JAK Inhibitor Analogs, Formulations, and Uses Thereof

Abstract

The present disclosure provides JAK inhibitor analogs, and compositions and methods thereof, for treating diseases or disorders (e.g., inflammatory bowel disease and ulcerative colitis).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 331,463, filed April 15, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] Field The present disclosure provides JAK inhibitor analogs, and compositions and methods thereof, for treating diseases or disorders (e.g., inflammatory bowel disease and ulcerative colitis). [Background technology]

[0003] Inflammatory bowel disease (IBD) affects more than 6.8 million people worldwide and 1-2 million people in the United States. Ulcerative colitis (UC) accounts for two-thirds of IBD cases, and Crohn's disease accounts for the remaining one-third of IBD cases. UC usually begins in the rectum and spreads to the proximal colon, where inflammation is confined to the innermost layer (mucosa) of the intestine, resulting in ulcers and serum diarrhea. In addition, UC patients have up to an 18% increased risk of developing colon cancer, depending on the severity and duration of the disease.

[0004] Current treatments have various limitations: anti-inflammatory treatments using controlled release formulations of 5-aminosalicylic acid and corticosteroids have limited effectiveness in reducing symptoms; anti-TNF antibody treatments are effective but require lifelong injections; immune system suppressants (e.g., azathioprine and cyclosporine) have limited effectiveness and exhibit severe side effects after long-term use.

[0005] Recently, inhibition of Janus kinases (JAK1, JAK2, JAK3, and TYK2) has emerged as a therapeutic approach for the treatment of UC. Several orally bioavailable small molecule JAK inhibitors (e.g., tofacitinib) have been developed and approved for the treatment of IBD and rheumatoid arthritis. However, tofacitinib and all other JAK inhibitors carry a black box warning for serious side effects, including high rates of major adverse cardiovascular events (MACE) (cardiovascular, myocardial infarction, stroke), arterial and venous thrombosis and pulmonary embolism, lymphoma and lung cancer malignancies, and increased risk of serious infections leading to death. Summary of the Invention

[0006] In one aspect, disclosed herein is a Janus kinase (JAK) inhibitor analog or a pharma- ceutically acceptable salt thereof, wherein the JAK inhibitor analog has the structure: ALB (In the formula, A is a JAK inhibitor moiety, L is a cleavable linker, B is a prodrug moiety.

[0007] In some embodiments, the JAK inhibitory moiety is derived from abrocitinib, baricitinib, celduratinib, delgocitinib, deuclavacitinib, fedratinib, filgotinib, gandotinib, lestaurtinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitory moiety comprises a benzimidazole moiety, a pyrrolopyrimidine moiety, or a biarylmethapyrimidine moiety.

[0008] 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.

[0009] In some embodiments, L is [ka] Including E 1 But, C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R 1a and R 1a is hydrogen or C1-C6 alkyl. 1 are independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R 1a C4-C optionally substituted with one or two substituents selected from 10 Arylene or C4-C 10 It is a heteroarylene.

[0010] In some embodiments, L is [ka] Includes.

[0011] In some embodiments, L is further selected from the group consisting of -CH2-, -O-, -NR 1b -, arylene, and heteroarylene; R 1b is hydrogen or C1-C6 alkyl. In some embodiments, L is further selected from the group consisting of: [ka] Includes.

[0012] In some embodiments, B is [ka] and G is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 and heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, or aminoC1-C6 alkyl; J is a bond, or -C(R 1c )2-, -CH=CH-, -C≡C-, -O-, -NR 1c -, -S-, -C(O)-, -C(NR 1c is a linker comprising a combination of one or more groups selected from -S(O)-, -S(O)-, and -S(O)-, 1c is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, J is -C(R 1c )2-, -NR 1c -, -C(O)-, and -C(O)-; 1c is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, J is [ka] In some embodiments, J is a bond.

[0013] In some embodiments, B is [ka] Includes.

[0014] In some embodiments, the JAK inhibitor analog is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Z is NR a and R a is H or C1-C6 alkyl; R 1 is alkyl or SO2-R 2 and R 2 is 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 both R b together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; X is O, SO2, or CH2; Y is NH, O, or CH2; W is for C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, or aminoC1-C6 alkyl; J' is a bond or -C(R c )2-, -CH=CH-, -C≡C-, -O-, -NR c -, -S-, -C(O)-, -C(NR c is a linker comprising a combination of one or more groups selected from -S(O)-, -S(O)-, and -S(O)-, c is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; n is 1, 2, 3, 4, 5, or 6; L' is a cleavable linker.

[0015] In some embodiments, J′ is —C(R c )2-, -NR c -, -C(O)-, and -C(O)-; c is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, J' is [ka] In some embodiments, J' is a bond.

[0016] In some embodiments, the JAK inhibitor analog is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0017] In some embodiments, Z is NH. In some embodiments, R 1 is -SO2-N(R b In some embodiments, one R b 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.

[0018] In some embodiments, L' is [ka] Including E 2 is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R d and R d is hydrogen or C1-C6 alkyl. 2 are independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R d C4-C optionally substituted with one or two substituents selected from 10 Arylene or C4-C 10 It is a heteroarylene.

[0019] In some embodiments, L' is [ka] Includes.

[0020] In some embodiments, L' is further selected from -CH2-, -O-, -NR e -, arylene, and heteroarylene.

[0021] In some embodiments, L' further comprises: [ka] Includes.

[0022] In some embodiments, the compound is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a JAK inhibitor analog disclosed herein (e.g., a compound of formula ALB or a compound of Formula (I) or Formula (Ia)), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0024] In another aspect, disclosed herein is a method of treating or preventing a disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a JAK inhibitory analog disclosed herein (e.g., a compound of formula ALB, or a compound of formula (I) or (Ia)), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a JAK inhibitory analog disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, the disease or disorder is cancer, an autoimmune disease, or an inflammatory disease. In some embodiments, the disease or disorder is a gastrointestinal inflammatory disease or disorder. In some embodiments, the disease or disorder is an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In some embodiments, the disease or disorder 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 pharmacologic acceptable salt or composition thereof is administered orally.

[0026] In another embodiment, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof is disclosed herein, Q is, [ka] and Z' is NR c and R cis H or C1-C6 alkyl; R 3 is alkyl or SO2-R 4 and R 4 is 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 both R d together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; R 5 is hydrogen, -CH2-OCH3, or -CH2-(OCH2CH2)-OCH3, R 6 is -OCH3 or -OCH2CH2-OCH3). In some embodiments, Z' is NH. In some embodiments, R 3 , SO2-N(R d In some embodiments, one R d is hydrogen and one R d is C1-C6 alkyl. In some embodiments, Q is [ka] and R 5 is -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3. In some embodiments, Q is [ka] and R 5 is hydrogen and R 6 is -OCH3 or -OCH2CH2-OCH3. In some embodiments, Q is [ka] and R 5 is -CH2-OCH3, R 6is -OCH3 or -OCH2CH2-OCH3. In some embodiments, Q is [ka] and R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 is -OCH3- or -OCH2CH2-OCH3.

[0027] In another aspect, disclosed herein is a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0028] In another aspect, disclosed herein is a method of treating or preventing a disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (II) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt thereof.

[0029] Other aspects and embodiments of the present disclosure will become apparent in light of the following detailed description and accompanying figures. [Brief description of the drawings]

[0030] [Figure 1A] FIG. 1 is a schematic diagram of the pharmacokinetics of an exemplary GI locally activating JAK inhibitor. [Figure 1B] FIG. 1 is a schematic diagram of the design of exemplary GI locally activating JAK inhibitors. [Figure 1C] The co-crystal structure of JAK2 and fedratinib (PDB 6VNE) is shown. [Diagram 2] 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) are shown. [Diagram 3]Graph of inhibition of different isoforms of JAK by MMT3-72 and active metabolite MMT3-72-M2. Inhibition of JAK activity by MMT3-72 and MMT3-72-M2 (0.01-10,000 nM) was measured using Kinase-GloMax assays against purified enzymes JAK1, JAK2, JAK3, and TYK2. Prism8 was used to calculate IC50 of compounds inhibiting various JAK isoforms. [Figure 4A] Graphs of MMT3-72 and MMT3-72-M2 concentrations in GI contents, GI tissues, and plasma.Graphs of MMT3-72 concentrations in plasma, colon tissue, small intestine tissue, colon contents, and small intestine contents at 0.5 hours, 2 hours, 4 hours, 12 hours, and 24 hours. [Figure 4B] Graphs of MMT3-72 and MMT3-72-M2 concentrations in GI contents, GI tissues, and plasma. Graphs of MMT3-72-M2 concentrations in plasma, colonic tissue, and small intestinal tissue at 0.5, 2, 4, 12, and 24 hours. Dotted lines indicate IC50 of MMT3-72-M2 to inhibit JAK1, JAK2, JAK3, and TYK2, respectively. [Figure 4C] Graphs of MMT3-72 and MMT3-72-M2 concentrations in GI contents, GI tissues, and plasma.Graphs of MMT3-72-M2 concentrations in colonic contents, small intestinal contents, and stomach contents at 0.5 hours, 2 hours, 4 hours, 12 hours, and 24 hours. [Figure 5A] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC.Figure 2 shows improvement in UC DAI scores after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). [Figure 5B] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC.Figure 2 shows recovery of colon length from DSS-induced colitis after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). [Figure 5C]Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC. Figure 2 shows the percentage of mice with severe colitis and gross bleeding on day 5 after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). [Figure 5D] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC. Figure 2 shows the percentage of mice with moderate colitis on day 5 after treatment with MMT3-72 and tofacitinib (1, 5 mg / kg). [Figure 5E] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC.Figure 2 shows improvement in UC DAI scores after treatment with MMT3-72 and tofacitinib (10 mg / kg). [Figure 5F] 1 is a graph showing the in vivo efficacy of MMT3-72 compared to tofacitinib in the treatment of UC. FIG. 2 is a graph showing recovery of colon length after treatment with MMT3-72 and tofacitinib (10 mg / kg). [Figure 5G] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC. Figure 2 shows the percentage of mice that developed severe colitis with macroscopic bleeding 5 days after treatment with MMT3-72 and tofacitinib (10 mg / kg). [Figure 5H] Figure 1 shows the in vivo efficacy of MMT3-72 compared to tofacitinib in treating UC. Figure 2 shows the percentage of mice that developed moderate colitis 5 days after treatment with MMT3-72 and tofacitinib (10 mg / kg). [Figure 6]H&E staining images of colonic tissues after treatment with MMT3-72 and tofacitinib in a DSS-induced colitis model. The control was H&E staining of colonic tissues from healthy mice. DSS-induced colitis showed epithelial destruction and immune cell infiltration in colonic tissues. In a DSS-induced colitis model, administration of MMT3-72 (5, 10 mg) reduced epithelial destruction and immune cell infiltration in colonic tissues compared with tofacitinib (5, 10 mg / kg). [Figure 7] The structures of MMT3-56, MMT3-84, MMT3-83, MMT3-85, MMT3-73, MMT3-89, MMT3-79, and MMT3-90 are shown. [Figure 8A] 1 is a graph of inhibition of cell growth in the JAK-associated cell line HEL cells. [Figure 8B] 1 is a graph of cell growth inhibition in SET-2 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] JAK inhibitor analogs and compositions thereof are described herein.Exemplary GI locally active JAK inhibitor analogs maximize drug exposure to intestinal tissue and reduce systemic drug exposure, thereby providing superior efficacy in treating UC while reducing the adverse side effects of JAK inhibitors.

[0032] The inactivated synthetic compound MMT3-72 showed minimal inhibitory activity against JAKs (JAK1, JAK2, JAK3, and TYK2) and low potential for absorption into the systemic circulation. However, upon activation, mainly in the colon, MMT3-72-M2 was released and showed potent inhibitory activity against JAK1 / 2 and TYK2. MMT3-72 accumulated in the GI lumen but not in GI tissue or plasma. Meanwhile, the released active metabolite MMT3-72-M2 accumulated in the colon lumen and colon tissue, but exposure to plasma was minimal. MMT3-72 (PO, 5, 10 mg / kg) achieved superior efficacy to tofacitinib in dextran sulfate sodium (DSS)-induced colitis in mice.

[0033] The section headings used in this section and throughout this disclosure are for organizational purposes only and are not intended to be limiting.

[0034] 1.Definition As used herein, the terms "comprise," "include," "having," "has," "can," "contain," and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "and," and "the" also include plural referents unless the context clearly indicates otherwise. The present disclosure also contemplates other embodiments that "comprising," "consisting of," and "consisting essentially of" the embodiments or elements presented herein, whether or not expressly stated.

[0035] With respect to references to numerical ranges herein, each intervening numerical value therebetween is expressly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 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.

[0036] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those skilled in the art. The meaning and scope of the terms must be clear, but in the event of any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. Furthermore, unless otherwise required by context, 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.

[0037] As used herein, the terms "linker", "linking group", and "bond" are used interchangeably to refer to a linking moiety that connects two groups and has a backbone of any suitable length. In some cases, the length of the backbone of the linker is 20 atoms or less. The linker or bond can be a covalent bond connecting two groups, or a chain of any convenient length (e.g., 1-20 atoms long), for example, about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, or 20 carbon atoms long, and the linker can be linear, branched, cyclic, or a single atom. Linkers can include, but are not limited to, poly(ethylene glycol), modified polyethylene glycol; ether, thioether, tertiary amine, alkyl (e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), etc.), which can be linear or branched. The linker backbone may include a cyclic group, e.g., an aryl, heterocyclic, or cycloalkyl group, where two or more atoms (e.g., 2, 3, or 4 atoms) of the cyclic group are included in the backbone. The linker may be cleavable or non-cleavable.

[0038] As used herein, the term "moiety" is used to refer to a portion of an entity or molecule, in some cases a portion having a particular function, structure, or structural feature.

[0039] As used herein, the terms "providing," "administering," and "introducing" are used interchangeably herein and refer to placing a composition of the present disclosure into a subject by a method or route that results in at least partial localization of the composition at a desired site. The composition can be administered by any suitable route that results in delivery to the desired location in the subject.

[0040] A "subject" or "patient" may be human or non-human, and may include animal strains or species used as "model systems" for research purposes, such as the mouse model described herein. Similarly, a patient may include an adult or a minor (e.g., a child). Furthermore, a patient may refer to any organism, preferably a mammal (e.g., human and non-human), that may benefit from administration of the compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the class Mammalia; humans, non-human primates (e.g., chimpanzees and other ape and monkey species); livestock animals (e.g., cows, horses, sheep, goats, wild boars); farm animals (e.g., rabbits, dogs, and cats); laboratory animals, including rodents (e.g., rats, mice, and guinea pigs, etc.). Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0041] As used herein, "treat", "treating" and the like refer to slowing, stopping, or reversing the progression of a disease or disorder when a compound or composition described herein is provided to a suitable control subject. The term also refers to reversing the progression of such a disease or disorder to the point where symptoms are eliminated or significantly reduced. Thus, "treating" refers to applying or administering a composition described herein to a subject, the subject having a disease or symptoms of a disease, with the purpose of curing, curing, alleviating, mitigating, altering, treating, improving, enhancing, or affecting the disease or symptoms of the disease.

[0042] Definitions of certain functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75 thIn addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in: Sorrell, Organic Chemistry, 2001, pp. 111-115, 1997; and in: Sorrell, Organic Chemistry, 2001, pp. 111-115, 1997. nd edition,University Science Books,Sausalito,2006;Smith,March's Advanced Organic Chemistry:Reactions,Mechanism,and Structure,7 th Edition,John Wiley & Sons,Inc.,New York,2013;Larock,Comprehensive Organic Transformations,3 rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987 (the entire contents of each of which are incorporated herein by reference).

[0043] The term "alkyl" as used herein 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.

[0044] The term "alkoxy" as used herein 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.

[0045] The term "alkoxyalkyl" as used herein refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one hydrogen atom) is replaced with an alkoxy group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, methoxymethyl.

[0046] The term "amino" as used herein refers to the group -NH2. The term "alkylamino" as used herein refers to the group -NHR, where R is an alkyl group as defined herein. The term "dialkylamino" as used herein refers to the group -NR2, where each R is independently an alkyl group as defined herein.

[0047] The term "aminoalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one hydrogen atom (eg, one hydrogen atom) has been replaced with an amino group.

[0048] As used herein, the term "aryl" refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms (e.g., C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", i.e., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl, for example, naphthyl, such as 1-naphthyl and 2-naphthyl.

[0049] As used herein, the term "arylene" refers to a divalent aryl radical.

[0050] As used herein, the term "azo group" refers to a group having the general formula RN=N-R', where R and R' can independently be either aryl or alkyl groups.

[0051] As used herein, the term "benzimidazole" refers to a bicyclic heteroaryl group having the formula: [ka]

[0052] As used herein, the term "biarylmethapyrimidine" refers to a group having the following structure: [ka]

[0053] The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring system containing 3 to 10 carbon atoms and 0 heteroatoms. Cycloalkyls can be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

[0054] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl radical.

[0055] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and associated hydrogen atoms) are each independently selected from the group consisting of a heteroatom group (e.g., -NH-, -O-, -S-, -S(O)-, -S(O)2-, -OP(O)(O - )O-, etc. As an example, 1, 2, 3, 4, 5, 6, or more carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroalkyl groups can also contain one or more carbonyl moieties (i.e., a carbon atom of the alkyl group is oxidized to a -C(O)- group).

[0056] As used herein, the term "heteroalkylene" refers to a divalent heteroalkyl radical.

[0057] 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 5- or 6-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 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. Exemplary bicyclic heteroaryl groups are monocyclic aryl groups as defined herein or monocyclic heteroaryl groups as defined herein fused with an additional monocyclic heteroaryl ring. Exemplary tricyclic heteroaryl groups are monocyclic heteroaryl rings fused with two rings independently selected from monocyclic aryl groups as defined herein and monocyclic heteroaryl groups as defined herein. Representative examples of monocyclic heteroaryls include, but are not limited to, pyridinyl (e.g., 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. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzodioxolyl, benzofuranyl, benzoxadiazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, chromenyl, imidazopyridine, imidazothiazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, pyridoimidazolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolopyridinyl, thiazolopyrimidinyl, thienopyrrolyl, and thienothienyl.Representative examples of tricyclic heteroaryls include, but are not limited to, dibenzofuranyl and dibenzothienyl. Monocyclic, bicyclic, and tricyclic heteroaryls are connected to the parent molecular moiety through any carbon or nitrogen atom contained within the ring.

[0058] As used herein, the term "heteroarylene" refers to a divalent heteroaryl radical.

[0059] 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 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")) and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl ring or the heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members will continue to indicate the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyls, with the term "membered ring" referring to the ring atoms other than hydrogen within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, 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, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,5-bicyclic heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups (also referred to as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (eg, 2,7-diazaspiro[3.5]nonanyl).Exemplary 6-membered heterocyclic groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclic groups (also referred to herein as 6,7-bicyclic heterocycles) fused to a cycloalkyl ring include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclic groups (also referred to herein as 6,8-bicyclic heterocycles) fused to a cycloalkyl ring include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0060] As used herein, the term "heterocyclylene" refers to a divalent heterocyclyl radical.

[0061] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0062] The term "hydroxyalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one hydrogen atom (eg, one hydrogen atom) has been replaced with a hydroxy group.

[0063] As used herein, the term "pyrrolopyrimidine" refers to a bicyclic heteroaryl group having the formula: [ka]

[0064] As used herein, the term "substituent" refers to a group substituted on an atom of a designated group.

[0065] Where 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 designated by the phrase can be replaced with the specified group recited or with suitable substituents known to those of skill in the art (e.g., one or more of the groups recited below), provided that the normal valence of the given 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, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamide, thiol, thione, thioxo, or combinations thereof.

[0066] As used herein, in chemical structures, the indications: [ka] represents the point of attachment of one moiety to another.

[0067] In some cases, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkylalkenyl) is indicated by the prefix “C x -C y " (where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent). Thus, for example, "C1-C3 alkyl" refers to an alkyl substituent containing 1 to 3 carbon atoms.

[0068] In the compounds described herein, groups and substituents thereof may be selected according to the allowed valences of atoms and substituents such that the selection and substitution result in stable compounds that do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like.

[0069] Where substituents are designated in a conventional chemical formula written from left to right, they optionally include the substituents resulting from writing the structure from right to left. For example, -CHO- is intended to include -OCH-, -C(O)NH- is intended to include -NHC(O)-.

[0070] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure. 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.

[0071] 2. Janus kinase (JAK) inhibitor analogues In one aspect, provided herein is a Janus kinase (JAK) inhibitor analog or a pharma- ceutically acceptable salt thereof. In some embodiments, the JAK inhibitor analog has the following structure: ALB (In the formula, A is a JAK inhibitor moiety, L is a cleavable linker, B is a prodrug moiety.

[0072] The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in the immune response. Inhibitors of JAK family members have therapeutic efficacy in the treatment of cancer and autoimmune and inflammatory diseases. Currently, there are four known members of the mammalian JAK family: JAK1 (also called Janus kinase 1), JAK2 (also called Janus kinase 2), JAK3 (Janus kinase, leukocyte; also called JAKL, L-JAK, and Janus kinase 3), and TYK2 (also called protein tyrosine kinase 2). JAK proteins are 120-140 kDa in size and contain seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain and the other is a pseudokinase domain that potentially plays a regulatory function and / or serves as a docking site for signal transducers and activators of transcription (STATs).

[0073] As used herein, "JAK inhibitory moiety" refers to a moiety that inhibits at least one activity of JAK kinase.In some embodiments, the JAK inhibitory moiety comprises a benzimidazole moiety, a pyrrolopyrimidine moiety, or a biarylmetapyrimidine moiety.For example, JAK inhibitor compounds having a biarylmetapyrimidine moiety are disclosed in WO2007 / 053452 (herein incorporated by reference).

[0074] JAK inhibitory moiety can be derived from any known JAK inhibitor.In some embodiments, JAK inhibitory moiety is derived from abrocitinib, baricitinib, celduratinib, delgocitinib, deuclavacitinib, fedratinib, filgotinib, gandotinib, lestaurtinib, momelotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib or upadacitinib.In some embodiments, JAK inhibitory moiety is derived from fedratinib.

[0075] The JAK inhibitory moiety may inhibit one or more members of the JAK family. In some embodiments, the JAK inhibitory moiety reduces the kinase activity of JAK1. In some embodiments, the JAK inhibitory moiety reduces the kinase activity of JAK2. In some embodiments, the JAK inhibitory moiety reduces the kinase activity of JAK3. In some embodiments, the JAK inhibitory moiety reduces the kinase activity of TYK2.

[0076] In some embodiments, the JAK inhibitory moiety decreases the kinase activity of JAK1 and JAK2. In some embodiments, the JAK inhibitory moiety decreases the kinase activity of JAK1 and JAK3. In some embodiments, the JAK inhibitory moiety decreases the kinase activity of JAK2 and JAK3. In some embodiments, the JAK inhibitory moiety decreases the kinase activity of JAK1, JAK2, and JAK3. In some embodiments, the JAK inhibitory moiety is a pan-JAK inhibitor.

[0077] Cleavable linkers include any linker that can be selectively cleaved to obtain at least two products. Thus, the cleavable linker may include at least one selectively cleavable group or bond. The cleavable linkers of the present invention are stable until contacted 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 electrophilically cleavable linkers, nucleophilically cleavable linkers, photocleavable linkers, metal cleavable linkers, electrolytically cleavable linkers, enzyme cleavable linkers, linkers that can be cleaved under reducing or oxidizing conditions (e.g., disulfide linkers or diazobenzene linkers), and linkers that can be cleaved using acidic or basic reagents.

[0078] In some embodiments, the cleavable linker comprises an enzymatically cleavable group or bond. Enzymatic reactions useful for cleaving the linker include reactions mediated by nucleases, peptidases, proteases, phosphatases, esterases, oxidases, reductases, sulfatases, etc. For example, in certain embodiments, the enzymatically cleavable linker includes, but is not limited to, a β-glucuronide linker, a peptide-based linker, and an aryl sulfate, disulfide, hydrazone, acetal, aminal, ester, phosphate, or azo linker.

[0079] In some embodiments, the cleavable linker is pH sensitive. In certain embodiments, the linker comprises a low pH labile group or bond. As used herein, a low pH labile group or bond is a group or bond that is selectively cleaved 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 polyphosphoester, a polyphosphazene, an acetal, a vinyl ether, a hydrazone, an azidomethyl methyl maleic anhydride, a thiopropionate, a masked endosomolytic agent, or a citraconyl group. In some embodiments, the cleavable bond is selected from: 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, silicon-nitrogen (silazane) bonds that are unstable under acidic conditions; silicon-carbon bonds (e.g., arylsilanes, vinylsilanes, and allylsilanes); maleamic acids (amide bonds synthesized from maleic anhydride derivatives and amines); orthoesters; hydrazones; acid-catalyzed hydrolysis designed to undergo activated carboxylic acid derivatives (e.g., esters, amides), or vinyl ethers.

[0080] In some embodiments, the linker is [ka] Including E 1 is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 and each cycloalkylene, independently, heterocyclylene, arylene, or heteroarylene is C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R 1a and R 1a is hydrogen or C1-C6 alkyl.

[0081] In some embodiments, E 1 are independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R 1a C4-C optionally substituted with one or two substituents selected from 10 Arylene or C4-C 10 Heteroarylene, R 1a is hydrogen or C1-C6 alkyl. 1 -COO-R 1a R is a monocyclic arylene or heteroarylene optionally substituted with 1a is hydrogen or C1-C6 alkyl. 1 is phenylene.

[0082] In some embodiments, the linker is [ka] Includes.

[0083] In some embodiments, the linker further comprises -C(R1b )2-, -CH=CH-, -C≡C-, -O-, -NR 1b -, -S-, -C(O)-, -C(NR 1b )-, -S(O)-, -S(O)2-, arylene, heteroarylene, cycloalkylene, and heterocyclylene; 1b is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl, heteroaryl, and heteroarylalkyl, where each alkyl, alkenyl, alkynyl, arylene, heteroarylene, cycloalkylene, and heterocyclylene is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents. In some embodiments, the linker is further selected from -CH2-, -O-, -NR 1b In some embodiments, the linker further comprises a combination of one or more groups selected from: [ka] Includes.

[0084] A prodrug moiety is a moiety that modulates the absorption, distribution, metabolism, or excretion characteristics of the compound to which it is attached or attached in order to improve the bioavailability and / or efficacy of the compound. In some cases, the prodrug moiety renders the compound more or less inactive until transformation converts the compound into a pharmacologically active form, usually as a result of removal of the prodrug moiety by enzyme-mediated or chemical transformation.

[0085] In some embodiments, the prodrug moiety is [ka] and G is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10Arylene, or C4-C 10 and heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, or aminoC1-C6 alkyl, and J is a bond or -C(R 1c )2-, -CH=CH-, -C≡C-, -O-, -NR 1c -, -S-, -C(O)-, -C(NR 1c is a linker comprising a combination of one or more groups selected from -S(O)-, -S(O)-, and -S(O)-, 1c is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0086] In some embodiments, G is a monocyclic arylene or heteroarylene. In some embodiments, G is phenylene. In some embodiments, G is a bicyclic arylene or heteroarylene.

[0087] In some embodiments, J is a linker that includes a combination of one or more groups selected from -CH- (e.g., methylene, ethylene, n-propylene, butylene, etc.), -C(O)-, and -NH-. In some embodiments, J is [ka] In some embodiments, J is a bond.

[0088] In some embodiments, the prodrug moiety is [ka] Includes.

[0089] In one aspect, the JAK inhibitor analog is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Z is NR a and R a is H or C1-C6 alkyl; R 1 is alkyl or SO2-R 2 and R 2 is 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 both R b together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; X is O, SO2, or CH2; Y is NH, O, or CH2; W is for C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, or aminoC1-C6 alkyl; J' is a bond or -C(R c )2-, -CH=CH-, -C≡C-, -O-, -NR c -, -S-, -C(O)-, -C(NR c is a linker comprising a combination of one or more groups selected from -S(O)-, -S(O)-, and -S(O)-, c is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; n is 1, 2, 3, 4, 5, or 6; L' is a cleavable linker.

[0090] 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' is [ka] In some embodiments, p is 0.

[0091] In some embodiments, the JAK inhibitor analog is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, Z is NR a and R a is H or C1-C6 alkyl; R 1 is alkyl or SO2-R 2 and R 2 is 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 both R b together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; X is O, SO2, or CH2; Y is NH, O, or CH2; n is 1, 2, 3, 4, 5, or 6; L' is a cleavable linker.

[0092] In some embodiments, Z is NH.

[0093] In some embodiments, R 1is SO2-N(R b In some embodiments, each R b is independently C1-C6 alkyl. In some embodiments, one R b is hydrogen and one R b is C1-C6 alkyl.

[0094] In some embodiments, Z is NH and R 2 is SO2-N(R b )2.

[0095] In some embodiments, X is O. In some embodiments, Y is O. In some embodiments, X and Y are O.

[0096] In some embodiments, n is 1, 2, or 3.

[0097] In some embodiments, L' is [ka] Including E 2 is C4-C 10 Cycloalkylene, C4-C 10 Heterocyclylene, C4-C 10 Arylene, or C4-C 10 heteroarylene, each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, or -COO-R d and R d is hydrogen or C1-C6 alkyl.

[0098] In some embodiments, E 2 are independently C1-C6 alkyl, amino, C1-C6 alkoxy, hydroxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, and -COO-Rd C4-C optionally substituted with one or two substituents selected from 10 Arylene or C4-C 10 Heteroarylene, R d is hydrogen or C1-C6 alkyl. 2 -COO-R d R is a monocyclic arylene or heteroarylene optionally substituted with d is hydrogen or C1-C6 alkyl. 1 is phenylene.

[0099] In some embodiments, L' is [ka] Includes.

[0100] In some embodiments, L' further comprises -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; e is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl, heteroaryl, and heteroarylalkyl, where each alkyl, alkenyl, alkynyl, arylene, heteroarylene, cycloalkylene, and heterocyclylene is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents. In some embodiments, the linker is further selected from CH2-, -O-, -NR e In some embodiments, L' further comprises a combination of one or more groups selected from -, arylene, and heteroarylene. [ka] Includes.

[0101] In some embodiments, the JAK inhibitor analog is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In another embodiment, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof is disclosed herein, Q is, [ka] and Z' is NR c and R c is H or C1-C6 alkyl; R 3 is alkyl or SO2-R 4 and R 4 is 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 both R d together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; R 5 is hydrogen, -CH2-OCH3, or -CH2-(OCH2CH2)-OCH3, R 6 is -OCH3 or -OCH2CH2-OCH3).

[0103] In some embodiments, Z' is NH.

[0104] In some embodiments, R 3 , SO2-N(R d In some embodiments, each R d is independently C1-C6 alkyl. In some embodiments, one R 4 is hydrogen and one R d is C1-C6 alkyl.

[0105] In some embodiments, Z' is NH and R 3 is SO2-N(R d In some embodiments, each R d is independently C1-C6 alkyl. In some embodiments, one R d is hydrogen and one R d is C1-C6 alkyl.

[0106] In some embodiments, Q is [ka] and R 5 is -CH2-OCH3 or -CH2-(OCH2CH2)-OCH3.

[0107] In some embodiments, Q is [ka] and R 5 is hydrogen and R 6 In some embodiments, Q is -OCH3. [ka] and R 5 is -CH2-OCH3, R 6 In some embodiments, Q is -OCH3. [ka] and R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 is -OCH3.

[0108] In some embodiments, Q is [ka] and R 5 is hydrogen and R 6 In some embodiments, Q is -OCHCH-OCH. [ka] and R 5 is -CH2-OCH3, R 6 In some embodiments, Q is -OCHCH-OCH. [ka] and R 5 is -CH2-(OCH2CH2)-OCH3, and R 6 is -OCH2CH2-OCH3.

[0109] In some embodiments, the compound of formula (II) is a compound shown in FIG. 7, or a pharma- ceutically acceptable salt thereof.

[0110] Compounds may exist as stereoisomers in which asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are configurations as defined in: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution techniques are exemplified by: (1) binding the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and, optionally, isolating the optically pure products 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 newer versions); or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column; or (3) fractional recrystallization techniques.

[0111] It should be understood that the compounds may have tautomeric and geometric isomeric forms and that these also constitute embodiments of the present disclosure.

[0112] The present disclosure also includes isotopically labeled compounds that are identical to those set forth in Formula (I), Formula (Ia), or Formula (II) except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine (such as, but not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Heavier isotopes (e.g., deuterium, e.g., 2 H) may provide certain therapeutic advantages resulting in improved metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some circumstances. Positron-emitting isotopes may be incorporated into the compounds for 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 processes similar to those described in the accompanying examples, using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents.

[0113] The disclosed compounds may exist as pharma- ceutically acceptable salts. The term "pharma- ceutically acceptable salts" refers to salts or zwitterions of compounds that are water- or oil-soluble or dispersible, suitable for the treatment of disorders without undue toxicity, irritation, and allergic responses, commensurate with a reasonable benefit / risk ratio, and effective for the intended use. The salts may be prepared during the final isolation and purification of the compounds, or may be prepared separately by reacting the amino group of the compounds with a suitable acid. For example, the compounds may be dissolved in a suitable solvent (e.g., but not limited to, methanol and water) and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salts may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salts. 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, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides, and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0114] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base (e.g., hydroxide, carbonate, or bicarbonate) of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium, or aluminum) or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, 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-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0115] The compounds may be synthesized according to a variety of methods, including those shown in the Examples. The reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions may be worked up in a conventional manner, for example by removing the solvent from the residue, and further purified according to methodologies generally known in the art (for example, but not limited to, crystallization, distillation, extraction, trituration, and chromatography). Unless otherwise indicated, starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, procedures analogous to the synthesis of known structurally similar compounds, or procedures analogous to those described in the Schemes or Synthetic Examples sections above.

[0116] Routine experimentation (e.g., proper manipulation of reaction conditions, reagents, and order of synthetic pathways, protection of any chemical functional groups that are not compatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method) is within the scope of the present disclosure. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of this can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006) (incorporated herein by reference in its entirety). Synthesis of the compounds of the present disclosure can be accomplished by methods similar to those described in the above synthetic schemes and specific examples.

[0117] The optically active forms of the disclosed compounds can be obtained by carrying out one of the procedures described herein using, if necessary, optically active starting materials (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolving a stereoisomeric mixture of the compound or intermediate using standard procedures (for example, chromatographic separation, recrystallization, or enzymatic resolution).

[0118] Similarly, if a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolving a mixture of geometric isomers of the compound or intermediates using standard procedures such as chromatographic separation.

[0119] It can 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 intended to be within the scope of the claims.

[0120] 3. Composition The disclosed JAK inhibitor analogs may be incorporated into pharma- ceutically acceptable compositions. The pharmaceutical compositions may include a "therapeutically effective amount" or a "prophylactically effective amount" of the JAK inhibitor analog(s). A "therapeutically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount of a composition can be determined by one skilled in the art and may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the composition to elicit a desired response in an individual. A therapeutically effective amount is also an amount in which any toxic or adverse effects of the compounds of the invention are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve a desired prophylactic result. Typically, since a prophylactic dose is used in a subject prior to or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0121] Pharmaceutical compositions and formulations may include a pharma- ceutically acceptable carrier. As used herein, the term "pharma- ceutically acceptable carrier" refers to a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrin, or formulation auxiliary of any type. Some examples of substances that may function as pharma- ceutically acceptable carriers include sugars (e.g., but are not limited to, lactose, glucose, and sucrose); starches (e.g., but are not limited to, corn starch and potato starch); cellulose and its derivatives (e.g., but are not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (e.g., but are not limited to, cocoa butter and suppository wax); oils (e.g., but are not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); surfactants (e.g., but are not limited to, Cremophor EL, Cremophor RH 60, Solutol HS 15, and Polysorbate 80); Chlodextrins (for example, but not limited to, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD); glycols (for example, but not limited to, propylene glycol); esters (for example, but not limited to, ethyl oleate and ethyl laurate); agar; buffers (for example, but not limited to, magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffers, as well as other non-toxic compatible lubricants (for example, but not limited to, sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants may also be present in the composition, at the discretion of the formulator.

[0122] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier to be used. The compositions may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral injection) or local administration (e.g., transdermal, pulmonary, nasal, otic, ocular, liposome delivery system, or iontophoresis).

[0123] Carriers for systemic administration typically include at least one of a diluent, lubricant, binder, disintegrant, colorant, flavorant, sweetener, antioxidant, preservative, glidant, solvent, suspending agent, wetting agent, surfactant, cyclodextrin, combinations thereof, etc. All carriers are optional in the composition.

[0124] Suitable diluents include sugars (e.g., glucose, lactose, dextrose, and sucrose); diols (e.g., propylene glycol); calcium carbonate; sodium carbonate; sugar alcohols (e.g., glycerin, mannitol, and sorbitol). The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0125] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycols, and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0126] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches (e.g., corn starch and potato starch), gelatin, tragacanth, and cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose). The amount of binder(s) in the systemic composition is typically about 5 to about 50%.

[0127] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0128] Suitable coloring agents include colorants such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0129] Suitable flavorings include menthol, peppermint, and fruit flavors. The amount of flavoring(s) used in a systemic or topical composition is typically from about 0.1 to about 1.0%.

[0130] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically from about 0.001 to about 1%.

[0131] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically from about 0.1 to about 5%.

[0132] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0133] Suitable glidants include silicon dioxide. The amount of lubricant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0134] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohol (e.g., ethanol), dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, and phosphate (or other suitable buffer). The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0135] Suitable suspending agents include AVICEL RC-591 (FMC Corporation, Philadelphia, Pa.) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0136] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS (Atlas Powder Company, Wilmington, Del.). Suitable surfactants include those disclosed in: CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in a systemic or topical composition is typically about 0.1% to about 5%.

[0137] Suitable cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl betadex (HP-beta-CD), and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD). The amount of cyclodextrin in a systemic or topical composition is typically about 0% to about 40%.

[0138] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but in general, a systemic composition will contain 0.01%-50% of an active compound and 50%-99.99% of one or more carriers. Compositions for parenteral administration will usually contain 0.1%-10% of an active ingredient and 90%-99.9% of a carrier (e.g., diluent and solvent).

[0139] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of active ingredient, usually at least about 5%, more specifically about 25% to about 50%. Oral dosage compositions contain about 50% to about 95%, more specifically about 50% to about 75% of carrier.

[0140] Tablets can be compressed tablets, powder tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multiple compressed tablets. Tablets usually contain active ingredients and carriers (e.g., components selected from diluents, lubricants, binders, disintegrants, colorants, flavorants, 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 croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Particular colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners (e.g., aspartame and saccharin) or flavors (e.g., menthol, peppermint, fruit flavors), or combinations thereof.

[0141] Capsules (e.g., implants, sustained release formulations, and extended release formulations) typically contain a compound disclosed herein and a carrier comprising one or more diluents disclosed above, in a capsule that typically contains gelatin. Granules typically contain a compound disclosed herein, preferably a glidant (e.g., silicon dioxide) to improve flow properties. Implants can be of the biodegradable or non-biodegradable type.

[0142] The choice of carrier components for oral compositions is determined by secondary considerations such as taste, cost, and storage stability, which are not critical for the purposes of the present invention.

[0143] The solid compositions can be coated in a conventional manner, usually with a pH or time dependent coating, such that the disclosed compounds are released in the gastrointestinal tract near the desired application or at various times and for extended periods of time to prolong the desired effect. The coating usually comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coating (available from Evonik Industries, Essen, Germany), wax, and shellac.

[0144] Compositions for oral administration can be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. Liquid compositions for oral administration usually include the disclosed compounds and carriers (i.e. carriers selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants). Oral liquid compositions preferably include one or more components selected from colorants, flavorants, and sweeteners.

[0145] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions usually include one or more of soluble fillers (e.g., diluents including sucrose, sorbitol, and mannitol) and binders (e.g., acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose). Such compositions may further include lubricants, colorants, flavorings, sweeteners, antioxidants, and glidants.

[0146] The compositions disclosed herein may further comprise at least one additional therapeutic agent, which may include immunosuppressants (e.g., azathioprine, mercaptopurine, cyclosporine, tacrolimus, and methotrexate), anti-inflammatory agents (e.g., corticosteroids and aminosalicylates), chemotherapeutic agents, immunotherapy, antibiotics, antidiarrheals, and analgesics.

[0147] 4.How to use The disclosure further provides a method for treating a disease or disorder comprising administering a compound 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 [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is a human.

[0148] The disease or disorder may be selected from cancer, an autoimmune disease, and an inflammatory disease.

[0149] In some embodiments, the disease or disorder is an inflammatory disease or disorder. Inflammatory diseases are characterized by activation of the immune system of a tissue or organ to abnormal levels that can cause abnormal function and / or disease of the tissue or organ. Inflammatory diseases and disorders 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, Sjogren's syndrome, or Churg-Strauss syndrome.

[0150] In some embodiments, the disease or disorder is an autoimmune disease or disorder. Autoimmune diseases and disorders refer to a condition in a subject characterized by cell, tissue, and / or organ damage caused by the subject's immune response to its own cells, tissues, and / or organs. Autoimmune diseases and disorders that may be treated by the methods of the present invention include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune disease of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, mixed essential cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITH), and / or other conditions. Irritable bowel disease (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 syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary Primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff man syndrome, systemic lupus erythematosus, lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis (e.g., dermatitis herpetiformis, vasculitis), vitiligo, and Wegener's granulomatosis.

[0151] Some autoimmune disorders are also associated with inflammatory conditions.Examples of inflammatory disorders that are also autoimmune disorders that can be prevented, treated or managed according to the method of the present invention include, but are not limited to, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergy disorders, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation caused by chronic viral or bacterial infection.Examples of types of psoriasis that can be treated according to the composition and method of the present invention include, but are not limited to, psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis, and inverse psoriasis.

[0152] In some embodiments, the disease or disorder is a gastrointestinal inflammatory disease or disorder. These diseases or disorders 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 disorders include any disease or disorder that causes inflammation and / or ulcers in the mucosa of the gastrointestinal tract.

[0153] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a hematological cancer or lymphoma. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the disclosed compounds, compositions, or methods result in the inhibition of removal of metastases. 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.

[0154] The compounds and compositions herein may be useful to treat a wide variety of cancers (e.g., carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma). The cancer may be of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, lymph node, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testis, thyroid, or uterus.

[0155] 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.

[0156] The JAK inhibitory analog or composition thereof can be administered to a subject in various ways. In any of the uses or methods described herein, administration can be by various routes known to those skilled in the art, such as, but not limited to, oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof. In some embodiments, the JAK inhibitory analog or composition thereof disclosed herein can be administered by oral administration.

[0157] The amount of the disclosed JAK inhibitor analog or composition thereof required for use in treatment or prevention will vary depending on the particular compound selected, as well as the route of administration, the nature and / or symptoms of the disease, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. The determination of effective dosage levels (dosage levels required to achieve the desired results) can be performed by those skilled in the art using routine methods (e.g., human clinical trials, in vivo studies, and in vitro studies). For example, the effective dosage of the JAK inhibitor analog or composition thereof can be determined by comparing in vitro activity and in vivo activity in animal models.

[0158] Dosage and dosing intervals can be individually adjusted to provide plasma levels of the active moiety sufficient to maintain the modulating effect, or minimum effective concentration (MEC). The MEC will vary from compound to compound, but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will be determined by individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosing intervals can also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels above the MEC 10-90% of the time, preferably 30-90%, most preferably 50-90%. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0159] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the administered dose in the management of the disorder of interest will vary with the severity of the condition to be treated and the route of administration. Furthermore, the dose, and perhaps the frequency of administration, will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above may also be used in veterinary medicine.

[0160] The JAK inhibitor analogs disclosed herein or compositions thereof can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of a particular compound, a subset of compounds sharing a particular chemical moiety, or a composition comprising a JAK inhibitor analog can be established by determining in vitro toxicity to a cell line (e.g., a mammalian cell line, preferably a human cell line). The results of such studies are often predictive of toxicity to animals (e.g., mammals), more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model (e.g., mice, rats, rabbits, dogs, or monkeys) can be determined using known methods. Efficacy can be established using several accepted methods (e.g., in vitro methods, animal models, or human clinical trials). When selecting a model to determine efficacy, one skilled in the art can be guided by the state of the art to select the appropriate model, dose, route of administration, and / or regimen.

[0161] A wide range of second therapies can be used in combination with the compounds and methods of the present disclosure. Second therapies can be administration of additional active agents or second therapies that are not associated with administration of another therapeutic agent. Such second therapies include, but are not limited to, surgery, immunotherapy, and radiation therapy.

[0162] The second therapy may be administered simultaneously with the first therapy, in the same composition, or in a separate composition that is administered substantially simultaneously with the first composition. In some embodiments, the second therapy may precede or follow the treatment of the first therapy by a time interval ranging from a few hours to a few months.

[0163] A therapeutically effective amount of a JAK inhibitor analog or compound disclosed herein, or a composition thereof, may be administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, an effective combination therapy is achieved using a single composition or pharmacological formulation containing both agents, or two different compositions or formulations, administered simultaneously, one composition containing a compound of the invention and the other containing the second agent(s).

[0164] The at least one additional therapeutic agent may include immunosuppressants (e.g., azathioprine, mercaptopurine, cyclosporine, tacrolimus, and methotrexate), anti-inflammatory agents (e.g., corticosteroids and aminosalicylates), chemotherapeutic agents, immunotherapy, antibiotics, antidiarrheals, and analgesics.

[0165] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term "chemotherapeutic agent" or "anti-cancer agent" includes any small molecule or other agent used in the treatment or prevention of cancer. Chemotherapeutic agents include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacirb, everolimus, alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib. In selected embodiments, the chemotherapy agent comprises paclitaxel.

[0166] In some embodiments, the second therapy comprises immunotherapy, which comprises chimeric antigen receptor (CAR) T cell therapy or T cell transfer therapy, cytokine therapy, immunomodulatory drugs, cancer vaccines, or administration of antibodies (e.g., monoclonal antibodies).

[0167] In some embodiments, immunotherapy involves the administration of antibodies. The antibodies may target either 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 called erbB or EGFR), VEGF, CTLA-4 (also called CD152), epithelial cell adhesion molecule (EpCAM, also called 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, and the like. In some embodiments, the additional therapeutic agent may include 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 conjugated to a chemotherapeutic agent. Thus, in some embodiments, the antibody is an antibody drug conjugate.

[0168] Immunotherapy (e.g., administration of an antibody) can be administered to a subject in a variety of ways. In any of the uses or methods described herein, administration can be by a variety of routes known to those skilled in the art (e.g., but not limited to, oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof). In some embodiments, the immunotherapy can be administered in the same manner or in a different manner than the JAK inhibitor analog or composition thereof. The immunotherapy can be administered by parenteral administration (e.g., but not limited to, subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac, and intraarticular injection).

[0169] 5. Kit In another aspect, the disclosure provides a kit comprising at least one of the disclosed JAK inhibitor analogs or a pharma- ceutically acceptable salt thereof, or a composition comprising the compound or a pharma- ceutically acceptable salt thereof, and instructions for using the compound or composition.

[0170] The kits may also include other agents and / or products that are co-packaged, combined, and / or co-delivered with other components. For example, a pharmaceutical manufacturer, pharmaceutical reseller, physician, compounding store, or pharmacist may provide a patient with a kit that includes the disclosed compounds and / or products and another agent (e.g., a chemotherapeutic agent, a monoclonal antibody, an analgesic, an immunosuppressant, an anti-inflammatory agent, an antibiotic, an antidiarrheal agent) for delivery.

[0171] The kit may also include instructions for use of the components of the kit. Instructions are materials or methodologies related to the kit. The materials may include any combination of background information, list of components, simple or detailed protocols for using the compositions, troubleshooting, reference materials, technical support, and other related documentation. The instructions may be provided with the kit or as a separate member component, in paper or electronic form, provided on a computer readable memory device, downloaded from an internet website, or provided as a recorded presentation.

[0172] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, etc. Individual member components of the kit may be physically packaged together or separately. EXAMPLES

[0173] 6. Working Example Abbreviations used in the schemes and examples below are as follows: DCE is dichloroethane; DMA is dimethylacetamide; DMF is dimethylformamide; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; HCl is hydrochloric acid; iPrOH is isopropyl alcohol; MeOH is methanol; Pd / C is palladium on carbon, and rt is room temperature.

[0174] All commercial products and solvents were purchased from Sigma-Aldrich, AK Scientific, and Fisher Scientific. Solvents were used as is or dried over molecular sieves (4 Å). All water- or air-sensitive reactions were carried out under an argon atmosphere with dry solvents and anhydrous conditions. All reactions were monitored by thin-layer chromatography (TLC) performed on aluminum-backed silica plates (0.2 mm, 60 F254). Purification by flash chromatography was performed on Merck silica gel 60 (230-400 mesh). Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous material unless otherwise stated.

[0175] NMR spectra were recorded on a Bruker instrument (500 or 300 MHz) and were calibrated using the solvent peak as an internal reference. Spectra were processed using MestReNova software. Chemical shifts δ are expressed in ppm and coupling constants (J) are expressed in Hz. Peak multiplicities are expressed as follows: s, singlet, t, triplet, and m, multiplet. High-resolution mass spectra were obtained on an AB Sciex X500R QTOF spectrometer or an AB Sciex 6600+Triple TOF mass spectrometer. The purity of all compounds submitted to biological testing was determined by analytical HPLC and was determined to be greater than 95%.

[0176] Example 1 Synthesis of compounds Using the fedratinib scaffold, compound MMT3-72 was designed (Figure 1A). Fedratinib is a semiselective JAK2 inhibitor. Fedratinib inhibits JAK2 (IC 50 15 nM), but not JAK1 (IC 50 10 nM) and TYK2 (IC 50 178 nM). JAK2 and TYK2 are JAK isoforms involved in IL-12 / IL-23 signaling, and inhibition of IL-12 / IL-23 (e.g., antibody ustekinumab) is effective in treating UC. The majority of fedratinib (77%) is excreted in the GI tract in the feces (23% as unchanged drug) after a single oral dose.

[0177] In MMT3-72, the solvent-exposed pyrrolidine moiety of fedratinib was exchanged for 5-aminosalicylic acid (5-ASA) via an azo bond to N-4-(aminobenzoyl)-beta-alanine. 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.

[0178] Compounds MMT3-72 and MMT3-72-M2 were synthesized according to the synthetic route shown in Scheme 1. Briefly, 4-nitrophenol was condensed with DCE or 2-chloroethanol to give intermediates 1 and 4, respectively. Subsequently, intermediates 1 and 4 were nitro-reduced with tin chloride or hydrogenated to give intermediates 2 and 5, respectively. Intermediate 2 or 5 was then coupled with N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide in the presence of a few drops of HCl in isopropanol to give compounds 3 and MMT3-72-M2, respectively. Finally, compound 3 was subjected to a nucleophilic substitution reaction with balsalazide disodium salt dihydrate to give the desired compound MMT3-72. Scheme 1: [ka] aReaction conditions: (a) DCE, K2CO3, DMF, 100 °C, 6 h, 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, 6 h, and 68%; (e) 2-chloroethanol, NaOH, H2O, 8 h, 80 °C, and 79%; (f) H2, Pd / C, MeOH, 50 °C, overnight, and 76%.

[0179] 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 equiv.) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (100 mg, 0.282 mmol) in isopropanol (2 mL), 3 drops of concentrated HCl (37%) were added and the reaction mixture was stirred at 80° C. overnight. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was taken up in aqueous NaHCO3 and extracted three times with CHCl2. The combined organic phases were washed with water, brine and dried over NaSO4. The solvent was concentrated in vacuo and the resulting solid was washed with EtOAc three times to give compound MMT3-72-M2 (105 mg, 79% yield). 1 H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.55 (s, 1H), 8.12 (d, J = 3.4 Hz, 2H), 7.90 (s, 1H), 7.62 - 7.39 (m, 4H), 6.80 (d, J = 8.9 Hz, 2H), 3.92 (t, J = 5.1 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 2.12 (s, 3H), 1.12 (s, 9H). HRMS(ESI)C 23 H 29 Calculated mass for N5O4S, 471.58; observed m / z, 472.1847 [M+H]+.

[0180] The synthesis and properties of compounds 1 and 4 have been previously described (see: Luo, et al., Bioorg Med Chem Lett 2017, 27(12), 2668-2673).

[0181] 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), K2CO3 (6 g, 43.131 mmol, 1.5 eq) was added and the resulting mixture was stirred at 100 °C for 6 h and monitored by TLC. Upon completion, the reaction mixture was quenched with water and the product was extracted three times with CHCl2. The combined organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give compound 1 (5.35 g, 92% yield). This intermediate was carried on to the next step without further purification.

[0182] 4-(2-Chloroethoxy)aniline (2): To a mixture of compound 1 (1 g, 4.96 mmol) in EtOH (30 mL), SnCl2.2H2O (4.5 g, 19.84 mmol, 4 equiv.) was added and the reaction mixture was stirred at 90 °C overnight. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was taken up in 5% aqueous NaOH and extracted three times with CHCl2. The combined organic phases were washed with 5% aqueous NaOH, water, brine and dried over NaSO4. The solvent was concentrated in vacuo and the residue was purified by silica gel column chromatography to give compound 2 (532.4 mg, 63% yield). 1 H NMR (500 MHz, CDCl3) δ 6.82 - 6.69 (m, 2H), 6.69 - 6.58 (m, 2H), 4.16 (t, J = 5.9 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H). HRMS(ESI):C8H 10 Mass calculated for ClNO, 171.05; observed m / z, 172.0425 [M+H]+.

[0183] 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 equiv.) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (413.53 mg, 1.165 mmol) in isopropanol (8 mL), three drops of concentrated HCl (37%) were added and the reaction mixture was stirred at 80° C. overnight. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was taken up in aqueous NaHCO3 and extracted three times with CHCl2. The combined organic phases were washed with water, brine and dried over NaSO4. The solvent was concentrated in vacuum and the resulting solid was washed three times with EtOAc to give compound 3 (482 mg, 84% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.55 (s, 1H), 8.12 (d, J = 5.6 Hz, 2H), 7.91 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 4.3 Hz, 2H), 7.51 - 7.45 (m, 2H), 6.87 - 6.80 (m, 2H), 4.18 (d, J = 6.0 Hz, 2H), 3.92 (d, J = 5.9 Hz, 2H), 2.16 - 2.06 (m, 3H), 1.12 (s, 9H). HRMS(ESI):C 23 H 28 Calculated mass for ClN5O3S, 489.16; observed m / z, 490.1506 [M+H]+.

[0184] 2-(4-Nitrophenoxy)ethan-1-ol (4): To a mixture of 4-nitrophenol (3 g, 21.56 mmol) and 2-chloroethanol (2.89 mL, 43.16 mmol, 2 equiv.) in HO (10 mL), NaOH (1.73 g, 43.16 mmol, 2 equiv.) was added and the reaction mixture was stirred at 80° C. overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with HO, and extracted three times with EtOAc. The combined organic phase was washed with water, brine, and dried over NaSO. The solvent was concentrated in vacuo to give compound 4 (3.1 g, 79% yield), which was carried on to the next step without further purification.

[0185] 2-(4-aminophenoxy)ethan-1-ol (5): To a mixture of compound 4 (1 g, 5.460 mmol) in MeOH (20 mL), Pd / C (0.1 g, 10% equiv.) was added and the reaction mixture was stirred overnight at 50° C. under H2 atmosphere. Upon completion of the reaction, Pd / C was filtered off through Celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 5 (635.2 mg, 76% yield). 1 H NMR (300 MHz, CDCl3) δ 6.82 - 6.72 (m, 2H), 6.70 - 6.59 (m, 2H), 4.01 (dd, J = 5.1, 3.5 Hz, 2H), 3.92 (dd, J = 5.1, 3.5 Hz, 2H). HRMS(ESI):C8H 11 Calculated mass for NO2, 153.18; observed m / z, 154.0770 [M+H]+.

[0186] (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 equiv.) and balsalazide disodium salt dihydrate (27.29 mg, 0.068 mmol, 1 equiv.) in DMF (2 mL), K2CO3 (37.6 mg, 0.272 mmol, 4 equiv.) was added and the resulting mixture was stirred at 100 °C overnight and monitored by TLC. Upon completion, the solvent was evaporated under reduced pressure. The residue was taken up in HO and the solution was acidified with H3PO4 until pH 2-3. The precipitate was filtered and recrystallized from CH2Cl2 to give the desired compound MMT3-72 (50.4 mg, 68%). 1 H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.29 (s, 1H), 8.08 (s, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 10.5 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H), 7.49 (t, J = 14.4 Hz, 4H), 6.86 (d, J = 9.7 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 4.36 (t, J = 4.5 Hz, 2H), 4.13 (t, J = 4.8 Hz, 2H), 3.61 - 3.48 (m, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.11 (s, 3H), 1.11 (s, 9H). HRMS(ESI):C 40 H 42 Calculated mass for N8O9S, 810.2; observed m / z, 811.2758 [M+H]+.

[0187] Compounds MMT3-83, MMT3-84, and MMT3-85 were synthesized according to the synthetic route shown in Scheme 2. Compound MMT3-56 was synthesized according to 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. Scheme 2: [ka] Reaction conditions: (a) Na2CO3, 6 hours, 50°C, and 88%; (b) DCE, K2CO3, DMF, 6 hours, 100°C, and 97%; (c) SnCl2.2H2O, EtOH, overnight, and 55%; (d) concentrated HCl, isopropanol, overnight at 80°C, and 62%; (e) DMA, 20 hours, and 90°C, and 79%; (f) pyrrolidine, DMA, 20 hours, 90°C, and 83%; and (g) DMA, 20 hours, 90°C, and 80%.

[0188] Step 1. A solution of 2-(chloromethyl)-4-nitrophenol (0.25 g; 1.33 mmol) in 2-methoxyethanol or appropriate alcohol (5 mL) was heated to 50 °C and stirred under argon. Sodium bicarbonate (0.23 g; 2.66 mmol, 2 equiv.) was added slowly over 1 h and the reaction was allowed to proceed at 50 °C for 7 h. Once the reaction was complete, excess NaHCO3 was removed by filtration, the alcohol was evaporated, and the product was crystallized from ethyl acetate (yields 88-97%).

[0189] 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 vol) in DMF (25 mL), K2CO3 (1.46 g, 10.55 mmol, 1.5 equiv) was added and the resulting mixture was stirred at 100° C. for 6 h and monitored by TLC. Upon completion, the reaction mixture was quenched with water and the product was extracted three times with CH2Cl2. The combined organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the product (1.97 g, 97% yield). This intermediate was carried on to the next step without further purification.

[0190] Step 3. To a mixture of the intermediate obtained in step 2 (1 g, 3.45 mmol) in EtOH (30 mL), SnCl2.2H2O (3.11 g, 13.807 mmol, 4 equiv.) was added and the reaction mixture was stirred at 90 °C overnight. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was taken up in 5% aqueous NaOH and extracted three times with CHCl2. The combined organic phases were washed with 5% aqueous NaOH, water, brine and dried over NaSO4. The solvent was concentrated in vacuum and the residue was purified by silica gel column chromatography to give the product (0.5 g, 55% yield).

[0191] Step 4. To a mixture of the intermediate obtained in step 3 (450 mg, 1.73 mmol, 2 equiv.) and N-tert-butyl-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]benzenesulfonamide (307 mg, 0.86 mmol) in isopropanol (8 mL), 3 drops of concentrated HCl (37%) were added and the reaction mixture was stirred at 80 °C overnight. Once the reaction was complete, the solvent was evaporated under reduced pressure and the residue was taken up in aqueous NaHCO3 and extracted three times with CHCl2. The combined organic phases were washed with water, brine and dried over NaSO4. The solvent was concentrated in vacuum and the solid obtained was washed three times with EtOAc to give the product (311.7 mg, 62% yield).

[0192] Step 5. To a mixture of the intermediate obtained in step 4 (80 mg, 0.138 mmol) in DMA (2 mL), the appropriate amine (2 vol) was added and the reaction mixture was stirred at 90 °C overnight. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the product (yield 80-95%).

[0193] Example 2 Local GI activation of MMT3-72 and identification of metabolites in GI contents, GI tissues, and plasma Materials and Methods Activation of MMT3-72 and identification of metabolites: 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). Chromatographic separation of MMT3-72 and its metabolites was performed using a Waters XBridage reversed-phase C18 column (15 cm × 2.1 mm I.D., 3.5 μm packing). To confirm the exact molecular weight, a high-resolution AB Sciex X500R QTOF mass spectrometer (AB Sciex, Farmingham, USA) in positive ion information-dependent acquisition (IDA) mode was used. The mass range was recorded from m / z 100 to 1000 Da. The collision energy of the TOF MSMS was set to 50 V. Data were collected with SCIEX OS software and then processed with MetabolitePilot2.0 software (AB Sciex, Framingham, USA).

[0194] In vitro activity of inhibiting JAK enzymes: JAK1, JAK2, JAK3, TYK2 assay kits were obtained from BPS Bioscience (San Diego, CA, USA). The assays were performed according to the manufacturer's protocol in 96-well microplates. Briefly, master mixes (25 μL per well) were prepared for JAK1 and TYK2 assays (6 μL 5x kinase assay buffer + 1 μL ATP (500 μM) + 5 μL × 10 IRS1-tide + 13 μL distilled water), or 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), respectively. Then, 5 μL of fedratinib, MMT3-73-72, MMT3-72-M2 solutions with different concentrations were added to the master mixture prepared above, followed by 20 μL of enzyme (JAK1 (5 ng / μL), JAK2 (2.5 ng / μL), JAK3 (0.4 ng / μL), or TYK2 (0.5 ng / μL)), respectively. The reaction mixtures were incubated at 30 °C for 40 min. Finally, 50 μL of Kinase-GloMax reagent (Promega, Madison, WI, USA) was added to each well, and the reaction was carried out at room temperature in the dark for 15 min. The luminescence of the reaction mixtures was read on a Synergy2 microplate reader (Biotek).

[0195] 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 measured with 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 performed using a Waters XBridage reversed-phase C18 column (5 cm x 2.1 mm ID, 3.5 μm packing). The flow rate for gradient elution was 0.4 ml / min with mobile phase A (0.1% formic acid in purified deionized water) and mobile phase B (0.1% formic acid in acetonitrile). For detection, an AB Sciex QTrap 4500 mass spectrometer (ABSciex, Farmingham, USA) in positive ion multiple reaction monitoring (MRM) mode was used. The protonated molecular ions and their respective ion products were monitored at the transition m / z 811.3>737.4 for MMT3-72 and 472.3>416.0 for MMT3-72-M2. Data were processed with Analyst software (version 1.6).

[0196] Pharmacokinetics in mice. Briefly, C57BL / 6 female mice were orally administered 10 mg / kg MMT3-72. After 0.5, 2, 4, 12, and 24 hours, mice were sacrificed and blood samples were collected by direct cardiac bleeding. Intestinal tissue samples were collected and homogenized to 10% homogenate in PBS. Small and large intestinal contents were collected and homogenized in PBS. Concentrations of MMT3-72, MMT3-72-M2, and 5-ASA in plasma, intestinal tissue, and intestinal contents were then measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis using the method described above.

[0197] 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 administering 3% DSS (MP Biomedicals, California, USA) dissolved in distilled water for 5 consecutive days, while the control group received pure water (Snider, et al., Methods Mol Biol 2016, 1438, 245-254). MMT3-72 or tofacitinib was dissolved in beta-cyclodextrin. The drugs were administered orally every other day in a volume of 0.1 mL / 10 g body weight. During model establishment, body weight, stool consistency, and gross blood in the stool were monitored and recorded daily. After 5 days, the mice were killed and blood was collected. Serum was obtained by centrifugation and stored at -80°C for further immunoassays. The colon was excised and the length was measured.

[0198] H&E staining of colonic tissue: After dissection and sectioning of the colon, the colon was intubated using a feeding needle and a 5ml syringe and the colon was washed with ice-cold PBS until feces were flushed out. Using scissors, the colon was incised longitudinally from the distal to the proximal end, and the colonic tissue could then be unfolded as a flat sheet. Using one pair of forceps, the distal colonic end was grasped and the colonic tissue was rotated into a Swiss roll. The roll was firmly grasped and cut using a 27G1 / 2 needle. The samples were then placed in 4% paraformaldehyde fixative solution (Thermo Scientific, USA) for 24 hours at room temperature. The Swiss roll was then paraffin embedded, sectioned, mounted, and H&E stained to determine the extent of colonic damage from the distal (inner end) to the proximal (outer end). Local GI activation of MMT3-72 and identification of metabolites in GI contents, GI tissues, and plasma

[0199] To confirm the activation of MMT3-72 in the colon, mice were orally administered 10 mg / kg MMT3-72 and sacrificed 6 hours later to collect plasma, colon tissue, and colon contents (feces). In the collected samples, five metabolites (M1-M5) were identified, the structures of which are shown in Figure 2. Interestingly, MMT3-72 was only detected in feces, and not in plasma or colon tissue. The major metabolite MMT3-72-M2 was only detected in colon tissue and feces, and was at low concentrations in plasma. The other four minor metabolites M1, M3, M4, and M5 were only identified in feces, and not detected in plasma or colon tissue. Since MMT3-72-M2 is the major metabolite and accumulates in colonic tissue, to test its activity in inhibiting JAK1-3 and TYK2, MMT3-72-M2 was synthesized according to the synthetic pathway shown in Figure 1 (Table 1). MMT3-72 is less active, whereas MMT3-72-M2 is more potent against JAK1, JAK2, and TYK2 by in vitro kinase assays.

[0200] The biological activities of MMT3-72 and its active metabolite MMT3-72-M2 were evaluated against JAK1, JAK2, JAK3, and TYK2 in 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 weak inhibitory activity against JAK3 and TYK2 (6821 nM and 2976 nM, respectively). However, 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 comparison, fedratinib strongly inhibited JAK1 (10.1 nM) and JAK2 (15.6 nM), but did not sufficiently inhibit JAK3 and TYK2. JAK2 / TYK2 / IL-12 / IL-23 signaling is strongly implicated in UC, but since JAK1 isoforms have long been identified as potential targets in the treatment of IBD, as seen with upadacitinib, the inhibition profile of JAK1, JAK2, and TYK2 of MMT3-72-M2 may have advantages in the treatment of UC. Furthermore, MMT3-72-M2 showed insufficient inhibitory activity against JAK3, which may also be favorable for reducing undesirable side effects in the treatment of UC. Tofacitinib inhibited JAK3 with an IC50 of 1.6 nM and showed severe side effects. It has been shown that JAK3 inhibition could potentially lead to lymphopenia, and thus hypothetically to an increased risk of infection. [Table 1] MMT3-72 was activated locally in the GI tract to release the active metabolite MMT3-72-M2, which achieved high exposure to GI tissues and minimal exposure to plasma.

[0201] To investigate the GI local activation and pharmacokinetics of MMT3-72 and its active metabolite MMT3-72-M2 in vivo, mice were orally administered 10 mg / kg MMT3-72 and sacrificed to harvest tissues at different time points from 0 to 24 h. As shown in Figure 4A, high concentrations (Cmax>50,000 ng / g) of compound MMT3-72 were observed in GI contents (e.g., gastric contents, small intestinal contents, and colonic contents). However, MMT3-72 was not detected in small intestinal tissue, colonic tissue, or systemic circulation. In contrast, high levels of the active metabolite MMT3-72-M2 were detected in colonic and small intestinal tissues (Cmax>1500 ng / g) (Figure 4B). After 24 hours, the Cmin in small and large intestinal tissues was 88.5 ng / ml, which represents an IC50 value for inhibition of JAK1, JAK2, and TYK2-related targets to treat UC. 50 Conversely, the MMT3-72-M2 concentration for 10–24 h was higher than the IC 50 In addition, the concentration of MMT3-72-M2 in plasma was minimal (Cmax 8ng / ml) and undetectable after 4 hours. Moreover, it activated MMT3-72 more to release MMT3-72-M2 in the colon than in the small intestine, because the colonic content of MMT3-72-M2 was 10 times higher than that in the small intestine (Fig. 4C). These findings indicated that: (1) MMT3-72 is not absorbed into the systemic circulation, but is retained in the GI tract and is mainly activated in the colon region to release the active metabolite MMT3-72-M2; (2) the active metabolite MMT3-72-M2 accumulates in large amounts in colon and small intestine tissues, which may inhibit JAK1, JAK2, and TYK2 for its therapeutic effect; and (3) no MMT3-72 is detected in the systemic circulation, and only low levels of the active metabolite MMT3-72-M2 are detected, which may potentially avoid the systemic toxicity of JAK inhibition.

[0202] It is worth noting that the design of MMT3-72 is distinct from that of izencitinib (TD-1473), which reduces absorption potential to limit systemic exposure, but does not have a local activation mechanism. Designing a drug with only reduced absorption potential but no activation mechanism (e.g., TD-1473) would reduce the penetration of the drug into colonic tissue. This would limit its efficacy in human clinical trials. In contrast, MMT3-72 was designed to not only reduce GI tract absorption potential, but also to have local activation properties that release the active form of MMT3-72-M2. This would easily penetrate colonic tissue to reach therapeutic concentrations in colonic tissue, but minimize drug exposure in the systemic circulation. MMT3-72 showed good efficacy in treating UC in mice.

[0203] To evaluate the efficacy of MMT3-72 in treating UC in vivo, a colitis model was established in mice using dextran sulfate sodium salt (DSS). DSS in drinking water can cause colitis in mice. The DSS-induced colitis model is widely used due to its relatively simple administration and high similarity to human UC. In this study, mice treated with 3% DSS water developed symptoms of colitis (e.g., bloody stool and diarrhea) on day 5. Disease activity index (DAI) was monitored for disease severity in mice: normal stool consistency negative for occult blood: score 0; loose stool positive for occult blood: score 1; very loose stool with traces of blood: score 2; watery stool with visible rectal bleeding: score 3. To evaluate the efficacy of MMT3-72 compared to an FDA-approved JAK inhibitor (tofacitinib) in treating UC, mice were orally treated with both drugs at 1 mg / kg and 5 mg / kg (Figures 5A, 5C, and 5D). MMT3-72 (5 mg / kg) improved the DAI score by 5-fold compared to DSS-induced colitis, whereas tofacitinib (5 mg / kg) did not improve the DAI score (Figure 5A). In the MMT3-72 (5 mg / kg) treatment group, no mice developed severe colitis, and only 10% (n = 10) mice developed moderate colitis (Figures 5C and 5D). In contrast, in the tofacitinib treatment group (5 mg / kg), 40% of mice (n = 10) developed severe colitis, and 80% developed moderate colitis (Figures 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 in DSS-induced colitis (Figures 5A, 5C, and 5D).

[0204] Both high doses (10 mg / kg) of MMT3-72 and tofacitinib were tested for the treatment of DSS-induced UC (Figures 5E, 5G, and 5H). MMT3-72 (10 mg / kg) improved the DAI score 10-fold in the DSS-induced colitis model, and none of the mice (n=10) developed moderate or severe colitis. In comparison, tofacitinib (10 mg / kg) also showed improvement in the DAI score, with only 10% of the mice developing severe disease with gross bleeding and only 20% of the mice developing moderate colitis. Both high doses (10 mg / kg) of MMT3-72 and tofacitinib restored colon length from DSS-induced colitis (Figure 5F). These data suggest that MMT3-72 has benefits for the treatment of UC.

[0205] To further evaluate the efficacy of MMT3-72 in reducing colonic inflammation and tissue damage, H&E staining of colonic tissues from the in vivo study above was performed, as shown in Figure 6. DSS-induced colitis showed severe and extensive destruction of the epithelial layer with extensive immune cell infiltration into the epithelium. MMT3-72 (5, 10 mg / kg) reduced epithelial loss and decreased immune cell infiltration in the DSS-induced colitis model. In contrast, tofacitinib (5 mg / kg) showed no improvement in epithelial cell loss and immune cell infiltration in the DSS-induced colitis model, while tofacitinib (10 mg / kg) showed a moderate improvement.

[0206] Example 3 JAK inhibitors with systemic activity for the treatment of cancer and autoimmune diseases To evaluate the effect of MMT3-72 and MMT3-72-M2 on growth inhibition of JAK-associated cell populations, cytotoxicity experiments were performed on HEL and SET-2 cell lines using commercially available JAK inhibitors (Figures 8A and 8B). MMT3-72 did not have strong inhibition on either cell line, whereas MMT3-72-M2 showed better inhibition (Table 2). [Table 2]

[0207] Cell culture and antiproliferative assays. Human cell lines HEL92.1.7 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 RMPI1640 medium (Life Technologies Corporation, New York, USA) supplemented with 10% or 20% fetal bovine serum (FBS, Life Technologies Corporation, New York, USA), respectively. Cells were cultured at 37°C in a humidified atmosphere of 5% CO2. Cells were seeded at a density of approximately 8000 cells per well in 96-well culture plates and treated with various concentrations of compounds for 3 days in a final volume of 200 μL. For endpoints, cells were treated using CellTiter 96 AQueous Assay Reagents (Promega Corporation, Madison, USA) according to the supplier's instructions. Briefly, MTS and PMS solutions were thawed and mixed (20:1, v / v) before use, and an 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 to 4 h. The absorbance at 490 nm was recorded using a CYTATION5 imaging reader (BioTek, VT, USA). The growth rate relative to the untreated control was used to calculate the IC 50 values ​​were calculated.

[0208] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and do not limit the scope of the present disclosure, which is defined solely by the appended claims and equivalents thereof.

[0209] Various changes and modifications to the disclosed embodiment, which will be apparent to those skilled in the art, can be made without departing from the spirit and scope thereof.

Claims

1. Janus kinase (JAK) inhibitory analog, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitory analog has the following structure: A-L-B (In the formula, A is the JAK inhibitory portion, L is a cutting linker, (B is the prodrug portion.) Having, The JAK inhibitor analog, or a pharmaceutically acceptable salt thereof.

2. The JAK inhibitory analog according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitory portion is derived from abrocitinib, baricitinib, celduratinib, delgocitinib, duklavacitinib, fedratinib, filgotinib, gandotinib, restaurtinib, momerotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, or upadacitinib.

3. The JAK inhibitor analog according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the cleavable linker comprises at least one selectively cleavable group or bond, the selectively cleavable group or bond being enzymatically cleavable and comprising an azo group.

4. L, 【Chemistry 1】 Includes, E 1 is C 4 -C 10 cycloalkylene, C 4 -C 10 heterocyclylene, C 4 -C 10 arylene, or C 4 -C 10 heteroarylene, and each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, hydroxy, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, or -COO-R 1a and may be substituted, R 1a However, hydrogen or C 1 -C 6 A JAK inhibitory analog according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor is alkyl.

5. L is further, -CH 2 -, -O-, -NR 1b -, comprising a combination of one or more groups selected from arylene and heteroarylene, R 1b However, hydrogen or C 1 -C 6 A JAK inhibitory analog according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor is alkyl.

6. B, 【Chemistry 2】 Includes, G is C 4 -C 10 Cycloalkylene, C 4 -C 10 Heterocyclylene, C 4 -C 10 Arirene, or C 4 -C 10 It is a heteroarylene, and each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently C 1 -C 6 Alkyl, amino, C 1 -C 6 Alkoxy, hydroxy, hydroxy C 1 -C 6 Alkyl or amino C 1 -C 6 It may be substituted with one, two, three, or four substituents selected from alkyl groups. J is bonded, or -C(R 1c ) 2 -, -CH=CH-, -C≡C-, -O-, -NR 1c -, -S-, -C(O)-, -C(NR 1c )-, -S(O)-, and -S(O) 2 A linker comprising a combination of one or more groups selected from -, each R 1c However, independently, hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 A JAK inhibitor analog according to claim 1 or 2, selected from alkynyl, or a pharmaceutically acceptable salt thereof.

7. J, 【Transformation 3】 A JAK inhibitory analog according to claim 6, or a pharmaceutically acceptable salt thereof, comprising or wherein J is a bond.

8. B, 【Chemistry 4】 A JAK inhibitor analog according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising the above.

9. The JAK inhibitor analog is a compound of formula (I): 【Transformation 5】 (In the formula, Z is NR a And R a is H or C 1 -C 6 It is alkyl, R 1 is alkyl or SO 2 -R 2 And R 2 C 1 -C 6 Alkyl, C 3 -C 9 Cycloalkyl, C 3 -C 9 Heterogeneous rings, and N(R) b ) 2 Selected from, each R b These are, independently, hydrogen and C 1 -C 6 Alkyl, C 3 -C 9 Cycloalkyl, and C 3 -C 9 Selected from or both R complex algebras b These, together with the nitrogen atoms to which they are bonded, form optionally substituted five-membered or six-membered rings. X is O, SO 2 , or CH 2 And, Y is NH, O, or CH 2 And, W is C 4 -C 10 cycloalkylene, C 4 -C 10 heterocyclylene, C 4 -C 10 arylene, or C 4 -C 10 heteroarylene, and each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, hydroxy, hydroxyC 1 -C 6 alkyl, or aminoC 1 -C 6 alkyl and may be substituted, J' is a bond, or -C(R c ) 2 -, -CH=CH-, -C≡C-, -O-, -NR c -, -S-, -C(O)-, -C(NR c )-, -S(O)-, and -S(O) 2 A linker comprising a combination of one or more groups selected from -, each R c These are, independently, hydrogen and C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Selected from Alkinir, n is 1, 2, 3, 4, 5, or 6. L' is a cutting linker. The JAK inhibitor analog according to claim 1, or a pharmaceutically acceptable salt thereof.

10. J', 【Transformation 6】 A JAK inhibitory analog according to claim 9, or a pharmaceutically acceptable salt thereof, comprising or having J' as a bond.

11. The JAK inhibitor analog is a compound of formula (Ia): 【Transformation 7】 The JAK inhibitor analog according to claim 9, or a pharmaceutically acceptable salt thereof.

12. A JAK inhibitory analog according to claim 9 or 11, or a pharmaceutically acceptable salt thereof, wherein Z is NH and X and Y are O.

13. R 1 However, -SO 2 -N(R) b ) 2 The JAK inhibitor analog according to claim 9 or 11, or a pharmaceutically acceptable salt thereof, wherein one Rb is hydrogen and the other is a C1-C6 alkyl group.

14. A JAK inhibitor analog according to claim 9 or 11, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

15. L' is 【Transformation 8】 Includes, E 2 However, C 4 -C 10 Cycloalkylene, C 4 -C 10 Heterocyclylene, C 4 -C 10 Arirene, or C 4 -C 10 It is a heteroarylene, and each cycloalkylene, heterocyclylene, arylene, or heteroarylene is independently C 1 -C 6 Alkyl, amino, C 1 -C 6 Alkoxy, hydroxy, hydroxy C 1 -C 6 Alkyl, amino C 1 -C 6 Alkyl, or -COO-R d It may be substituted with one, two, three, or four substituents selected from the following: R d However, hydrogen or C 1 -C 6 A JAK inhibitory analog according to claim 9 or 11, or a pharmaceutically acceptable salt thereof, wherein the JAK inhibitor is alkyl.

16. L' is further, -CH 2 -, -O-, -NR e A JAK inhibitory analog according to claim 15, comprising a combination of one or more groups selected from -, arylene, and heteroarylene, or a pharmaceutically acceptable salt thereof.

17. The aforementioned compound, 【Chemistry 9-1】 【Chemistry 9-2】 The JAK inhibitor analog according to claim 1, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising an effective amount of the JAK inhibitor analog described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition for treating or preventing a disease or disorder, comprising the JAK inhibitor analog described in Claim 1, or a pharmaceutically acceptable salt thereof.

20. Compound of formula (II): 【Chemistry 10】 (In the formula, Q is, 【Chemistry 11】 And, Z' is NR c And R c is H or C 1 -C 6 It is alkyl, R 3 is alkyl or SO 2 -R 4 And R 4 C 1 -C 6 Alkyl, C 3 -C 9 Cycloalkyl, C 3 -C 9 Heterogeneous rings, and N(R) d ) 2 Selected from, each R d These are, independently, hydrogen and C 1 -C 6 Alkyl, C 3 -C 9 Cycloalkyl, and C 3 -C 9 Selected from or both R complex algebras d These, together with the nitrogen atoms to which they are bonded, form optionally substituted five-membered or six-membered rings. R 5 is hydrogen, -CH 2 - OCH 3 , or -CH 2 - (OCH 2 CH 2 ) - OCH 3 And, R 6 is, -OCH 3 or -OCH 2 CH 2 - OCH 3 (is) or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising an effective amount of the compound according to claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition for treating or preventing a disease or disorder, comprising the compound according to claim 20, or a pharmaceutically acceptable salt thereof.

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