0123] The JAK inhibitor portion can be derived from any known JAK inhibitor. In some embodiments, the JAK inhibitor portion is derived from abrocitinib, baricitinib, cerdutinib, degotinib, deuterocelexinib, fedratinib, filgotinib, gandotinib, lestaurtinib, molotinib, oclacitinib, pactinib, piricitinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitor portion is derived from fedratinib.

[0124] The JAK inhibitor portion can inhibit one or more JAK family members. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK1. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK2. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK3. In some embodiments, the JAK inhibitor portion reduces the kinase activity of TYK2.

[0125] In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK1 and JAK2. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK1 and JAK3. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK2 and JAK3. In some embodiments, the JAK inhibitor portion reduces the kinase activity of JAK1, JAK2, and JAK3. In some embodiments, the JAK inhibitor portion is a pan-JAK inhibitor.

[0126] Cleavable linkers include any linker that can be selectively cleaved to produce at least two products. Therefore, a cleavable linker may include at least one selectively cleavable group or bond. The cleavable linker of the present invention is stable before contact with a cleavage-inducing stimulus (e.g., an enzyme, a chemical agent, or a change in chemical conditions) that cleaves the selectively cleavable group or bond. Cleavable linkers include electrophilic cleavable linkers, nucleophilic cleavable linkers, photocleavable linkers, metal cleavable linkers, electrolytic cleavable linkers, enzymatic cleavable linkers, cleavable linkers (e.g., disulfide linkers or diazobenzene linkers) under reducing or oxidizing conditions, and cleavable linkers using acidic or alkaline agents.

[0127] In some embodiments, the cleavable linker includes an enzymatically cleavable group or bond. Enzymatic reactions that can be used to cleave the linker include reactions mediated by nucleases, peptidases, proteases, phosphatases, esterases, oxidases, reductases, sulfatases, and the like. For example, in certain embodiments, the enzymatically cleavable linker includes, but is not limited to, a β-glucuronic acid linker, a peptide-based linker, and an aryl sulfate, disulfide, hydrazone, acetal, aminal, ester, phosphate, or azo linker.

[0128] In some embodiments, the cleavable linker is pH sensitive. In certain embodiments, the linker comprises a low pH unstable group or bond. As used herein, a low pH unstable group or bond is a group or bond that selectively breaks under acidic conditions (pH <7). For example, in certain embodiments, the linker comprises an amine, an imine, an ester, a benzoic acid imine, an amino ester, a diortho ester, a polyphosphate, a polyphosphazene, an acetal, a vinyl ether, a hydrazone, an azidomethyl-methyl maleic anhydride, a thiopropionate, a masked endosomal dissolution agent or a citraconyl. In some embodiments, the cleavable bond is selected from the following: ketals that are unstable in acidic environments (e.g., pH less than 7, greater than about 4) to form diols and ketones; acetals that are unstable in acidic environments (e.g., pH less than 7, greater than about 4) to form diols and aldehydes; imines or iminiums that are unstable in acidic environments (e.g., pH less than 7, greater than about 4) to form amines and aldehydes or ketones; silicon-oxygen-carbon bonds that are unstable under acidic conditions; silicon-nitrogen (silazane) bonds; silicon-carbon bonds (e.g., aromatic silanes, vinyl silanes, and allyl silanes); maleamic acid (amide bonds synthesized from maleic anhydride derivatives and amines); orthoesters; hydrazones; activated carboxylic acid derivatives (e.g., esters, amides) designed for acid-catalyzed hydrolysis; or vinyl ethers.

[0129] In some embodiments, the linker comprises: Where E 1 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R 1a , where R 1a It is hydrogen or C1-C6 alkyl.

[0130] In some embodiments, E 1 C4-C 10 Arylene or C4-C 10 Heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, or -COO-R 1a , where R 1a is hydrogen or C1-C6 alkyl. 1 is a monocyclic arylene or heteroarylene group, optionally substituted by -COO-R 1aSubstitution, where R 1a is hydrogen or C1-C6 alkyl. 1 It is phenylene.

[0131] In some embodiments, the linker comprises:

[0132] In some embodiments, the linker further comprises a combination of one or more groups selected from: -C(R 1b )2-, -CH=CH-, -C≡C-, -O-, -NR 1b -、-S-、-C(O)-、-C(NR 1b )-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene and heterocyclylene, wherein each R 1b In some embodiments, the linker further comprises a combination of one or more groups selected from the group consisting of: -CH2-, -O-, -NR 1b -, arylene and heteroarylene. In some embodiments, the linker further comprises

[0133]

[0134] A prodrug moiety is a moiety that modulates the absorption, distribution, metabolism, or excretion characteristics of a compound to which it is attached or linked to improve the bioavailability and / or efficacy of the compound. In some cases, the prodrug moiety renders the compound largely inactive until a transformation converts the compound to a pharmacologically active form, which is typically the result of removal of the prodrug moiety by enzyme-mediated or chemical transformation.

[0135] In some embodiments, the prodrug moiety comprises Where G is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl, and J is a bond or a linker comprising a combination of one or more groups selected from the group consisting of: -C(R 1c)2-, -CH=CH-, -C≡C-, -O-, -NR 1c -、-S-、-C(O)-、-C(NR 1c )-, -S(O)- and -S(O)2-, where each R 1c Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.

[0136] In some embodiments, G is a monocyclic arylene or heteroarylene. In some embodiments, G is a phenylene. In some embodiments, G is a bicyclic arylene or heteroarylene.

[0137] In some embodiments, J is a linker comprising a combination of one or more groups selected from: -CH2- (e.g., methylene, ethylene, n-propylene, butylene, etc.), -C(O)-, and -NH-. In some embodiments, J comprises In some embodiments, J is a bond.

[0138] In some embodiments, the prodrug moiety comprises:

[0139] In one aspect, the JAK inhibitor analog is a compound of formula (I):

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein:

[0142] Z is NR a , where R a is H or C1-C6 alkyl;

[0143] R 1 Alkyl or SO2-R 2 , where R 2 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R b )2, and each R b are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring;

[0144] X is O, SO2 or CH2;

[0145] Y is NH, O or CH2;

[0146] W is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C10 Arylene or C4-C 10 Heteroarylene, wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl;

[0147] J' is a bond or a linker comprising a combination of one or more groups selected from: -C(R c )2-, -CH=CH-, -C≡C-, -O-, -NR c -、-S-、-C(O)-、-C(NR c )-, -S(O)- and -S(O)2-, where each R c independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl;

[0148] n is 1, 2, 3, 4, 5 or 6; and

[0149] L' is a cleavable linker.

[0150] In some embodiments, J' comprises a combination of one or more groups selected from: -CH2- (e.g., methylene, ethylene, n-propylene, butylene, etc.), -C(O)-, and -NH-. In some embodiments, J' comprises In some embodiments, p is 0.

[0151] In some embodiments, the JAK inhibitor analog is a compound of Formula (Ia):

[0152]

[0153] or a pharmaceutically acceptable salt thereof, wherein:

[0154] Z is NR a , where R a is H or C1-C6 alkyl;

[0155] R 1 Alkyl or SO2-R 2 , where R 2 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R b )2, and each R b are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring;

[0156] X is O, SO2 or CH2;

[0157] Y is NH, O or CH2;

[0158] n is 1, 2, 3, 4, 5 or 6; and

[0159] L' is a cleavable linker.

[0160] In some embodiments, Z is NH.

[0161] In some embodiments, R 1 SO2-N(R d )2. In some embodiments, each R b are independently C1-C6 alkyl. b is hydrogen, and one R b It is a C1-C6 alkyl group.

[0162] In some embodiments, Z is NH, and R 2 -SO2-N(R b )2.

[0163] In some embodiments, X is O. In some embodiments, Y is O. In some embodiments, X and Y are O.

[0164] In some embodiments, n is 1, 2, or 3.

[0165] In some embodiments, L' comprises Where E 2 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R d ; where R d It is hydrogen or C1-C6 alkyl.

[0166] In some embodiments, E 2 C4-C 10 Arylene or C4-C 10 heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl and -COO-R d, where R d is hydrogen or C1-C6 alkyl. 2 is a monocyclic arylene or heteroarylene group, optionally substituted by -COO-R d Substitution, where R d is hydrogen or C1-C6 alkyl. 1 It is phenylene.

[0167] In some embodiments, L' comprises:

[0168] In some embodiments, L' further comprises a combination of one or more groups selected from: -C(R e )2-, -CH=CH-, -C≡C-, -O-, -NR e -、-S-、-C(O)-、-C(NR e )-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene and heterocyclylene, wherein each R e In some embodiments, the linker further comprises a combination of one or more groups selected from the group consisting of: -CH2-, -O-, -NR e -, arylene and heteroarylene. In some embodiments, L' further comprises

[0169]

[0170] In some embodiments, the JAK inhibitor analog is:

[0171]

[0172]

[0173] or a pharmaceutically acceptable salt thereof.

[0174] In another aspect, disclosed herein is a compound of formula (II):

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein:

[0177] Q is

[0178] Z' is NRc , where R c is H or C1-C6 alkyl;

[0179] R 3 Alkyl or SO2-R 4 , where R 4 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R d )2, and each R d are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R d Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring;

[0180] R 5 is hydrogen, -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3; and

[0181] R 6 It is -OCH3 or -OCH2CH2-OCH3.

[0182] In some embodiments, Z' is NH.

[0183] In some embodiments, R 3 SO2-N(R d )2. In some embodiments, each R d are independently C1-C6 alkyl. 4 is hydrogen, and one R d It is a C1-C6 alkyl group.

[0184] In some embodiments, Z' is NH, and R 3 SO2-N(R d )2. In some embodiments, each R d are independently C1-C6 alkyl. d is hydrogen, and one R d It is a C1-C6 alkyl group.

[0185] In some embodiments, Q is And R 5 It is -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3.

[0186] In some embodiments, Q is R 5 is hydrogen, and R 6 In some embodiments, Q is R 5is -CH2-OCH3, and R 6 In some embodiments, Q is R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 It is -OCH3.

[0187] In some embodiments, Q is R 5 is hydrogen, and R 6 In some embodiments, Q is R 5 is -CH2-OCH3, and R 6 In some embodiments, Q is R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 It is -OCH2CH2-OCH3.

[0188] In some embodiments, the compound of formula (II) is Figure 7 The compound shown, or a pharmaceutically acceptable salt thereof.

[0189] Compounds can exist as stereoisomers, wherein there is an asymmetric or chiral center. A stereoisomer is "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. A single stereoisomer of a compound can be synthesized from commercially available starting materials containing an asymmetric or chiral center, or by preparing a racemic mixture followed by a resolution method well known to those of ordinary skill in the art. Examples of these resolution methods are as follows: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and optionally liberating the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th Edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or its most recent edition), or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0190] It is to be understood that compounds may have tautomeric forms as well as geometric isomers and these also constitute embodiments of the present disclosure.

[0191] The present disclosure also includes isotopically labeled compounds, which are identical to those described in Formula (I), Formula (Ia) or Formula (II), but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as but not limited to, respectively 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36Cl. With heavier isotopes (such as deuterium, e.g. 2 H) substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. The compounds may incorporate positron emitting isotopes for use in medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron emitting isotopes that may be incorporated into the compounds are 11 C. 13 N. 15 O and 18 F. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of a non-isotopically labeled reagent.

[0192] The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt or zwitterion of a compound that is water-soluble or oil-soluble or dispersible, suitable for treating a condition without excessive toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Salts can be prepared during the final separation and purification of the compound, or prepared separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of an acid (such as hydrochloric acid). The resulting salt can be precipitated, separated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, etc. The amino group of the compound can also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, etc.

[0193] Basic addition salts can be prepared by reacting the carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation (such as lithium, sodium, potassium, calcium, magnesium or aluminum), or an organic primary, secondary or tertiary amine during the final isolation and purification of the disclosed compounds. Quaternary ammonium salts such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine and N,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc. can be prepared.

[0194] Compounds can be synthesized according to a variety of methods, including those shown in the examples. The reaction conditions and reaction times of each individual step can vary according to the specific reactants used and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reaction can be carried out in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methods generally known in the art, such as but not limited to crystallization, distillation, extraction, wet grinding and chromatography. Unless otherwise described, starting materials and reagents are commercially available or can be prepared from commercially available materials by those skilled in the art using the methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by a procedure selected from standard organic chemistry techniques, a technique similar to the synthesis of known structurally similar compounds, or a technique similar to the procedure described in the above-mentioned scheme or the Synthesis Example section.

[0195] Routine experiments, including appropriate manipulation of reaction conditions, reagents and synthetic route sequences, protection of any chemical functional groups incompatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method are all included in the scope of the present disclosure. Suitable protecting groups and methods of using such suitable protecting groups to protect different substituents and deprotection are well known to those skilled in the art; examples thereof can be found in PGM Wuts and TW Greene, in Greene's booktitled Protective Groups in Organic Synthesis (4th edition), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present disclosure can be accomplished by methods similar to those described in the synthetic schemes described above and the specific embodiments.

[0196] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using optically active starting materials (e.g., by asymmetric induced preparation by appropriate reaction steps) or by resolving the mixture of stereoisomers of the compounds or intermediates using standard procedures (such as chromatographic separation, recrystallization or enzymatic resolution).

[0197] Similarly, when pure geometric isomers of compounds are required, they may be obtained by carrying out one of the above procedures using the pure geometric isomers as starting materials, or by resolving a mixture of geometric isomers of compounds or intermediates using standard procedures such as chromatographic separation.

[0198] It should be understood that the synthetic schemes and specific examples described are illustrative and should not be construed as limiting the scope of the disclosure as defined in the appended claims. All alternatives, modifications and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0199] 3. Composition

[0200] The disclosed JAK inhibitor analogs may be incorporated into pharmaceutically acceptable compositions. A pharmaceutical composition may include a "therapeutically effective amount" or a "prophylactically effective amount" of one or more JAK inhibitor analogs. A "therapeutically effective amount" refers to an effective amount that achieves the desired therapeutic outcome at the necessary dosage and time period. The therapeutically effective amount of the composition can be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the compounds of the present invention are exceeded by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an effective amount that achieves the desired preventive outcome at the necessary dosage and time period. Typically, since a preventive dose is used on a subject before or in the early stages of the disease, the preventive effective amount will be less than the therapeutically effective amount.

[0201] Pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrin or any type of formulation auxiliary. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as but not limited to lactose, glucose and sucrose; starches, such as but not limited to corn starch and potato starch; cellulose and its derivatives, such as but not limited to sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth; malt; gelatin; talc; excipients, such as but not limited to cocoa butter and suppository waxes; oils, such as but not limited to peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; surfactants, such as but not limited to cremophor EL, cremophor RH 60, Solutol HS15 and polysorbate 80; cyclodextrins, such as but not limited to α-CD, β-CD, γ-CD, HP-β-CD, SBE-β-CD; glycols; such as propylene glycol; esters, such as but not limited to ethyl oleate and ethyl laurate; agar; buffers, such as but not limited to magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, and other non-toxic compatible lubricants, such as but not limited to sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and flavor enhancers, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[0202] The route of administration of the disclosed compounds and the form of the composition will determine the type of carrier to be used. The composition can be in a variety of forms, such as those suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant or parenteral injection) or local administration (e.g., dermal, pulmonary, nasal, otic, ocular, liposome delivery system or iontophoresis).

[0203] Carriers for systemic administration generally include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, cyclodextrins, combinations thereof, etc. All carriers are optional in the composition.

[0204] Suitable diluents include sugars such as glucose, lactose, dextrose and sucrose; glycols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerol; mannitol; and sorbitol. The amount of one or more diluents in a systemic or topical composition is generally about 50% to about 90%.

[0205] Suitable lubricants include silicon dioxide, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter. The amount of one or more lubricants in the systemic or local composition is generally about 5% to about 10%.

[0206] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of one or more binders in the systemic composition is generally from about 5% to about 50%.

[0207] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, cross-linked carboxymethylcellulose, cross-linked povidone, sodium carboxymethyl starch, sodium starch glycolate, clays and ion exchange resins. The amount of one or more disintegrants in the systemic or topical composition is generally from about 0.1% to about 10%.

[0208] Suitable coloring agents include colorants such as FD&C dyes.When used, colorants are generally present in systemic or topical compositions in amounts of from about 0.005% to about 0.1%.

[0209] Suitable flavors include menthol, mint, and fruit flavors.When used, the amount of one or more flavors in the systemic or topical compositions is generally from about 0.1% to about 1.0%.

[0210] Suitable sweeteners include aspartame and saccharin.The amount of one or more sweeteners in the systemic or topical compositions is generally from about 0.001% to about 1%.

[0211] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of one or more antioxidants in the systemic or topical compositions is generally from about 0.1% to about 5%.

[0212] Suitable preservatives include benzalkonium chloride, methylparaben and sodium benzoate.The amount of one or more preservatives in the systemic or topical compositions is generally from about 0.01% to about 5%.

[0213] Suitable glidants include silicon dioxide.The amount of glidant in the systemic or topical composition is generally from about 1% to about 5%.

[0214] Suitable solvents include water, isotonic saline, ethyl oleate, glycerol, hydroxylated castor oil, alcohols such as ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide and phosphate (or other suitable buffers). The amount of one or more solvents in a systemic or topical composition is generally from about 0% to about 100%.

[0215] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, Pa.) and sodium alginate. The amount of one or more suspending agents in the systemic or topical compositions is generally from about 1% to about 8%.

[0216] Suitable surfactants include lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEENS from Atlas Powder Company of Wilmington, Del. Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th edition 1975, pp. 335-337; and McCutcheon, Vol. 1, Emulsifiers & Detergents, 1994, North American edition, pp. 236-239. The amount of one or more surfactants in the systemic or topical composition is generally from about 0.1% to about 5%.

[0217] Suitable cyclodextrins include α-CD, β-CD, γ-CD, hydroxypropyl β-cyclodextrin (HP-β-CD), sulfobutyl ether β-cyclodextrin (SBE-β-CD).The amount of cyclodextrin in the systemic or topical composition is generally from about 0% to about 40%.

[0218] Although the amounts of the components in systemic compositions may vary depending on the type of systemic composition being prepared, in general, systemic compositions include 0.01% to 50% active compound and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% active substance and 90% to 99.9% carriers, including diluents and solvents.

[0219] Compositions for oral administration can have a variety of dosage forms. For example, solid forms include tablets, capsules, granules and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, more particularly about 25% to about 50% of the active substance. Oral dosage form compositions include about 50% to about 95% of a carrier, more particularly, about 50% to about 75%.

[0220] Tablets can be compressed, tablet milled, enteric coated, sugar coated, film coated or multi-compressed. Tablets typically include active ingredients, and carriers containing ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin and sucrose. Specific disintegrants include alginic acid and cross-linked carboxymethyl cellulose. Specific lubricants include magnesium stearate, stearic acid and talc. Specific colorants are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners, such as aspartame and saccharin, or flavors, such as menthol, mint, fruit flavors, or combinations thereof.

[0221] Capsules (including implants, timed release and sustained release formulations) typically include a compound disclosed herein and a carrier of one or more diluents disclosed above in a capsule comprising gelatin. The particles typically include a disclosed compound and preferably a glidant such as silicon dioxide to improve flow characteristics. Implants can be biodegradable or non-biodegradable types.

[0222] The choice of ingredients in the carrier for the oral composition will depend on secondary considerations such as taste, cost and shelf stability, which factors are not critical for the purposes of the present invention.

[0223] Solid compositions can be coated by conventional methods, usually with a pH or time-dependent coating, so that the disclosed compounds are released in the gastrointestinal tract near the desired administration, or at different points and times to prolong the desired effect. The coating generally includes one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0224] Compositions for oral administration can have liquid form.For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions redissolved by non-effervescent granules, suspensions redissolved by non-effervescent granules, effervescent preparations redissolved by effervescent granules, elixirs, tinctures, syrups, etc.Liquid oral administration compositions generally include disclosed compounds and carriers, i.e., carriers selected from diluents, colorants, spices, sweeteners, preservatives, solvents, suspending agents and surfactants.Oral liquid compositions preferably include one or more components selected from colorants, spices and sweeteners.

[0225] Other compositions that can be used to achieve systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials, such as diluents, including sucrose, sorbitol and mannitol; and binders, such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Such compositions may also include lubricants, colorants, flavors, sweeteners, antioxidants and glidants.

[0226] The compositions disclosed herein may further comprise at least one additional therapeutic agent. At least one additional therapeutic agent may include immunosuppressants (e.g., azathioprine, mercaptopurine, cyclosporine, tacrolimus, and methotrexate), anti-inflammatory agents (e.g., corticosteroids and aminosalicylate), chemotherapeutic agents, immunotherapy, antibiotics, antidiarrheals, and analgesics.

[0227] 4. Usage

[0228] The present disclosure also provides a method for treating a disease or condition, comprising administering a compound as disclosed herein (e.g., a JAK inhibitor analog) or a composition thereof to a subject in need thereof. In some embodiments, the JAK inhibitor analog is a compound of formula (I), formula (Ia), or formula (II). In some embodiments, the JAK inhibitor analog is

[0229] or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human.

[0230] The disease or disorder may be selected from cancer, autoimmune disease and inflammatory disease.

[0231] In some embodiments, the disease or condition is an inflammatory disease or condition. The feature of inflammatory diseases is that the immune system in tissues or organs is activated to abnormal levels, which may cause tissue or organ dysfunction and / or disease. Inflammatory diseases and conditions that can be treated by the methods of the present invention include but are not limited to arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu's arteritis or Behcet's syndrome), inflammatory neuropathy, psoriasis, systemic lupus erythematosus (SLE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjögren's syndrome or Churg-Strauss syndrome.

[0232] In some embodiments, the disease or disorder is an autoimmune disease or disorder.Autoimmune diseases and disorders refer to conditions in a subject characterized by damage to cells, tissues, and / or organs caused by an immune response of the subject to its own cells, tissues, and / or organs. Autoimmune diseases and conditions treatable by the methods of the invention include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Tschag-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), irritable bowel syndrome (IBD), IgA neuropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, myotonia solium, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis such as dermatitis herpetiformis vasculitis, vitiligo, and Wegener's granulomatosis.

[0233] Some autoimmune disorders are also associated with inflammatory diseases. Examples of inflammatory disorders that are also autoimmune disorders that can be prevented, treated or managed according to the methods of the present invention include, but are not limited to, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergic disorders, pulmonary fibrosis, undifferentiated spondyloarthropathies, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation caused by chronic viral or bacterial infections. Examples of psoriasis types that can be treated according to the compositions and methods of the present invention include, but are not limited to, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis, and inverse psoriasis.

[0234] In some embodiments, the disease or condition is a gastrointestinal inflammatory disease or condition. These diseases or conditions include, for example, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, indeterminate colitis, and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis, and proctitis), necrotizing enterocolitis, and esophagitis. In general, gastrointestinal inflammatory diseases or conditions include any disease or condition that causes inflammation and / or ulcers in the gastrointestinal mucosa.

[0235] In some embodiments, the disease or condition is cancer. In some embodiments, cancer comprises solid tumors. In some embodiments, cancer comprises blood cancer or lymphoma. In some embodiments, cancer is metastatic cancer. In some embodiments, the disclosed compounds, compositions or methods result in the elimination of inhibition of metastasis. In some embodiments, the disclosed compounds, compositions or methods result in a reduction in tumor growth. In some embodiments, the disclosed compounds, compositions or methods prevent tumor recurrence.

[0236] The compounds and compositions herein can be used to treat various cancers, including carcinomas, sarcomas, lymphomas, leukemias, melanomas, mesotheliomas, multiple myeloma, or seminoma. The cancer can be bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon / rectum cancer, endometrial cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymph node cancer, muscle tissue cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer, thyroid cancer, or uterine cancer.

[0237] In some embodiments, the cancer is an invasive and / or metastatic cancer (e.g., stage II cancer, stage III cancer, or stage IV cancer). In some embodiments, the cancer is an early stage cancer (e.g., stage 0 cancer, stage I cancer), and / or is not an invasive and / or metastatic cancer.

[0238] JAK inhibitor analogs or compositions thereof can be administered to subjects by a variety of methods. In any use or method described herein, it can be administered by various routes known to those skilled in the art, including but not limited to oral, inhaled, intravenous, intramuscular, topical, subcutaneous, systemic and / or intraperitoneal administration to subjects in need. In some embodiments, JAK inhibitor analogs or compositions thereof as disclosed herein can be administered by oral administration.

[0239] The amount of the JAK inhibitor analog or composition thereof disclosed herein required for treatment or prevention will vary not only with the specific compound selected, but also with the route of administration, the nature and / or symptoms of the disease, and the age and condition of the patient, and will ultimately be determined by the attending physician or clinician. The determination of the effective dose level (i.e., the dose level required to achieve the desired result) can be accomplished by those skilled in the art using conventional methods (e.g., human clinical trials, in vivo studies, and in vitro studies). For example, the useful dose of a JAK inhibitor analog or composition thereof can be determined by comparing its in vitro activity with its in vivo activity in an animal model.

[0240] The amount and interval of the dosage can be adjusted individually to provide a plasma level of the active part sufficient to maintain the modulatory effect, or the minimum effective concentration (MEC). The MEC of each compound will vary, but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90%, and most preferably between 50-90%. In the case of local administration or selective uptake, the effective local concentration of the drug may be independent of the plasma concentration.

[0241] It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunction. Conversely, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. In the management of the condition of interest, the size of the administered dose will vary with the severity of the symptoms to be treated and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, weight and response of the individual patient. Comparable procedures to those discussed above can be used in veterinary medicine.

[0242] The JAK inhibitor analogs disclosed herein or compositions thereof can be evaluated for their efficacy and toxicity using known methods. For example, the toxicology of a specific compound, a subset of compounds sharing certain chemical moieties, or a composition comprising a JAK inhibitor analog can be established by determining the in vitro toxicity to a cell line (such as a mammal, and preferably a human cell line). The results of such studies can generally predict the toxicity in an animal (such as a mammal or more specifically, a human). Alternatively, the toxicity of a specific compound in an animal model, such as a mouse, rat, rabbit, dog, or monkey model, can be determined using known methods. The efficacy can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine the efficacy, those skilled in the art can select an appropriate model, dosage, route of administration, and / or regimen under the guidance of the prior art.

[0243] A variety of second therapies can be used in combination with the compounds and methods of the present disclosure. The second therapy can be the administration of an additional active agent, or can be a second therapy unrelated to the administration of another agent. Such second therapies include, but are not limited to, surgery, immunotherapy, radiotherapy.

[0244] The second therapy can be administered simultaneously with the initial therapy, or in the same composition, or in a separate composition that is administered substantially simultaneously with the first composition. In some embodiments, the second therapy can precede or follow treatment with the first therapy with a time interval ranging from a few hours to several months.

[0245] A therapeutically effective amount of a JAK inhibitor analog or compound disclosed herein, or a composition thereof, can be administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, effective combination therapy is achieved by a single composition or pharmacological formulation comprising two agents, or two different compositions or formulations administered simultaneously, wherein one composition comprises a compound of this invention and the other comprises one or more second agents.

[0246] The at least one additional therapeutic agent may include immunosuppressants (eg, azathioprine, mercaptopurine, cyclosporine, tacrolimus, and methotrexate), anti-inflammatory agents (eg, corticosteroids and aminosalicylates), chemotherapeutic agents, immunotherapy, antibiotics, antidiarrheals, and analgesics.

[0247] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent.As used herein, the term "chemotherapeutic drug" or "anti-cancer drug" includes any small molecule or other drug used for cancer treatment or prevention. Chemotherapeutic drugs include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemaciclib, everolimus, apellis, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, imatinib, lapatinib, olaparib, megestrol acetate, neratinib, palbociclib, ribociclib, talazopanib, thiotepa, toremifene, methotrexate and tucatinib. In selected embodiments, the chemotherapeutic agent comprises paclitaxel.

[0248] In some embodiments, the second therapy comprises immunotherapy. Immunotherapy includes chimeric antigen receptor (CAR) T cells or T cell transfer therapy, cytokine therapy, immunomodulators, cancer vaccines, or administration of antibodies (e.g., monoclonal antibodies).

[0249] In some embodiments, immunotherapy includes administering antibodies. Antibodies can target antigens specifically expressed by tumor cells or antigens shared with normal cells. In some embodiments, immunotherapy may include antibodies targeting, for example, CD20, CD33, CD52, CD30, HER (also known as erbB or EGFR), VEGF, CTLA-4 (also known as CD152), epithelial cell adhesion molecule (EpCAM, also known as CD326), and PD-1 / PD-L1. Suitable antibodies include, but are not limited to, rituximab, blinatumomab, trastuzumab, gemtuzumab, alemtuzumab, ibritumomab, tositumomab, bevacizumab, cetuximab, panitumumab, ofatumumab, ipilimumab, brentuximab, pertuzumab, etc.). In some embodiments, the additional therapeutic agent may comprise an anti-PD-1 / PD-L1 antibody, including but not limited to pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab. The antibody may also be linked to a chemotherapeutic agent. Thus, in some embodiments, the antibody is an antibody-drug conjugate.

[0250] Immunotherapy (e.g., administration of antibodies) can be administered to a subject by a variety of methods. In any of the uses or methods described herein, it can be administered by various routes known to those skilled in the art, including but not limited to oral, inhaled, intravenous, intramuscular, topical, subcutaneous, systemic and / or intraperitoneal administration to subjects in need. In some embodiments, immunotherapy can be administered in the same or different manner as a JAK inhibitor analog or a composition thereof. Immunotherapy can be administered by parenteral administration (including but not limited to subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac and intraarticular injection).

[0251] 5. Kit

[0252] In another aspect, the present disclosure provides a kit comprising at least one disclosed JAK inhibitor analog or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof, and instructions for using the compound or composition.

[0253] The kit may also include other agents and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, doctor, pharmacy, or pharmacist may provide a kit comprising a disclosed compound and / or product and another agent (e.g., a chemotherapeutic, a monoclonal antibody, an analgesic, an immunosuppressant, an anti-inflammatory, an antibiotic, an antidiarrheal) for delivery to a patient.

[0254] The kit may also include instructions for using the kit components. Instructions are related materials or methods related to the kit. Materials may include any combination of background information, component lists, brief or detailed schemes for using the composition, problem solving, references, technical support, and any other related documents. Instructions may be provided with the kit or as separate element components (as written or electronic form that can be provided on a computer-readable storage device or downloaded from an Internet website), or as a recorded demonstration.

[0255] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, etc. The various member components of the kit can be physically packaged together or individually packaged.

[0256] 6. Examples

[0257] Abbreviations used in the following schemes and examples are: DCE is dichloroethane; DMA is dimethylacetamide; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; HCl is hydrochloric acid; iPrOH is isopropanol; MeOH is methanol; Pd / C is palladium on carbon; and rt is room temperature.

[0258] All commercially available products and solvents were purchased from Sigma-Aldrich, AK Scientific, and Fisher Scientific. Solvents were used as received or filtered through molecular sieves Drying. All water or air sensitive reactions were carried out under argon atmosphere, dry solvents and anhydrous conditions. All reactions were monitored by thin layer chromatography (TLC) performed on aluminum backed silica plates (0.2 mm, 60F254). Flash chromatography purification was performed on Merck silica gel 60 (230-400 mesh). Unless otherwise stated, yields refer to chromatographic and spectral (1H NMR) homogeneous material.

[0259] NMR spectra were recorded on a Bruker instrument (500 or 300 MHz) and calibrated using the solvent peak as an internal reference. Spectra were processed using MestReNova software. Chemical shift δ is in ppm, and coupling constants (J) are in Hz. Peak multiplicity is described as follows: s is a singlet, t is a triplet, and m is a multiplet. High resolution mass spectra were obtained on an AB Sciex X500R QTOF mass spectrometer or an AB Sciex 6600+Triple TOF mass spectrometer. The purity of all compounds tested biologically was determined by analytical HPLC and found to be > 95%.

[0260] Example 1

[0261] Compound synthesis

[0262] Compound MMT3-72 was designed using the fedratinib scaffold ( Figure 1A Fedratinib is a semi-selective JAK2 inhibitor. Fedratinib inhibits JAK2 (IC 50 15nM), and it also inhibited JAK1 (IC 50 10 nM) and TYK2 (IC 50 178nM). JAK2 and TYK2 are JAK isoforms involved in IL-12 / IL-23 signaling, and inhibition of IL-12 / IL-23 (such as the antibody Ustekinumab) is effective for the treatment of UC. After a single oral dose, most (77%) of Fedratinib is excreted into the feces of the GI tract (23% is unchanged drug).

[0263] In MMT3-72, the solvent-exposed pyrrolidine moiety of fedratinib is replaced by 5-aminosalicylic acid (5-ASA) linked to N-4-(aminobenzoyl)-β-alanine via an azo bond. The azo bond can be cleaved by colonic bacteria to release the active metabolite in the GI tract, which is absorbed and accumulated in colonic tissue with minimal exposure to the systemic circulation.

[0264] Compounds MMT3-72 and MMT3-72-M2 were synthesized according to the synthetic route shown in Scheme 1. In short, 4-nitrophenol was condensed with DCE or 2-chloroethanol to generate intermediates 1 and 4, respectively. Intermediates 1 and 4 were subsequently reduced with tin chloride or nitrohydride to give intermediates 2 and 5, respectively. Then, intermediates 2 or 5 were coupled with N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide in an isopropanol solution with a few drops of HCl to generate compounds 3 and MMT3-72-M2, respectively. Finally, compound 3 was subjected to a nucleophilic substitution reaction with balsalazide disodium salt dihydrate to produce the desired compound MMT3-72.

[0265] Scenario 1:

[0266]

[0267] a Reaction conditions: (a) DCE, K2CO3, DMF, 100°C, 6h and 92%; (b) SnCl2.2H2O, EtOH, rt, overnight and 63%; (c) Concentrated HCl, iPrOH, 80°C and 79-84%; (d) Balsalazide disodium, K2CO3, DMF, 100°C, 6h and 68%; (e) 2-chloroethanol, NaOH, H2O, 8h, 80°C and 79%. (f) H2, Pd / C, MeOH, 50°C, overnight and 76%.

[0268] N-(tert-butyl)-3-((2-((4-(2-hydroxyethoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (MMT3-72-M2): To a mixture of compound 5 (130 mg, 0.846 mmol, 3 eq.) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (100 mg, 0.282 mmol) in isopropanol (2 mL) were added 3 drops of 37% concentrated HCl, and the reaction mixture was stirred at 80° C. overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was taken up in NaHCO aqueous solution and extracted three times with CH Cl. The combined organic phases were washed with water, brine and dried over Na SO. The solvent was concentrated in vacuo and the solid obtained was washed three times with EtOAc to provide compound MMT3-72-M2 (105 mg, 79% yield).

[0269] 1 H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.55(s,1H),8.12(d,J=3.4Hz,2H),7.90(s,1H),7.62–7.39(m ,4H),6.80(d,J=8.9Hz,2H),3.92(t,J=5.1Hz,2H),3.69(t,J=5.0Hz,2H),2.12(s,3H),1.12(s,9H). HRMS(ESI):C 23 H 29 Calculated mass of N5O4S 471.58; experimental m / z 472.1847 [M+H]+.

[0270] The synthesis and characterization of compounds 1 and 4 have been described previously (see, Luo, et al., Bioorg Med Chem Lett 2017, 27(12), 2668-2673).

[0271] 1-(2-Chloroethoxy)-4-nitrobenzene (1): To a mixture of 4-nitrophenol (4 g, 28.754 mmol) and 1,2-dichloromethane (20 mL, 5 vol) in DMF (25 mL) was added KCO (6 g, 43.131 mmol, 1.5 eq) and the resulting mixture was stirred at 100 °C for 6 h and monitored by TLC. After completion, the reaction mixture was quenched with water and the product was extracted three times with CHCl. ​​The combined organic phase was washed with water, brine, dried over NaSO and concentrated under vacuum to afford compound 1 (5.35 g; yield, 92%). This intermediate was used directly in the next step without further purification.

[0272] 4-(2-Chloroethoxy)aniline (2): To a mixture of compound 1 (1 g, 4.96 mmol) in EtOH (30 mL) was added SnCl2.2H2O (4.5 g, 19.84 mmol, 4 equiv.), and the reaction mixture was stirred at 90°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was taken up in a 5% NaOH aqueous solution and extracted three times with CH2Cl2. The combined organic phases were washed with a 5% NaOH aqueous solution, water, brine and dried over Na2SO4. The solvent was concentrated in vacuo and the residue was purified by silica gel column chromatography to provide compound 2 (532.4 mg, 63% yield).

[0273] 1 H NMR (500MHz, CDCl3) δ6.82–6.69(m,2H), 6.69–6.58(m,2H), 4.16(t,J=5.9Hz,2H), 3.77(t,J=5.9Hz,2H). HRMS(ESI):C8H 10 Calculated mass of ClNO 171.05; observed m / z 172.0425 [M+H]+.

[0274] N-(tert-butyl)-3-((2-((4-(2-chloroethoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (3): To a mixture of compound 2 (400 mg, 2.330 mmol, 2 eq.) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (413.53 mg, 1.165 mmol) in isopropanol (8 mL) were added 3 drops of 37% concentrated HCl and the reaction mixture was stirred at 80 °C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was taken up in NaHCO aqueous solution and extracted three times with CHCl. ​​The combined organic phases were washed with water, brine and dried over NaSO. The solvent was concentrated in vacuo and the solid obtained was washed three times with EtOAc to afford compound 3 (482 mg, 84% yield).

[0275] 1 H NMR (500MHz, DMSO-d6) δ8.82(s,1H),8.55(s,1H),8.12(d,J=5.6Hz,2H),7.91(d,J=1.0Hz,1H),7.56(d,J=4.3Hz,2H) ,7.51–7.45(m,2H),6.87–6.80(m,2H),4.18(d,J=6.0Hz,2H),3.92(d,J=5.9Hz,2H),2.16–2.06(m,3H),1.12(s,9H). HRMS(ESI):C 23 H 28 Calculated mass of ClN5O3S 489.16; experimental m / z 490.1506 [M+H]+.

[0276] 2-(4-Nitrophenoxy)ethane-1-ol (4): To a mixture of 4-nitrophenol (3 g, 21.56 mmol) and 2-chloroethanol (2.89 mL, 43.16 mmol, 2 eq.) in H2O (10 mL) was added NaOH (1.73 g, 43.16 mmol, 2 eq.) and the reaction mixture was stirred at 80°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with H2O and extracted three times with EtOAc. The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was concentrated in vacuo to give compound 4 (3.1 g, 79% yield), which was used in the next step without further purification.

[0277] 2-(4-Aminophenoxy)ethane-1-ol (5): To a mixture of compound 4 (1 g, 5.460 mmol) in MeOH (20 mL) was added Pd / C (0.1 g, 10% equiv.), and the reaction mixture was stirred overnight at 50 °C under H2 atmosphere. After completion of the reaction, Pd / C was filtered off on celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 5 (635.2 mg, 76% yield).

[0278] 1 H NMR (300MHz, CDCl3) δ6.82–6.72(m,2H), 6.70–6.59(m,2H), 4.01(dd,J=5.1,3.5Hz,2H), 3.92(dd,J=5.1,3.5Hz,2H). HRMS(ESI):C8H 11 The calculated mass of NO2 is 153.18; the experimental m / z value is 154.0770 [M+H]+.

[0279] (E)-2-(2-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)ethoxy)-5-((4-((2-carboxyethyl)carbamoyl)phenyl)diazenyl)benzoic acid (MMT3-72): To a mixture of compound 3 (45 mg, 0.09 mmol, 1.5 eq.) and balsalazide disodium salt dehydrate (27.29 mg, 0.068 mmol, 1 eq.) in DMF (2 mL) was added KCO (37.6 mg, 0.272 mmol, 4 eq.) and the resulting mixture was stirred at 100 °C overnight and monitored by TLC. After completion, the solvent was evaporated under reduced pressure. The residue was taken up in H0 and the solution was acidified with HPO until pH was 2-3. The precipitate was filtered and recrystallized from CH2Cl2 to provide the desired compound MMT3-72 (50.4 mg, 68%).

[0280] 1H NMR (500MHz, DMSO-d6) δ8.68(s,1H),8.29(s,1H),8.08(s,2H),7.96(d,J=8.3Hz, 2H),7.88(d,J=10.5Hz,2H),7.82(d,J=8.3Hz,2H),7.57(s,1H),7.49(t,J=14.4Hz ,4H),6.86(d,J=9.7Hz,1H),6.80(d,J=8.5Hz,2H),4.36(t,J=4.5Hz,2H),4.13(t, J=4.8Hz,2H),3.61–3.48(m,2H),2.66(t,J=6.9Hz,2H),2.11(s,3H),1.11(s,9H). HRMS(ESI):C 40 H 42 The calculated mass of N8O9S is 810.2; the experimental m / z value is 811.2758 [M+H]+.

[0281] Compounds MMT3-83, MMT3-84 and MMT3-85 were synthesized according to the synthetic route shown in Scheme 2. Compound MMT3-56 was synthesized by a method similar to that shown for MMT3-83. Compounds MMT3-73 and MMT3-79 were synthesized according to a method similar to that shown for MMT3-72. Compounds MMT3-89 and MMT3-90 were synthesized according to a method similar to that shown for MMT3-84 and MMT3-85.

[0282] Scenario 2:

[0283]

[0284] Reaction conditions: (a) Na2CO3, 6h, 50℃ and 88%; (b) DCE, K2CO3, DMF, 6h, 100℃ and 97%; (c) SnCl2.2H2O, EtOH, overnight and 55%; (d) concentrated HCl, isopropanol, at 80℃ overnight and 62%; (e) DMA, 20h and 90℃ and 79%; (f) pyrrolidine, DMA, 20h, 90℃ and 83%; (g) DMA, 20h, 90℃ and 80%.

[0285] Step 1. A solution of 2-(chloromethyl)-4-nitrophenol (0.25 g; 1.33 mmol) in 5 mL of 2-methoxyethanol or an appropriate alcohol was heated to 50° C. and stirred under argon. Sodium bicarbonate (0.23 g; 2.66 mmol, 2 eq.) was gradually added over 1 h, and the reaction was allowed to proceed at 50° C. for 7 h. After the reaction was complete, the excess NaHCO3 was removed by filtration, the alcohol was evaporated, and the product was crystallized from ethyl acetate (yield 88-97%).

[0286] Step 2. To a mixture of the intermediate obtained in step 1 (1.95 g; 7.03 mmol) and 1,2-dichloromethane (10 mL, 5 volumes) in DMF (25 mL) was added KCO (1.46 g, 10.55 mmol, 1.5 equiv), and the resulting mixture was stirred at 100 ° C for 6 h and monitored by TLC. After completion, the reaction mixture was quenched with water and the product was extracted three times with CHCl. ​​The combined organic phases were washed with water, brine, dried over NaSO and concentrated under vacuum to give the product (1.97 g; yield, 97%). This intermediate was used directly in the next step without further purification.

[0287] Step 3. Add SnCl to the mixture of the intermediate (1g, 3.45mmol) obtained in step 2 in EtOH (30mL) .2H O (3.11g, 13.807mmol, 4 equivalents), and the reaction mixture is stirred overnight at 90°C. After the reaction is complete, the solvent is evaporated under reduced pressure, and the residue is absorbed in the 5% NaOH aqueous solution and extracted three times with CH Cl. The organic phases merged are washed with 5% NaOH aqueous solution, water, brine and dried over Na SO. The solvent is concentrated in vacuo and the residue is purified by silica gel column chromatography to provide product (0.5g, 55% yield).

[0288] Step 4. To the mixture of the intermediate obtained in step 3 (450 mg, 1.73 mmol, 2 eq) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (307 mg, 0.86 mmol) in isopropanol (8 mL) was added 3 drops of 37% concentrated HCl, and the reaction mixture was stirred at 80°C overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was absorbed into a NaHCO3 aqueous solution and extracted three times with CH2Cl2. The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was concentrated in vacuo and the solid obtained was washed three times with EtOAc to provide the product (311.7 mg, 62% yield).

[0289] Step 5. To a mixture of the intermediate obtained in step 4 (80 mg, 0.138 mmol) in DMA (2 mL) was added appropriate amine (2 volumes) and the reaction mixture was stirred overnight at 90° C. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford the product (yield 80-95%).

[0290] Example 2

[0291] GI local activation of MMT3-72 and identification of metabolites in GI contents, GI tissues, and plasma

[0292] Materials and methods

[0293] Activated MMT3-72 and metabolite identification: In vivo metabolite identification was performed using mouse plasma, colon and fecal samples collected 6 h after oral administration of MMT3-72 (10 mg / kg). Liquid chromatography tandem mass spectrometry was used to separate and identify possible metabolites. The LC-MS / MS method consisted of a Shimadzu LC-20AD HPLC system (Kyoto, Japan). MMT3-72 and its metabolites were chromatographically separated using a Waters XBridage reversed-phase C18 column (15 cm×2.1 mm ID, filled with 3.5 μm). The accurate molecular weight was confirmed using a high-resolution AB Sciex X500R QTOF mass spectrometer (AB Sciex, Farmingham, USA) in positive ion information-dependent acquisition (IDA) mode. The recorded mass range was from m / z 100 to 1000 Da. For TOFMSMS, the collision energy was set to 50 V. Data were collected using the software SCIEX OS and then processed using the software MetabolitePilot 2.0 (AB Sciex, Farmingham, USA).

[0294] Inhibition of in vitro activity of JAK enzymes: JAK1, JAK2, JAK3, and TYK2 assay kits were obtained from BPS Bioscience (San Diego, CA, USA). The assay was performed in a 96-well microplate according to the manufacturer's protocol. Briefly, a master mix (25 μL / well) was prepared for JAK1 and TYK2 assays (6 μL 5x kinase assay buffer + 1 μL ATP (500 μM) + 5 μL x10 IRS1-tide + 13 μL distilled water), or for JAK2 and JAK3 assays (6 μL 5x kinase assay buffer + 1 μL ATP (500 μM) + 1 μL PTK substrate Poly (Glu: Tyr 4: 1) (10 mg / mL) + 17 μL distilled water). Then 5 μL of Fedratinib, MMT3-73-72, MMT3-72-M2 solution was added to the master mix prepared above at different concentrations, and then 20 μL of enzyme (JAK1 at 5 ng / μL, JAK2 at 2.5 ng / μL, JAK3 at 0.4 ng / μL or TYK2 at 0.5 ng / μL) was added. The reaction mixture was incubated at 30°C for 40 minutes. Finally, 50 μL of Kinase-Glo Max reagent (Promega, Madison, WI, USA) was added to each well, and the reaction was carried out for 15 minutes under dark conditions at room temperature. The luminescence of the reaction mixture was read on a Synergy 2 microplate reader (Biotek).

[0295] LC-MS analysis of MMT3-72 and MMT3-72-M2 in biological samples: MMT3-72 and MMT3-72-M2 concentrations in plasma (ng / ml) and tissues (ng / g) were determined by an LC-MS / MS method developed and validated for this study. The HPLC method was performed on a Shimadzu LC-20AD HPLC system (Kyoto, Japan), and chromatographic separation was achieved using a Waters XBridage reverse phase C18 column (5 cm×2.1 mm ID, packed with 3.5 μm). The gradient elution had a flow rate of 0.4 ml / min and mobile phases A (purified deionized water containing 0.1% formic acid) and B (acetonitrile containing 0.1% formic acid). Detection was performed using an AB Sciex QTrap 4500 mass spectrometer (AB Sciex, Farmingham, USA) in positive ion multiple reaction monitoring (MRM) mode. Protonated molecular ions and corresponding ion products were monitored at the transitions of m / z 811.3>737.4 for MMT3-72 and m / z 472.3>416.0 for MMT3-72-M2. Data processing was performed using the software Analyst (version 1.6).

[0296] Mouse pharmacokinetics. In brief, 10 mg / kg MMT3-72 was orally administered to C57BL / 6 female mice. Mice were killed at 0.5, 2, 4, 12, and 24 h, and blood samples were drawn directly from the heart. Intestinal tissue samples were collected and homogenized to 10% homogenate in PBS. The contents of the small intestine and large intestine were collected and homogenized in PBS. Subsequently, the concentrations of MMT3-72, MMT3-72-M2, and 5-ASA in plasma, intestinal tissue, and intestinal contents were determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis using the above method.

[0297] In vivo efficacy of MMT3-72 in treating DSS-induced colitis in mice: 6-8 week-old C57BL / 6 female mice were purchased from Charles River Laboratories and randomly divided into different treatment groups. Acute colitis was induced by applying 3% DSS (MP Biomedicals, CA, USA) in distilled water for 5 consecutive days, and the control group received purified water (Snider, et al., Methods Mol Biol 2016, 1438, 245-254). MMT3-72 or tofacitinib was dissolved in β-cyclodextrin. The drug was orally administered by gavage every other day in an amount of 0.1 mL / 10 g body weight. During the model establishment period, body weight, stool consistency, and total blood volume in feces were monitored and recorded daily. After 5 days, mice were killed and blood was collected. Serum was obtained by centrifugation and stored at -80 ° C for further immunoassays. The colon was removed and the length was measured.

[0298] H&E staining of colon tissue: After dissection and transecting the colon, the cannula was cannulated using a feeding needle and a 5 ml syringe, and the colon was flushed using ice-cold PBS until the stool was flushed out. The colon was cut longitudinally from the distal to the proximal end using scissors, and the colon tissue was then unfolded into a flat plate. A pair of forceps was used to grasp the edges of the distal colon and the colon tissue was rotated into a Swiss roll. The roll was firmly grasped with a 27G 1 / 2 needle and transected. The sample was then placed in 4% paraformaldehyde fixative (ThermoScientific, USA) and left at room temperature for 24 hours. The Swiss roll was then paraffin-embedded, sectioned, mounted and stained with H&E to determine the extent of colon damage from the distal (inner end) to the proximal (outer end).

[0299] GI local activation of MMT3-72 and identification of metabolites in GI contents, GI tissues, and plasma

[0300] To confirm the activation of MMT3-72 in the colon, mice were orally administered with 10 mg / kg MMT3-72 and sacrificed 6 h later to collect plasma, colon tissue, and colon contents (feces). Five metabolites (M1 to M5) were identified in the collected samples, and their structures are shown in Figure 2 Shown. Interestingly, MMT3-72 was only detected in feces, but not in plasma and colon tissue. The main metabolite MMT3-72-M2 was only detected in colon tissue and feces, and had lower levels in plasma. The remaining four minor metabolites M1, M3, M4 and M5 were only identified in feces and were not detected in plasma and colon tissue. Since MMT3-72-M2 is the main metabolite and accumulates in colon tissue, MMT3-72-M2 was synthesized according to the synthetic route shown in Scheme 1 to test its activity in inhibiting JAK1-3 and TYK2 (Table 1).

[0301] MMT3-72 is less active, but MMT3-72-M2 is more potent, against JAK1, 2, and TYK2 by in vitro kinase assays

[0302] The biological activities of MMT3-72 and its active metabolite MMT3-72-M2 against JAK1, JAK2, JAK3, and TYK2 were evaluated using kinase assays. Figure 3 , Table 1). Compound MMT3-72 showed moderate inhibitory activity against JAK1 and JAK2 (199.3 nM and 448.3 nM, respectively), and poor inhibitory activity against JAK3 and TYK2 (6821 nM and 2976 nM, respectively). However, the active metabolite MMT3-72-M2 showed strong inhibitory activity against JAK1 (2.0 nM), JAK2 (16.3 nM), and TYK2 (55.2 nM), but only weak inhibitory activity against JAK3 (701.3 nM). In contrast, Fedratinib strongly inhibited JAK1 (10.1 nM) and JAK2 (15.6 nM), but weakly inhibited JAK3 and TYK2. The inhibitory profile of MMT3-72-M2 against JAK1, 2, and TYK2 may be advantageous for the treatment of UC, as JAK2 / TYK2 / IL-12 / IL-23 signaling is closely associated with UC, and the JAK1 isoform has long been identified as a potential target for the treatment of IBD, as seen with upadacitinib. In addition, MMT3-72-M2 exhibits poor inhibitory activity against JAK3, which is also preferred in the treatment of UC to reduce undesirable adverse reactions. Tofacitinib inhibits JAK3 with an IC50 of 1.6 nM and exhibits severe adverse reactions. JAK3 inhibition has been shown to potentially cause lymphopenia and, therefore, is presumed to increase the risk of infection.

[0303] Table 1. In vitro inhibitory activity (IC50) of MMT3-72 and its active metabolite MMT3-72-M2 against different JAK isoforms

[0304]

[0305] MMT3-72 is activated locally in the GI tract to release the active metabolite MMT3-72-M2, thereby achieving high exposure in GI tissues and minimizing exposure in plasma.

[0306] To investigate the GI local activation and pharmacokinetics of MMT3-72 and its active metabolite MMT3-72-M2 in vivo, mice were orally administered with 10 mg / kg MMT3-72 and sacrificed at different time points from 0 to 24 hr to collect tissues. Figure 4A It is shown that high concentrations (Cmax>50,000 ng / g) of the compound MMT3-72 were observed in GI contents (including gastric contents, small intestinal contents, and colonic contents). However, MMT3-72 was not detected in small intestinal tissues, colonic tissues, or systemic circulation. In contrast, high levels of the active metabolite MMT3-72-M2 (Cmax>1500 ng / g) were detected in colonic tissues and small intestinal tissues ( Figure 4B At 24 hr, the Cmin in small and large intestinal tissues was 88.5 ng / ml, which was higher than the IC of inhibiting JAK1, JAK2, and TYK2-related targets for the treatment of UC. 50 In contrast, MMT3-72-M2 inhibited JAK3 at concentrations below the IC at 10-24 hr. 50 In addition, the concentration of MMT3-72-M2 in plasma was minimal (Cmax 8 ng / ml) and was undetectable after 4 hr. In addition, MMT3-72 was activated more in the colon than in the small intestine to release MMT3-72-M2, because the MMT3-72-M2 in the colon content was 10 times that in the small intestine ( Figure 4C These results showed that: (1) MMT3-72 was not absorbed into the systemic circulation, but was retained in the GI tract and activated mainly in the colon to release the active metabolite MMT3-72-M2; (2) the active metabolite MMT3-72-M2 accumulated in large amounts in colonic and small intestinal tissues and could inhibit JAK1, JAK2, and TYK2 due to its therapeutic effects; (3) MMT3-72 was undetectable in the systemic circulation, and only a low level of the active metabolite MMT3-72-M2 was detected, which has the potential to avoid the systemic toxicity of JAK inhibitors.

[0307] It is worth noting that the design of MMT3-72 is very different from that of Izencitinib (TD-1473), which reduces absorption potential to limit systemic exposure but has no local activation mechanism. The design of drugs such as TD-1473 that only reduce absorption potential but have no activation mechanism will reduce the permeability of the drug in colon tissue, limiting its effectiveness in human trials. In contrast, MMT3-72 is designed to not only reduce GI absorption potential, but also have local activation properties to release the active form of MMT3-72-M2, which can easily penetrate colon tissue, reach therapeutic concentrations in colon tissue, while minimizing drug exposure in the systemic circulation.

[0308] MMT3-72 showed excellent efficacy in treating UC in mice.

[0309] To evaluate the efficacy of MMT3-72 in treating UC in vivo, a colitis model was established in mice using dextran sulfate sodium (DSS). DSS in drinking water can induce colitis in mice. The DSS-induced colitis model is widely used because it is relatively easy to manage and highly similar to human UC. In this study, mice treated with 3% DSS water developed colitis symptoms such as bloody stools and diarrhea on day 5. The disease activity index (DAI) was monitored for disease severity in mice: normal stool consistency and negative for occult blood: score 0; soft stool and positive for occult blood: score 1; very soft stool with blood stains: score 2; watery stool with visible rectal bleeding: score 3. To evaluate the efficacy of MMT3-72 in combination with the FDA-approved JAK inhibitor (tofacitinib) for the treatment of UC, mice were treated orally with 1 mg / kg and 5 mg / kg of the two drugs ( Figure 5A , 5C and 5D). Compared with DSS-induced colitis, MMT3-72 (5 mg / kg) increased the DAI score 5-fold, while tofacitinib (5 mg / kg) did not show any improvement in the DAI score ( Figure 5A In the MMT3-72 (5 mg / kg) treatment group, no mice developed severe colitis, and only 10% of the mice (n=10) developed moderate colitis ( Figure 5C and 5D In contrast, in the tofacitinib-treated group (5 mg / kg), 40% of mice (n=10) developed severe colitis and 80% of mice developed moderate colitis ( Figure 4C , 4D). Low doses (1 mg / kg) of MMT3-72 (1 mg / kg) and tofacitinib (1 mg / kg) did not improve the DAI score or disease severity of DSS-induced colitis ( Figure 5A , 5C and 5D).

[0310] A high dose (10 mg / kg) of MMT3-72 and tofacitinib were tested for the treatment of DSS-induced UC ( Figure 5E , 5G MMT3-72 (10 mg / kg) increased the DAI score in the DSS-induced colitis model by 10-fold, and no mice (n=10) developed moderate or severe colitis. In contrast, tofacitinib (10 mg / kg) also showed an improvement in DAI scores, and only 10% of mice developed severe disease with heavy bleeding, and only 20% of mice developed moderate colitis. Both MMT3-72 and tofacitinib at high doses (10 mg / kg) restored colon length in DSS-induced colitis ( Fig. 5F ). These data suggest that MMT3-72 has advantages in the treatment of UC.

[0311] To further evaluate the efficacy of MMT3-72 in reducing colonic inflammation and tissue damage, H&E staining was performed on colon tissues from the above in vivo studies, as shown in Figure 6 Shown. DSS-induced colitis shows severe and diffuse destruction of the epithelial layer, with a large number of immune cell infiltrations in the epithelium. MMT3-72 (5, 10 mg / kg) reduces epithelial loss and reduces immune cell infiltration in the DSS-induced colitis model. In contrast, tofacitinib (5 mg / kg) did not show improvement in epithelial cell loss and immune cell infiltration in the DSS-induced colitis model, while tofacitinib (10 mg / kg) showed moderate improvement.

[0312] Example 3

[0313] JAK inhibitors with systemic activity for the treatment of cancer and autoimmune diseases

[0314] To evaluate the growth inhibitory effects of MMT3-72 and MMT3-72-M2 on JAK-associated cell populations, cytotoxicity experiments were performed on HEL and SET-2 cell lines using commercially available JAK inhibitors ( Fig. 8A and 8B ). MMT3-72 had no strong inhibition on both cell lines, while MMT3-72-M2 showed better inhibition (Table 2).

[0315] Table 2. IC of different JAK inhibitors in HEL cells and SET-2 cells 50

[0316] Compound <![CDATA[HEL IC 50 (μM)]]> <![CDATA[SET-2IC 50 (μM)]]> Baricitinib 0.3399 About 0.007836 Deuterated lexitinib About 347.0 7.384 Fedratinib 0.9036 0.2097 MMT3-56 1.031 0.2301 MMT3-72 5.591 0.515 MMT3-83 2.038 0.6448 MMT3-72-M2 2.594 0.3316 Ruxolitinib 0.1139 About 0.1452 Tofacitinib 3.693 About 7.308e-6 Upadacitinib 1.009 0.06963

[0317] Cell culture and antiproliferation assay. Human cell lines HEL 92.1.7 and SET-2 were obtained from the American Type Culture Collection (ATCC) and the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH, respectively. HEL and SET-2 cells were cultured in RMPI 1640 culture medium (Life Technologies Corporation, New York, USA) supplemented with 10% or 20% fetal bovine serum (FBS, Life Technologies Corporation, New York, USA), respectively. The cells were incubated at 37°C in a humid atmosphere of 5% CO2. The cells were seeded into 96-well culture plates at a density of approximately 8000 cells / well and treated with compounds of different concentrations of 200 μL in a final volume for 3 days. After reaching the end point, the cells were treated with CellTiter 96AQueous assay reagent (Promega Corporation, Madison, USA) according to the instructions of the supplier. Briefly, the MTS and PMS solutions were thawed and mixed (20:1, volume / volume) before use, and the appropriate amount of the mixed solution was pipetted into each well of a 96-well assay plate. The plate was incubated at 37°C in a humidified atmosphere of 5% CO2 for 1-4 hours. The absorbance at 490 nm was recorded using a CYTATION 5 imaging reader (BioTek, VT, USA). IC 50 Values ​​were calculated using the percentage of growth relative to untreated controls.

[0318] It should be understood that the foregoing detailed description and the accompanying examples are merely illustrative and should not be taken as limiting the scope of the present disclosure, which is defined solely by the appended claims and their equivalents.

[0319] Various changes and modifications to the disclosed embodiment will become apparent to those skilled in the art and can be made without departing from the spirit and scope thereof.

Claims

1. A Janus kinase (JAK) inhibitor analog or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor analog has the following structure: ALB in: A is the JAK inhibitor part; L is a cleavable linker; and B is a prodrug moiety.

2. The JAK inhibitor analog or pharmaceutically acceptable salt thereof of claim 1, wherein the JAK inhibitor portion is derived from abrocitinib, baricitinib, cerdutinib, degotinib, deuteroceletinib, fedratinib, filgotinib, gandotinib, lestaurtinib, molotinib, oclacitinib, paclitinib, piricitinib, ruxolitinib, tofacitinib or upadacitinib.

3. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein the JAK inhibitor moiety comprises a benzimidazole moiety, a pyrrolopyrimidine moiety or a biarylpyrimidine moiety.

4. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the cleavable linker comprises at least one selectively cleavable group or bond.

5. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 4, wherein the selectively cleavable group or bond is enzymatically cleavable.

6. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the cleavable linker comprises an azo group.

7. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein L contains in: E 1 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R 1a ;and R 1a It is hydrogen or C1-C6 alkyl.

8. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 7, wherein E 1 C4-C 10 Arylene or C4-C 10 Heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, or -COO-R 1a .

9. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein L comprises 10. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 7 to 9, wherein L further comprises a combination of one or more groups selected from the following: -CH2-, -O-, -NR 1b -, arylene and heteroarylene, and R 1b It is hydrogen or C1-C6 alkyl.

11. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 7 to 10, wherein L further comprises 12. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein B contains in: G is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 heteroarylene, wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl; and J is a bond or a linker comprising a combination of one or more groups selected from: -C(R 1c )2-, -CH=CH-, -C≡C-, -O-, -NR 1c -、-S-、-C(O)-、-C(NR 1c )-, -S(O)- and -S(O)2-, where each R 1c Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl.

13. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 12, wherein J is a linker comprising a combination of one or more groups selected from the group consisting of: -C(R 1c )2-、-NR 1c - and -C(O)-, where each R 1c Independently selected from hydrogen and C1-C6 alkyl.

14. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to claim 12 or claim 13, wherein J comprises 15. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 12, wherein J is a bond.

16. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein B comprises 17. The JAK inhibitor analogue of any one of claims 1 to 16, wherein the JAK inhibitor analogue is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is NR a , where R a is H or C1-C6 alkyl; R 1 Alkyl or SO2-R 2 , where R 2 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R b )2, and each R b are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring; X is O, SO2 or CH2; Y is NH, O or CH2; W is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 Heteroarylene, wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl or amino-C1-C6-alkyl; J' is a bond or a linker comprising a combination of one or more groups selected from: -C(R c )2-, -CH=CH-, -C≡C-, -O-, -NR c -、-S-、-C(O)-、-C(NR c )-, -S(O)- and -S(O)2-, where each R c independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; n is 1, 2, 3, 4, 5 or 6; and L' is a cleavable linker.

18. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 17, wherein J' is a linker comprising a combination of one or more groups selected from the group consisting of: -C(R c )2-、-NR c - and -C(O)-, where each R c Independently selected from hydrogen and C1-C6 alkyl.

19. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to claim 17 or claim 18, wherein J' comprises 20. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 17, wherein J' is a bond.

21. The JAK inhibitor analog of any one of claims 1 to 20, wherein the JAK inhibitor analog is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof.

22. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 21, wherein Z is NH.

23. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 22, wherein R 1 -SO2-N(R b )2.

24. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 23, wherein one R b is hydrogen, and the other is C1-C6 alkyl.

25. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 24, wherein X and Y are O.

26. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to any one of claims 17 to 25, wherein n is 1, 2 or 3.

27. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 26, wherein L'includes E 2 C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene or C4-C 10 wherein each cycloalkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl or -COO-R d ;and R d It is hydrogen or C1-C6 alkyl.

28. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to claim 27, wherein E 2 C4-C 10 Arylene or C4-C 10 Heteroarylene, optionally substituted by 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, amino, C1-C6-alkoxy, hydroxy, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, or -COO-R d .

29. The JAK inhibitor analog or pharmaceutically acceptable salt thereof according to any one of claims 17 to 28, wherein L' comprises 30. The JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 27 to 29, wherein L' further comprises a combination of one or more groups selected from the group consisting of: -CH2-, -O-, -NR e -, arylene and heteroarylene.

31. A JAK inhibitor analog or a pharmaceutically acceptable salt thereof as described in any one of claims 27 to 30, wherein L' further comprises 32. The JAK inhibitor analog of any one of claims 1 to 31, wherein the compound is: or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising an effective amount of the JAK inhibitor analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32 and a pharmaceutically acceptable carrier.

34. A method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof an effective amount of a JAK inhibitor analogue or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32 or a pharmaceutical composition according to claim 33.

35. The method of claim 34, wherein the disease or condition is cancer, an autoimmune disease, or an inflammatory disease.

36. The method of claim 34 or claim 35, wherein the disease or condition is a gastrointestinal inflammatory disease or condition.

37. The method of any one of claims 34 to 36, wherein the disease or disorder is inflammatory bowel disease.

38. The method of claim 37, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

39. The method of claim 34 or claim 35, wherein the disease or condition is cancer.

40. The method of claim 39, wherein the subject has cancer, has had cancer, is susceptible to cancer, or has a family history of cancer.

41. The method of any one of claims 34 to 40, wherein the JAK inhibitor analog or a pharmaceutically acceptable salt or composition thereof is administered orally.

42. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Q is Z' is NR c , where R c is H or C1-C6 alkyl; R 3 Alkyl or SO2-R 4 , where R 4 is selected from C1-C6 alkyl, C3-C9 cycloalkyl, C3-C9 heterocycle and N(R d )2, and each R d are independently selected from hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl and C3-C9 heterocycle, or two R d Together with the nitrogen atom to which it is attached, it forms an optionally substituted 5- or 6-membered ring; R 5 is hydrogen, -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3; and R 6 It is -OCH3 or -OCH2CH2-OCH3.

43. The compound of claim 42, wherein Z' is NH.

44. The compound of claim 42 or 43, wherein R 3 SO2-N(R d )2.

45. The compound of claim 44, wherein one R d is hydrogen, and one R d It is a C1-C6 alkyl group.

46. ​​A compound as described in any one of claims 42 to 45, wherein Q is And R 5 It is -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3.

47. A compound as described in any one of claims 42 to 45, wherein Q is R 5 is hydrogen, and R 6 It is -OCH3 or -OCH2CH2-OCH3.

48. A compound as described in any one of claims 42 to 45, wherein Q is And R 5 is -CH2-OCH3, and R 6 It is -OCH3 or -OCH2CH2-OCH3.

49. A compound as described in any one of claims 42 to 45, wherein Q is R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 It is -OCH3- or -OCH2CH2-OCH3.

50. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 42 to 49 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

51. A method of treating or preventing a disease or condition comprising administering to a subject in need thereof an effective amount of a compound as described in any one of claims 42 to 49 or a pharmaceutically acceptable salt thereof, or in another aspect, a composition as disclosed herein as described in claim 50.

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