Triazine compounds and methods of making and using same - Patents.com

Abstract

Disclosed herein are triazine compounds (e.g., triazines and pyrazole triazines) and methods of treating diseases and / or conditions (e.g., inflammation) using the triazine compounds disclosed herein. In some embodiments, the disclosed triazine compounds are used to inhibit Jumonji domain-containing protein D3 (JMJD3) and / or treat JMJD3-related pathologies.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 141,316, filed January 25, 2021. The disclosure of the aforementioned application is incorporated herein by reference in its entirety. Any and all applications for which a foreign or domestic priority claim is identified in an Application Data Sheet filed with this application are incorporated herein by reference under 37 CFR 1.57.

[0002] Disclosed herein are triazine compounds (e.g., triazines), including functionalized triazine compounds (e.g., pyrazole triazines), pharmaceutical compositions comprising same, methods of using same, and methods of making the disclosed triazine compounds. [Background technology]

[0003] Jumonji proteins are the basic members of a group of proteins characterized by a novel structural motif, the JmjC domain. This is a broad group of demethylase enzymes that can be defined in several families according to sequence similarity within the JmjC domain and the presence of other domains in the full-length protein. The JmjC domain of some members of this family has been shown to have lysine demethylation activity, which depends on iron (Fe(II)) and a-ketoglutarate as a cofactor. JmjC domain-containing histone demethylases (JHDMs) can remove all three histone lysine-methylation states, unlike LSD1, which can only remove mono- and dimethyl-lysine modifications. Jumonji domain-containing protein D3 (JMJD3) is a member of this family of JmjC histone demethylases. Summary of the Invention [Means for solving the problem]

[0004] Some embodiments disclosed herein relate to triazine compounds and their use as inhibitors of Jumonji proteins, including JMJD3. Some embodiments relate to methods of making such compounds. Some embodiments relate to methods of using these compounds as therapeutics for treating disease conditions, such as inflammatory diseases, autoimmune diseases, and cancer. In some embodiments, the triazine compounds include substituted triazines linked to a heteroaryl group. In some embodiments, the heteroaryl is a pyrazole (e.g., pyrazolyl). In some embodiments, the heteroaryl group is pyridinyl. In some embodiments, one or more triazine compounds can be used to treat a disease condition by inhibiting the activity of JMJD3 in a subject.

[0005] Some embodiments include triazine compounds, pharma- ceutically acceptable salts thereof, enantiomers, methods of preparation, and / or methods of use thereof in the treatment of a medical condition. In some embodiments, the triazine compounds (or pharmaceutical compositions comprising triazine compounds) comprise, consist of, or consist essentially of a structure of formula (I) (or any other structure disclosed herein), a pharma- ceutically acceptable salts thereof, and / or enantiomers. Some embodiments include methods of preparation of compounds of formula (I) and / or methods of use of compounds of formula (I) in the treatment of a medical condition. In some embodiments, one or more compounds of formula (I) (or any other structure disclosed herein) can be used to treat a medical condition by inhibiting the activity of JMJD3 in a subject. In some embodiments, the medical condition is associated with inflammation. In some embodiments, the medical condition is associated with an autoimmune disorder.

[0006] Some embodiments include a structure represented by formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, L is -C(R 1 )2-, -N-, -NR 1 -, -N(R 1 )2, optionally substituted amine (alkyl), -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, and optionally substituted heterocyclyl, or L is absent, and A a is selected from the group consisting of optionally substituted C1-C6 alkylene and C1-C6 alkyl, or A a does not exist, and A b is selected from the group consisting of -C(=O)- and -N(CH3)-, or A b is absent, A1 is -H, hydroxyl, amino, optionally substituted C 1~12 Alkyl, optionally substituted C1-C 12 Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted carbamide, C-amide, optionally substituted C 6~10 Aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10 or A1 is absent and A2 is selected from the group consisting of optionally substituted C 6~10 aryl, optionally substituted 5-12 membered heteroaryl, and optionally substituted 3-12 membered heterocyclyl; A c is C 1~3 alkylene, C1-C3 alkamino, and -O-; or c is absent, A3 is -H, optionally substituted C 1~12 Alkyl, optionally substituted C1-C 12 Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted C 6~10Aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10 carbocyclyl, and optionally substituted 3- to 12-membered heterocyclyl; R 1 is, when present, independently at each occurrence, -H, halogen, hydroxy, C 1~6 Alkyl, C1-C6 alkoxy, C 1~6 Haloalkyl, and C 6~10 aryl, or two R 1 When the R group is present, 1 The groups taken together form an optionally substituted 3- to 12-membered heterocycle or an optionally substituted C 3~10 to form a carbocyclyl].

[0008] In some embodiments, L is -N(R 1 )2, and R 1 The groups taken together form a 3- to 12-membered heterocyclyl group. In some embodiments, L is a 6-membered heterocyclyl group containing 1 or 2 heteroatoms. In some embodiments, the heteroatom of L is N. In some embodiments, A a and A b is absent. In some embodiments, A1 is a 3-12 membered heterocyclyl group. In some embodiments, the ring of A1 and the ring of L together form a spiro ring system. In some embodiments, L, A a , A b , and A1, taken together,

[0009] [ka] This results in a structure selected from the group consisting of:

[0010] In some embodiments, L is -NH-. a is C1-C6 alkylene. ais C1-C3 alkylene. b In some embodiments, A is -C(=O)- or absent. 1~3 In some embodiments, L, A are carbamido optionally substituted with alkyl, methyl or ethyl, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, or C1-C3 alkoxy. a , A b , and A1, taken together,

[0011] [ka] Any one of the preceding structures may be provided with one or more -H atoms in a group selected from the group consisting of L, A a , A b and optionally further substituted by replacing any carbon or nitrogen atom present within the A1 structure.

[0012] In some embodiments, A a In some embodiments, A is absent. b In some embodiments, A is C optionally substituted with hydroxyl or halogen. 1~4 Alkyl, optionally substituted C 3~6 In some embodiments, L, A are independently selected from the group consisting of carbocyclyl, 3- to 6-membered heterocyclyl, 3- to 6-membered aryl optionally substituted with halogen, and 3- to 6-membered heteroaryl. a , A b , and A1, taken together,

[0013] [ka] Any one of the preceding structures may be provided with one or more -H atoms in a group selected from the group consisting of L, A a , A band optionally further substituted by replacing any carbon or nitrogen atom present within the A1 structure.

[0014] In some embodiments, A2 is selected from the group consisting of optionally substituted 5-6 membered heteroaryl or optionally substituted 5-6 membered heterocyclyl.

[0015] [ka] Any one of the foregoing structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the A2 structure.

[0016] In some embodiments, A c is -O- or absent. In some embodiments, A3 is C 1~5 alkyl, phenyl optionally substituted with -F, C1-C3 alkamino, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10 In some embodiments, A is selected from the group consisting of carbocyclyl and optionally substituted 3- to 12-membered heterocyclyl. c and A3, taken together,

[0017] [ka] Any one of the preceding structures may be provided with one or more -H atoms in an A c and A3 may be optionally further substituted by replacing any carbon or nitrogen atom present within the structure.

[0018] In some embodiments, A c is C 1~3In some embodiments, A3 is phenyl optionally substituted with -F and optionally substituted C 3~7 In some embodiments, A is selected from the group consisting of carbocyclyl. c and A3, taken together,

[0019] [ka] Any one of the preceding structures may be provided with one or more -H atoms in an A c and A3 may be optionally further substituted by replacing any carbon or nitrogen atom present within the structure.

[0020] Some embodiments include a structure represented by formula (I):

[0021] [ka] In some embodiments, L is -C(R 1 )2-, -N-, -NR 1 -, -N(R 1 )2, optionally substituted amines (alkyl), -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, and a single bond. In some embodiments, A a is selected from the group consisting of optionally substituted C1-C6 alkylene and C1-C6 alkyl. In some embodiments, A a In some embodiments, A is absent. b is selected from the group consisting of -C(=O)- or -N(CH3)-. b In some embodiments, A is hydroxyl, amino, optionally substituted C 1~12 Alkyl, optionally substituted C1-C 12Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted carbamide, C-amide, optionally substituted C 6~10 Aryl, 5-12 membered heteroaryl, C 3~10 In some embodiments, A1 is absent. In some embodiments, A2 is selected from the group consisting of C 6~10 In some embodiments, A is selected from the group consisting of aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl. c is C 1~3 In some embodiments, A3 is selected from the group consisting of optionally substituted C 1~12 Alkyl, C1-C 12 Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted C 6~10 In some embodiments, R is selected from the group consisting of aryl, 5-12 membered heteroaryl, and optionally substituted 3-12 membered heterocyclyl. 1 is, when present, independently at each occurrence, -H, halogen, hydroxy, C 1~6 Alkyl, C1-C6 alkoxy, C 1~6 Haloalkyl, and C 6~10 In some embodiments, two R 1 When the R group is present, 1 The groups taken together form a 3- to 12-membered heterocycle or C 3~10 Forms a carbocyclyl.

[0022] In some embodiments, A a , A b When any one of A1, A2, and A3 is substituted with one or more optional substituents, each of the one or more optional substituents is independently selected from the group consisting of -OH, C 1~3 Alkyl, C 1~3In some embodiments, when A is substituted with one or more optional substituents, the one or more optional substituents are independently selected from the group consisting of acyl, C 1~6 Alkyl, C 1~6 In some embodiments, when the A3 group is substituted with one or more optional substituents, the one or more optional substituents are independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Cycloalkyl, C 6~10 It is selected from the group consisting of aryl, halogen, and hydroxy.

[0023] In some embodiments, the compound of formula (I) has the structure of formula (Ia):

[0024] [ka] where n is an integer equal to 1, 2, or 3.

[0025] In some embodiments, the compound of formula (I) has the structure of formula (Ib):

[0026] [ka] In some embodiments, the definition of a similar variable in a different formula (such as A2 for formula (I) and formula (Ia), A3 for formula (I) and formula (Ib)) can be used to define that similar variable for any formula in which the variable occurs. Thus, any definition of a variable for formula (I) can be defined using that same variable for any one or more of formulas (Ia), (Ib), (Ic), (Id), and (Ie) (or vice versa).

[0027] In some embodiments, the compound of formula (I) is one of the following:

[0028] [ka] [ka] In some embodiments, the compound of formula (I) has the structure of formula (Ic):

[0029] [ka] In some embodiments, the ring containing A4 is a 5- or 6-membered heteroaryl. In some embodiments, the compound of formula (I) is one of the following:

[0030] [ka] [ka] This is further represented by:

[0031] In some embodiments, the compound of formula (I) has the structure of formula (Id):

[0032] [ka] In some embodiments, X is selected from the group consisting of -CH2-, -NH-, and -O-, m is an integer equal to 1, 2, 3, or 4, and o is an integer equal to 1, 2, 3, or 4. In some embodiments, the compound of formula (I) is

[0033] [ka] It is represented by:

[0034] In some embodiments, the compound of formula (I) has the structure of formula (Ie):

[0035] [ka] In some embodiments, the compound of formula (I) is further represented by:

[0036] [ka] It is represented by:

[0037] In some embodiments, A1 is selected from the group consisting of CH3-, CF3-, CH3(CH2)3-, (CH3)2CH-, (CH3)2CHCH2-, CH3(CH2)3-, CH3(HO)CH-, HOCH2-, CH3CHOCH2-, NH2C(=O)CH2-, CH3O-, CH3CHO-, NH2-, NH2C(=O)NH-, and CH3CH2NHC(=O)NH-. In some embodiments, A1 is selected from the group consisting of:

[0038] [ka] is selected from the group consisting of:

[0039] In some embodiments, A2 is selected from the group consisting of pyrazole and pyridine.

[0040] In some embodiments, A3 is

[0041] [ka] is selected from the group consisting of:

[0042] Some embodiments relate to methods of inhibiting the activity of Jumonji proteins, including JMJD3. In some embodiments, the triazine compounds disclosed herein inhibit (are used to inhibit) one or more of TNF-alpha (TNFA), interleukin 6 (IL6), interleukin 1 beta (IL1B), interleukin 8 (IL8), interleukin 5 (IL5) and interleukin 13 (IL13). In some embodiments, the triazine compounds disclosed herein are suitable for use in methods of treating autoimmune diseases, including ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, psoriasis, type 1 diabetes, graft-versus-host disease (GVHD), autoimmune encephalitis, Behcet's disease, Sjogren's syndrome, asthma, pulmonary allergy, and atopic dermatitis. In some embodiments, the triazine compounds disclosed herein are suitable for use in methods of treating lupus, rheumatoid arthritis (reumatoid), atopic dermatitis, and psoriasis. In some embodiments, the method comprises administering a triazine compound (e.g., a pyrazolyltriazine) disclosed herein to a patient in need of treatment, thereby treating the patient. In some embodiments, in response to determining the presence of inflammatory and autoimmune diseases in a sample from a subject, the subject is administered an effective amount of a compound, thereby treating the inflammatory and autoimmune diseases in the subject.

[0043] In some embodiments, the triazine compounds disclosed herein are suitable for use in methods of treating cancer (e.g., kidney, breast, prostate, skin, hematopoietic system, myelodysplastic syndromes (MDS), esophageal squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and ovarian cancer). In some embodiments, the methods include administering a triazine compound disclosed herein (e.g., a pyrazolyl triazine) to a patient in need of treatment, thereby treating the patient. In some embodiments, in response to determining the presence of cancer in a sample from the subject, the subject is administered an effective amount of the compound, thereby treating the cancer in the subject. [Brief description of the drawings]

[0044] [Figure 1A] 1 provides reaction routes for the preparation of some embodiments of compounds of formula (I). [Figure 1B] 1 is a scheme providing three synthetic routes for the preparation of some embodiments of compounds of formula (I). [Diagram 2] 1 is a scheme providing additional synthetic routes for the preparation of some embodiments of compounds of formula (I). [Diagram 3] 4 provides data from a cellular assay for the FoxP3-inducing activity of JMJD3 inhibitors. [Figure 4A] This paper provides cellular data for compounds disclosed herein that resulted in suppression of TNF-alpha (TNFA) expression following LPS (lipopolysaccharide) treatment in THP-1 human monocytes, providing data (p<005) for the JMJD3 inhibitors compound 89 and compound 91. [Figure 4B] Disclosed herein is cellular data for compounds that resulted in suppression of TNF-alpha (TNFA) expression following LPS (lipopolysaccharide) treatment in THP-1 human monocytes, with data provided for JMJD3 inhibitors Compound 97, Compound 92, and Compound 93 (p<0.01). [Figure 4C] Disclosed herein is cellular data for compounds that resulted in suppression of TNF-alpha (TNFA) expression following LPS (lipopolysaccharide) treatment in THP-1 human monocytes, with data provided for the JMJD3 inhibitor compound 94 (p less than 0.01). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Some embodiments disclosed herein provide compounds useful for inhibiting the activity of JMJD3 in a subject. Some embodiments also provide methods of utilizing these compounds to treat disease or pharmaceutical compositions including these compounds. In some embodiments, the compounds are triazine compounds. In some embodiments, multiple functional groups are attached to a core triazine structure, including heteroaryls (e.g., pyrazolyl, pyridinyl, etc. attached to the triazine ring). In some embodiments, the disclosed triazines can be used in methods of treating inflammatory and autoimmune diseases. In some embodiments, the disclosed triazines can be used in methods of treating cancer. The following description provides context and examples, but should not be construed as limiting the scope of the invention contained in the claims that follow this specification or to any other application claiming priority hereto. No single component or collection of components is necessary or essential. For example, in some embodiments where a structure is disclosed, one or more variables of the structure may be omitted (e.g., R 1 , L., A. a , A b etc. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment herein may be used in conjunction with or in place of any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment herein.

[0046] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications, and other publications are incorporated by reference in their entirety.In the event that there are multiple definitions for terms herein, the definitions in this section shall prevail unless otherwise stated.

[0047] A "prodrug" refers to a drug that is converted to the parent drug in vivo. Prodrugs are often useful because they can be administered more easily than the parent drug in certain situations. Prodrugs can be, for example, bioavailable by oral administration, whereas the parent is not. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. Examples of prodrugs include, but are not limited to, compounds that are administered as esters ("prodrugs") to facilitate penetration across cell membranes where water solubility would be detrimental to mobility, and then metabolically hydrolyzed to the active entity, a carboxylic acid, once inside the cell where water solubility would be beneficial. A further example of a prodrug can be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference in its entirety.

[0048] The term "prodrug ester" refers to derivatives of the compounds disclosed herein formed by adding any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other such groups known in the art, including (5-R-2-oxo-1,3-dioxolen-4-yl)methyl groups. Other examples of prodrug ester groups can be found, for example, in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series, American Chemical Society (1975), and "Bioreversible Carriers in Drug Design: Theory and Application," EB Roche, ed., Pergamon Press: New York, pp. 14-21 (1987) (providing examples of esters useful as prodrugs of compounds containing a carboxyl group). Each of the aforementioned references is incorporated herein by reference in their entirety.

[0049] "Metabolites" of the compounds disclosed herein include active species produced upon introduction of the compounds into the biological milieu.

[0050] "Solvate" refers to a compound formed by the interaction of a solvent with a compound described herein, its metabolite, or salt. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0051] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound that are biologically and otherwise desirable for use in a pharmaceutical product. In many cases, the compounds herein are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium, potassium, sodium, calcium and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO87 / 05297, published September 11, 1987 by Johnston et al., which is incorporated herein by reference in its entirety.

[0052] When referring to numerical values, the term "or a range including and / or spanning the aforementioned value" (and variations thereof) is meant to include any range including or spanning the aforementioned value. For example, if a reaction temperature is expressed as "20°C, 30°C, 40°C, 50°C, or a range including and / or spanning the aforementioned value," this includes the specific temperature provided or the temperature range spanning 20°C-50°C, 20°C-40°C, 20°C-30°C, 30°C-50°C, 30°C-40°C, or 40°C or 50°C.

[0053] As used herein, "C a ~C b (where "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl group ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, or heteroaryl ring can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons (e.g., 1, 2, 3, or 4), i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. A "C1-C6 alkyl" group refers to any alkyl group having 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6). When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl group, the ranges described in those definitions are included (including the broadest range).

[0054] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group can have 1 to 20 carbon atoms (as disclosed elsewhere herein, whenever an alkyl group appears herein, a numerical range such as "1 to 20" refers to each integer in the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, although the definition of the present invention also covers occurrences of the term "alkyl" where no numerical range is specified). An "alkyl" group can also be a medium-sized alkyl having 1 to 12 carbon atoms. An "alkyl" group can also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be a "C 1~6 By way of example only, "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. By way of example only, "C1-C5 alkyl" indicates that there are 1 to 5 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight chain), and the like. Typical alkyl groups include, but are not limited to, methyl ("Me" or -CH3), ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. Alkyl groups can be unsubstituted or substituted.

[0055] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. Alkenyl groups can be unsubstituted or substituted as described in the definition of "alkyl."

[0056] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in the straight or branched hydrocarbon chain. Alkynyl groups can be unsubstituted or substituted as described in the definition of "alkyl."

[0057] As used herein, the term "alkylene" refers to a divalent, fully saturated, straight-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. An alkylene group is:

[0058] [ka] followed by that number of carbon atoms, * " followed by ". For example,

[0059] [ka] represents ethylene. The alkylene group can have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as "1 to 20" refer to each integer in the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition of the present invention also covers occurrences of the term "alkylene" where no numerical range is specified). The alkylene group can also be a medium size alkyl having 1 to 12 carbon atoms. The alkylene group can also be a lower alkyl having 1 to 6 carbon atoms. For example, a lower alkylene group can be obtained by replacing one or more hydrogens with a lower alkylene group and / or by replacing both hydrogens on the same carbon with a C 3~6 Monocyclic cycloalkyl groups, such as

[0060] [ka] ) can be substituted. It should also be understood that certain radical naming conventions can include either monoradicals or diradicals depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as alkyl, which requires two points of attachment, includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene." Alkylene groups can be substituted or unsubstituted.

[0061] The term "halogen" or "halo" as used herein means any one of the radiation-stable atoms in the seventh column of the periodic table of the elements, e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0062] As used herein, "haloalkyl" refers to a straight or branched chain alkyl group in which one or more hydrogens are replaced with halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that may be considered equivalent to any one of the preceding examples in light of ordinary skill in the art and the teachings provided herein. Haloalkyl groups may be medium-sized or lower haloalkyl groups. Haloalkyl groups may be substituted or unsubstituted.

[0063] As used herein, "alkoxy" refers to a group of the formula -OR, where R is alkyl as defined above, such as, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. 1~9 R refers to "alkoxy." R can also be a carbocyclyl group. The alkoxy group can be substituted or unsubstituted.

[0064] As used herein, "polyethylene glycol" refers to a compound of the formula

[0065] [ka] where n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by reference to the number of members. Thus, for example, "2-5 membered polyethylene glycol" refers to n being an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0066] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain (e.g., alkyl) containing one or more heteroatoms. Heteroatoms are given their plain and ordinary meaning in organic chemistry and include elements other than carbon, including, but not limited to, nitrogen (e.g., amino, etc.), oxygen (e.g., alkoxy, ether, hydroxyl, etc.), sulfur, and halogens. Heteroalkyl groups can have 1-20 carbon atoms, although the definition of the present invention also covers occurrences of the term "heteroalkyl" where no numerical range is specified. Heteroalkyl groups can also be medium size heteroalkyls having 1-12 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having 1-6 carbon atoms. In various embodiments, heteroalkyls can have 1-4 heteroatoms, 1-3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl groups of a compound are defined as "C 1~4 A heteroalkyl group may be designated as "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" indicates that the heteroalkyl chain has 1 to 4 carbon atoms, and that in addition, one or more heteroatoms are present in the backbone of the chain. Heteroalkyl groups can be substituted or unsubstituted.

[0067] The term "aromatic" refers to a ring or ring system having a conjugated pi-electron system, and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (e.g., pyridine) groups. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0068] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, all rings of the system are aromatic. An aryl group can have 6 to 18 carbon atoms, although the definition of the present invention also covers occurrences of the term "aryl" where no numerical range is specified. In some embodiments, an aryl group has 6 to 10 carbon atoms. An aryl group is defined as "C 6~10 Aryl, C6 or C 10 Aryl groups may be designated as C6 to C8, or similar names. For example, an aryl group may be any group having a C 14 Aryl groups, C6-C 10 It may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl. The aryl group may be substituted or unsubstituted.

[0069] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, including, but not limited to, phenyloxy. 6~10 aryloxy" or "C 6~10 The aryloxy or arylthio group may be substituted or unsubstituted.

[0070] "Aralkyl" or "arylalkyl" refers to an aryl group attached as a substituent via an alkylene group, including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. 7~14 In some cases, the alkylene group is a lower alkylene group (i.e., C 1~6 An aralkyl or arylalkyl group may be substituted or unsubstituted.

[0071] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in the ring backbone. When a heteroaryl is a ring system, all rings of the system may be aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although the definition of the present invention also covers occurrences of the term "heteroaryl" where no numerical range is specified. For example, heteroaryl groups can contain 4 to 14 ring members (atoms in the ring(s)), 5 to 10 ring members (atoms in the ring(s)), 5 to 7 ring members (atoms in the ring(s)), 5 to 6 ring members (atoms in the ring(s)). Heteroaryl groups may be designated as "5-7 membered heteroaryl", "5-10 membered heteroaryl", or similar designations. In various embodiments, the heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom.Examples of heteroaryl rings include furan (e.g., furyl), furazan (e.g., furazanyl), thiophene (e.g., thienyl), benzothiophene (e.g., benzothienyl), phthalazine (e.g., phthalazinyl), pyrrole (e.g., pyrrolyl), oxazole (e.g., oxazolyl), benzoxazole (e.g., benzoxazolyl), 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole (e.g., thiazolyl), 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole (e.g., benzothiazolyl), imidazole (e.g., imidazolyl), benzimidazole (e.g., benzimidazolyl), indole (e.g., indolyl), isoindole (e.g., isoindole), and the like. Heteroaryl rings include, but are not limited to, pyrazole (e.g., pyrazolyl), indazole, pyrazole (e.g., pyrazolyl), benzopyrazole, isoxazole (e.g., isoxazolyl), benzisoxazole, isothiazole (e.g., isothiazolyl), triazole (e.g., triazolyl), benzotriazole, thiadiazole (e.g., thiadiazolyl), tetrazole, pyridine (e.g., pyridinyl), pyridazine (e.g., pyridazinyl), pyrimidine (e.g., pyrimidinyl), pyrazine (e.g., pyrazinyl), purine, pteridine, quinoline (e.g., quinolinyl), isoquinoline (e.g., isoquinlinyl), quinazoline, quinoxaline, cinnoline, and triazine (e.g., triazinyl). Heteroaryl rings may also contain a bridgehead nitrogen atom. Examples include, but are not limited to, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. Heteroaryl groups can be substituted or unsubstituted.

[0072] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group bonded as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. Heteroaralkyl groups can be substituted or unsubstituted.

[0073] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl is a ring system, two or more rings may be bonded to each other in a fused, bridged or spiro-linked fashion. A carbocyclyl can have any degree of saturation, provided that at least one ring in the ring is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, although the definition of the present invention also covers occurrences of the term "carbocyclyl" where no numerical range is specified. A carbocyclyl group can also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group can also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is defined as a "C 3~6 Carbocyclyl groups may be designated as "carbocyclyl" or similar names. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl. Carbocyclyl groups may be substituted or unsubstituted.

[0074] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds present). When composed of more than one ring, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s), or as described elsewhere herein. Cycloalkyl groups can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0075] "(Carbocyclyl)alkyl" refers to a carbocyclyl group attached as a substituent via an alkylene group, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. 4~10 (carbocyclyl)alkyl." In some cases, the alkylene group is a lower alkylene group.

[0076] As used herein, "cycloalkenyl" refers to a carbocyclyl ring or ring system having at least one double bond and where no ring in the ring system is aromatic. An example is cyclohexenyl. Cycloalkenyl groups can contain 4 to 10 atoms in the ring(s). Cycloalkenyl groups can be substituted or unsubstituted.

[0077] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, up to 20-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms together with 1-5 heteroatoms constitute the ring system. The heterocycle may optionally contain one or more unsaturated bonds, but the unsaturated bonds are positioned in such a way that a completely delocalized pi-electron system does not occur throughout all rings. The heteroatom(s) may be present in either non-aromatic or aromatic rings in the ring system. The heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functionalities such that the definition includes oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of more than one ring, the rings may be joined together in a fused fashion. In addition, any nitrogen in a heteroalicyclic may be quaternized. A heterocyclyl or heteroalicyclic group may be unsubstituted or substituted.Examples of such "heterocyclyl" or "heteroalicyclyl" groups include 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxophenyl, phenylmethylsulfonyl ... Examples of heterocyclyl groups include, but are not limited to, sazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl). The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. Heterocyclyl groups may be designated as "3- to 6-membered heterocyclyl" or similar designations. Heterocyclyl groups can be substituted or unsubstituted.

[0078] In various embodiments, the heterocyclyl contains 1-4 heteroatoms, 1-3 heteroatoms, 1-2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains 1-4 nitrogen atoms, 1-3 nitrogen atoms, 1-2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred 6-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1-3 of O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2H-1,2-oxazinyl, trioxanyl, hexanyl, 1,3-dioxan ... Examples of heterocyclyl groups include, but are not limited to, sahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline. The sulfur of the heterocyclyl ring may be provided as a dioxide (e.g., -S(O)2-).

[0079] "(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0080] A "(heterocyclyl)alkynyl" is a heterocyclyl group attached as a substituent via an alkynylene group.

[0081] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl groups may be substituted or unsubstituted.

[0082] An "O-carboxy" group refers to a "-OC(=O)R" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. O-carboxy may be substituted or unsubstituted.

[0083] A "C-carboxy" group (or "ester") refers to a "-C(=O)OR" group, where R is hydrogen, -NH, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7It is selected from carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A non-limiting example includes carboxyl (i.e., -C(=O)OH). C-carboxy may be substituted or unsubstituted.

[0084] As used herein, the term "hydroxy" refers to an --OH group.

[0085] A "cyano" group refers to a "-CN" group.

[0086] A "cyanate" group refers to a "-OCN" group.

[0087] An "isocyanate" group refers to a "-NCO" group.

[0088] A "thiocyanate" group refers to a "-SCN" group.

[0089] An "isothiocyanate" group refers to a "-NCS" group.

[0090] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. The sulfinyl may be substituted or unsubstituted.

[0091] A "sulfonyl" group refers to a "-SO2R" or "-SO2-" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10It is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. The sulfonyl can be provided on the heterocyclyl ring. The sulfonyl can be substituted or unsubstituted.

[0092] The "S-sulfonamide" group is "-SONR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R B can be taken together to provide a heteroaryl or heterocycle. S-sulfonamides can be substituted or unsubstituted.

[0093] An “N-sulfonamide” group is defined as “-N(R A )SO2R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. N-sulfonamide may be substituted or unsubstituted.

[0094] The "O-carbamyl" group is "-OC(=O)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R B can be taken together to provide a heteroaryl or heterocycle. O-carbamyl can be substituted or unsubstituted.

[0095] The "N-carbamyl" group is defined as "-N(R A )OC(=O)R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. N-carbamyl may be substituted or unsubstituted.

[0096] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R B can be taken together to provide a heteroaryl or heterocyclic ring. O-thiocarbamyl can be substituted or unsubstituted.

[0097] The "N-thiocarbamyl" group is defined as "-N(R A )OC(=S)RB " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. N-thiocarbamyl may be substituted or unsubstituted.

[0098] A "C-amide" group is defined as "-C(=O)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R B can be taken together to provide a heteroaryl or heterocycle. The C-amide can be substituted or unsubstituted.

[0099] An "N-amide" group is defined as "-N(R A )C(=O)R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R Bcan be taken together to provide a heteroaryl or heterocycle. N-amides can be substituted or unsubstituted.

[0100] The "amino" group is "-NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 R is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. A and R B can be taken together to provide a heteroaryl or heterocycle. Amino can be substituted or unsubstituted.

[0101] The "alkamino" group is "-NR A R B " group, where R A is C 1~6 Alkylene (e.g., bonded to a specified structural substituent) or C 1~6 is alkyl, R B are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 Alkamino is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Alkamino may be substituted or unsubstituted.

[0102] An "aminoalkyl" group refers to an amino group attached via an alkylene group. The aminoalkyl can be substituted or unsubstituted.

[0103] The "carbamide" or "carbamido" group is defined as "(R A R B)NC(=O)N(R C )-" group, where R A , R B , and R C may be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein. Carbamide may be substituted or unsubstituted.

[0104] An "alkoxyalkyl" group is an alkoxy group attached via an alkylene group, e.g., "C 2~8 Alkoxyalkyl" and the like. Alkoxyalkyl can be substituted or unsubstituted.

[0105] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", it is understood that the group is selected from the group consisting of C1-C6 alkyl (optionally substituted with -OH or C-carboxy), C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 5-10 membered heterocyclyl (optionally substituted with N-amido, -OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5-10 membered heteroaryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), haloalkoxy, cycloalkenyl, halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3),It means substituted with one or more substituents independently selected from halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, monosubstituted amine group, disubstituted amine group, monosubstituted amine (alkyl), disubstituted amine (alkyl), nitro, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanate, isocyanate, thiocyanate, isothiocyanate, sulfenyl, sulfinyl, sulfonyl, -O-NH2, oxo (=O), diamino group, polyamino, diether group, and polyether (e.g., diethylene glycol, triethylene glycol, oligoethylene glycol, polyethylene glycol, etc.). Whenever a group is described as being "optionally substituted" (or other similar language) or as containing one or more "optional substituents," the group may be substituted or unsubstituted with the said substituents.

[0106] In some embodiments, the substituted group(s) are substituted with one or more substituent(s) individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0107] Two substituents, together with the atom or atoms to which they are attached, can form a ring, which is spiro or fused to the remainder of the compound.

[0108] As used herein, any "R" group(s) includes, but is not limited to, R 1 , R 2 , R 3etc. represent substituents that may be attached to the specified atom. The R group may be substituted or unsubstituted. When two "R" groups are described as "together" (or similar language), the R groups and the atoms to which they are attached can form a cycloalkyl, aryl, heteroaryl, or heterocyclic ring. When two R groups are described as forming a ring "together with the atom to which they are attached" (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring), it is meant that the collective unit of that atom and the two R groups is the described ring. The ring is otherwise not limited by the definition of each R group when taken individually. For example, the substructure

[0109] [ka] exists and R 1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the moiety may be selected from the structure

[0110] [ka] where Ring A is the nitrogen-containing heterocyclyl ring as shown. Further examples include, but are not limited to, NR 1a R 1b R in the group 1a and R 1b When are specified as "together," they are covalently bonded to each other to form a ring.

[0111] [ka] This means forming

[0112] The cyclic structures may be represented using the following structures (or similar structures having different ring sizes, heteroatoms, etc.):

[0113] [ka] When a cyclic structure is depicted using this type of structure, it is meant that the R group may be attached at any position on the ring by replacing the -H of the ring with -R. For example, the ring

[0114] [ka] With respect to the above, any one of the following ring structures is included:

[0115] [ka] During the ceremony, ``

[0116] [ka] " indicates a bond to the remainder of the structure. Similarly, the following structure

[0117] [ka] [In the formula, “

[0118] [ka] " indicates a bond to the remainder of the structure, and n is 1-5], any of the following structures, or other variations (as would be readily appreciated by one of skill in the art) are envisioned:

[0119] [ka]

[0120] When two "adjacent" R groups are described as forming a ring "together with the atom to which they are attached," it is meant that the atom, the intervening bond, and the collective unit of the two R groups is the described ring. For example, the substructure

[0121] [ka] exists and R 1 and R 2 is defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or alternatively, the moiety may be selected from the structure

[0122] [ka] where A is an aryl ring or a carbocyclyl containing the double bond as shown.

[0123] Whenever a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, -AE- or

[0124] [ka] Substituents depicted as include those oriented as if "A" is attached at an attachment point on the left side of the molecule and as if "A" is attached at an attachment point on the right side of the molecule.

[0125] It should also be understood that certain radical naming conventions, as described in the definition of alkylene, can include either monoradicals or diradicals depending on the context. For example, if a substituent (e.g., in a generic structure) requires two points of attachment to the remainder of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as alkamino, which requires two points of attachment, includes diradicals such as -NHCH2-, -NHCH2CH2-, -NHCH2CH(CH3)CH2-, etc. Other examples where a substituent may require two points of attachment include alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl, etc.

[0126] As used herein, a radical refers to a species that has a single unpaired electron such that the species containing the radical can be covalently bonded to another species. Thus, in this context, a radical is not necessarily a free radical. Rather, a radical refers to a specific portion of a larger molecule.

[0127] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly specified, it is understood that each center may be independently R-configuration or S-configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a mixture of stereoisomers. In addition, in any compound described herein having one or more double bonds that result in geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. In any compound described herein having one or more chiral centers, it is understood that all possible diastereomers are also envisioned. In any compound described herein, it is understood that all tautomers are envisioned. It is also understood that in any compound described herein, all isotopes of the atoms involved are envisioned. For example, hydrogen may, in any case, include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes; carbon may, in any case, include carbon-12, carbon-13, carbon-14, or other isotopes; oxygen may, in any case, include oxygen-16, oxygen-17, oxygen-18, or other isotopes; fluorine may, in any case, include one or more of fluorine-18, fluorine-19, or other isotopes; and sulfur may, in any case, include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0128] As used herein, the term "inhibitor" refers to any compound, molecule, or composition that inhibits or reduces the activity of a target biomolecule. Inhibition can be achieved, for example, by blocking phosphorylation of the target (e.g., competing with the phosphorylating entity adenosine triphosphate (ATP)), by binding to a site outside the active site and affecting its activity by conformational changes, or by depriving kinases of access to the molecular chaperone systems that they depend on for their cellular stability, leading to their ubiquitination and degradation.

[0129] As used herein, "subject," "host," "patient," and "individual" are used interchangeably and shall be given their ordinary meanings and shall refer to organisms that possess the JMJD3 protein. This includes mammals, such as humans, non-human primates, ungulates, dogs, cats, horses, mice, rats, etc. The term "mammal" includes both human and non-human mammals.

[0130] "Diagnosis," as used herein, shall be given its ordinary meaning, and shall include determining a subject's susceptibility to a disease or disorder, determining whether a subject is currently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identifying a cancer or cancerous condition, the stage of a cancer, or the responsiveness of a cancer to treatment), and the use of therametrics (e.g., monitoring a subject's condition to provide information regarding the efficacy or effectiveness of treatment).

[0131] The term "sample" or "biological sample" shall be given its ordinary meaning and shall include various sample types obtained from an organism and may be used in imaging, diagnostic, prognostic, or monitoring assays. The term shall include blood, as well as other liquid samples of biological origin, solid tissue samples, such as biopsy specimens or tissue cultures, or cells derived therefrom and their progeny. The term shall include samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment of certain components. The term shall include clinical samples, including cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

[0132] As used herein, "natural amino acid side chain" refers to a side chain substituent of a naturally occurring amino acid. Naturally occurring amino acids have a substituent attached to the α-carbon. Naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0133] As used herein, "unnatural amino acid side chain" refers to the side chain substituents of an amino acid that does not occur naturally. Unnatural amino acids include β-amino acids (β 3 and β 2), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, and N-methyl amino acids. Exemplary unnatural amino acids are available from Sigma-Aldridge, listed under "Unnatural Amino Acids and Derivatives." See also, Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285:11039-11044, which is incorporated by reference in its entirety.

[0134] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or combination thereof. The term includes, but is not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. The term may be a natural product, a synthetic or chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent", "substance", and "compound" are used interchangeably herein.

[0135] The term "analog" is used herein to refer to a molecule that is structurally similar to a reference molecule, but is modified in a targeted and controlled manner by replacing certain substituents of the reference molecule with alternative substituents. Analogs can be expected by those skilled in the art to exhibit the same, similar, or improved utility compared to the reference molecule. The synthesis and screening of analogs to identify variants of known compounds that have improved characteristics (e.g., higher binding affinity to target molecules) is a well-known technique in pharmaceutical chemistry.

[0136] The "patient" or "subject" treated as disclosed herein is, in some embodiments, a human patient, although it should be understood that the principles of the subject matter disclosed herein demonstrate that the subject matter disclosed herein is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms "subject" and "patient". Suitable subjects are generally mammalian subjects. The subject matter described herein is used in research, as well as veterinary and medical applications. The term "mammal" is used in its normal biological sense. Thus, the term includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, among others, as well as many other species.

[0137] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants such as those commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0138] An "effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent that is effective to alleviate to some extent one or more of the symptoms of a disease or condition, or to reduce the likelihood of its onset, including curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated, although there may be certain long-term or permanent effects even after a cure is achieved (e.g., extensive tissue damage).

[0139] "Treat", "treatment", or "treating" as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to or otherwise at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering a treatment to a subject.

[0140] As used herein, the term "weight percent," when referring to a component, is the weight of the component divided by the weight of the composition in which it is contained, multiplied by 100%. For example, if 5 grams of component A is added to 95 grams of component B, the weight percent of component A is 5% (e.g., 5gA / (5gA+95gB)×100%).

[0141] The term "control" shall be given its ordinary meaning and shall include a sample or standard used to compare with a sample being studied, processed, characterized, analyzed, etc. In some embodiments, a control is a sample obtained from a healthy patient, or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In some embodiments, a control is a reference value or range of values ​​of a historical control or standard. In some embodiments, a control is a comparison to a wild-type JMJD3 configuration or scenario.

[0142] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open ended rather than limiting, unless expressly stated otherwise. As examples of the foregoing, the term "including" should be read to mean "including, without limitation," "including but not limited to," and the like; the term "comprising," as used herein, is synonymous with "including," "containing," or "characterized by," is inclusive or open ended, and does not exclude additional unrecited elements or method steps; the term "having" should be interpreted as "having at least," and the term "includes" should be interpreted as "includes but is not limited to." The term "examples" is used to provide illustrative instances of the item being discussed, rather than an exhaustive or exclusive listing of the item. The use of terms such as "preferably," "preferred," "desired," or "desirable," and terms of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function of the invention, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term "comprising" should be interpreted as synonymous with the phrase "having at least" or "including at least." The term "comprising," when used in the context of a process, means that the process includes at least the recited steps, but may include additional steps.The term "comprising," when used in the context of a compound, composition, or device, means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components. Similarly, a group of items connected by the conjunction "and" should not be read as requiring each and every one of the items to be present in the group, but rather as "and / or" unless expressly stated otherwise. Similarly, a group of items connected by the conjunction "or" should not be read as requiring mutual exclusivity among the group, but rather as "and / or" unless expressly stated otherwise.

[0143] In addition, the phrase "consisting essentially of" will be understood to include the elements specifically recited, as well as additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0144] With respect to the use of substantially any term expressing plural and / or singular in this specification, a person skilled in the art can translate from plural to singular and / or from singular to plural, where appropriate to the context and / or application. Various singular / plural permutations may be expressly described in this specification for clarity. The indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting their scope.

[0145] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. Features disclosed under one heading (e.g., Compositions) can be used in combination with features disclosed under a different heading (Methods of Treatment).

[0146] introduction Jumonji protein activity (e.g., JMJD3) is associated with several diseases, including ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, psoriasis, type 1 diabetes, graft-versus-host disease (GVHD), autoimmune encephalitis, Behcet's disease, and autoimmune diseases, including Sjogren's syndrome. Furthermore, the effects of JMJD3 inhibitors on IL5 and IL13 suggest their use in asthma, pulmonary allergy, and atopic dermatitis. Small molecule inhibitors of Jumonji protein activity (e.g., JMJD3) have been used to treat inflammatory and autoimmune diseases. However, despite the fact that various inhibitors of JMJD3 are known, there is still a need for selective inhibitors that confer one or more advantages over current compounds for the treatment of diseases. These advantages include improved activity and / or efficacy; beneficial target selectivity profile according to the respective treatment needs; improved side effect profile, e.g. fewer undesirable side effects, lower side effect intensity; improved targeting of mutant receptors in disease state cells; improved physicochemical properties, e.g. solubility / stability in water, body fluids, and / or pharmaceutical formulations; improved pharmacokinetic properties, e.g. allowing dose reduction or easier administration schemes; easier drug substance production, e.g. by shorter synthetic route or easier purification. Some embodiments disclosed herein relate to compounds that achieve one or more of these advantages (or others). Some embodiments disclosed herein relate to compounds that address one or more deficiencies of known drug substances.

[0147] Genus and compounds of formula (I) Some embodiments relate to substituted triazine compounds (e.g., pyrazole-triazines). Triazines are molecules having the following numbering convention:

[0148] [ka] In some embodiments, the substituted triazine is a compound having the structure of formula (I) (or a pharma- ceutically acceptable salt thereof).

[0149] [ka] In some embodiments, the variables are as disclosed elsewhere herein.

[0150] In some embodiments, L is -C(R 1 )2-, -NR 1 -, -N(R 1 )2, optionally substituted amine (alkyl), -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, and optionally substituted heterocyclyl, or L is absent. In some embodiments where an intermediate variable (e.g., a variable between two other structural features) is described as being "absent" as optional, the variable when absent can be represented as a single bond between two adjacent groups. For example, when L is absent, the triazine ring is selected from the group consisting of A shown in formula (I). a Similarly, L and A a When is not present, the triazine ring is b As will be appreciated by those of skill in the art, in some embodiments, the triazine ring of formula (I) may be directly bonded to L (when L is present), A a (L does not exist, but A a exists), A b (L and A a does not exist, but A b exists), or A1(L, A a , and A bis not present).

[0151] In some embodiments, A a is selected from the group consisting of optionally substituted C1-C6 alkylene and optionally substituted C1-C6 alkyl. In some embodiments, A a In some embodiments, A is absent. a does not exist.

[0152] In some embodiments, A b is selected from the group consisting of -C(=O)- or -N(CH3)-. b In some embodiments, A is absent. b does not exist, and A1 is A a or directly bonded to L.

[0153] In some embodiments, A is -H, hydroxyl, amino, optionally substituted C 1~12 Alkyl, optionally substituted C1-C 12 Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted carbamide, C-amide, optionally substituted C 6~10 Aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10 In some embodiments, A is selected from the group consisting of: carbocyclyl, and optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, A is absent.

[0154] In some embodiments where a terminal variable (e.g., a variable that leads to the end of a structure) is described as "absent" as optional, the variable when absent may be absent or may be a hydrogen atom on an adjacent substituent if necessary to complete the valence of the adjacent substituent. For example, A, A a , A b does not exist and L is -N(R 1)2, then L is

[0155] [ka] As a further example, A1 and A b does not exist and A a When is alkylene, A1 is a and A1 may be represented as -H to provide the combination as alkyl. In some embodiments, A1 is absent and L is A a Also A b and L is bonded to other groups as described elsewhere herein (eg, formula (Id)).

[0156] In some embodiments, A2 is optionally substituted C 6~10 It is selected from the group consisting of aryl, optionally substituted 5-12 membered heteroaryl, and optionally substituted 3-12 membered heterocyclyl.

[0157] In some embodiments, A c is replaced as necessary 1~3 Alkylene, optionally substituted C1-C3 alkamino, -O-, -NR 1 -, -N(R 1 In some embodiments, A is selected from the group consisting of: c is not present and A3 is directly bonded to the triazine ring of formula (I).

[0158] In some embodiments, A3 is optionally substituted C 1~12 Alkyl, optionally substituted C1-C 12 Alkoxy, optionally substituted C1-C 12 Alkamino, optionally substituted C 6~10 Aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10It is selected from the group consisting of carbocyclyl, and optionally substituted 3- to 12-membered heterocyclyl.

[0159] In some embodiments, R 1 is, when present, independently at each occurrence, -H, halogen, hydroxy, optionally substituted C 1~6 Alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C 1~6 Haloalkyl and optionally substituted C 6~10 In some embodiments, two R 1 When the R group is present, 1 The groups taken together form an optionally substituted 3- to 12-membered heterocycle or an optionally substituted C 3~10 Forms a carbocyclyl. Two or more R 1 If they exist, their R 1 The variables may be the same or different.

[0160] In some embodiments, A a , A b , A c , A1, A2, A3, or R 1 Any one of the substituents of (or any other variable disclosed herein) can be optionally substituted. In some embodiments, A a , A b , A c , A1, A2, A3, or R 1 When any one of A (or any other variable disclosed herein) is substituted with one or more optional substituents, each of the one or more optional substituents is independently selected from the optional substituents disclosed in the Definitions section. a , A b , A c , A1, A2, A3, or R 1(or any other variable disclosed herein) is substituted with one or more optional substituents, each of the one or more optional substituents is independently selected from the group consisting of -OH, C 1~3 Alkyl, C 1~3 In some embodiments, A is selected from the group consisting of alkoxy, or halogen. a , A b , A1, A2, A3, or R 1 (or any other variable disclosed herein) is substituted with one or more optional substituents, each of the one or more optional substituents is independently selected from the group consisting of -Me or -F. In some embodiments, when the A group is substituted with one or more optional substituents, the one or more optional substituents are independently selected from the group consisting of acyl, C 1~6 Alkyl, C 1~6 In some embodiments, when the A group is substituted with one or more optional substituents, the one or more optional substituents are independently selected from the group consisting of C 1~6 Alkyl, C 1~6 Cycloalkyl, C 6~10 It is selected from the group consisting of aryl, halogen, and hydroxy.

[0161] In some embodiments, L is -N(R 1 In some embodiments, L is -N(R 1 )2, and R 1The groups taken together form an optionally substituted 3-12 membered heterocyclyl group. In some embodiments, L is substituted with a heterocyclyl group. In some embodiments, L is a 6 membered heterocyclyl group containing 1 or 2 heteroatoms. In some embodiments, the heteroatom of L is N. In some embodiments, L is substituted with a 4-6 membered heterocyclyl group. In some embodiments, when L is a heterocyclyl group substituted with an additional heterocyclyl group, the two rings result in a spiro conformation. In some embodiments, L is substituted with a 4 membered heterocyclyl group. In some embodiments, A a , A b , and A1 is absent, and L is 2-oxa-5,8-diazaspiro[3.5]nonane.

[0162] In some embodiments, L is -N(R 1 )2, and R 1 The groups taken together form an optionally substituted 3- to 12-membered heterocyclyl group. In some embodiments, A a and A b is absent. In some embodiments, A1 is a 3-12 membered heterocyclyl group (e.g., 3-6 membered heterocyclyl, 3-5 membered heterocyclyl, 4 membered heterocyclyl, etc.) and the ring of A1 and the ring of L form a spiro ring system.

[0163] In some embodiments, L is -N(R 1 )2, and R 1 The groups taken together form an optionally substituted 3- to 12-membered heterocyclyl group. In some embodiments, A a and A b In some embodiments, L, A a , A b , and A1, taken together,

[0164] [ka] This results in a structure selected from the group consisting of:

[0165] In some embodiments, L is -N(R 1 )- or -NH-. In some embodiments, A a is C1-C6 alkylene. a is C1-C3 alkylene. b In some embodiments, A is -C(=O)- or absent. 1~3 carbamido optionally substituted with alkyl, methyl or ethyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heteroaryl, or C1-C3 alkoxy.

[0166] In some embodiments, L, A a , A b , and A1, taken together,

[0167] [ka] Any one of the preceding structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the structure.

[0168] In some embodiments, L is -N(R 1 )- or -NH-. In some embodiments, A a In some embodiments, A is absent. b In some embodiments, A is C optionally substituted with hydroxyl or halogen. 1~4 Alkyl, optionally substituted C 3~6 In some embodiments, L, A are independently selected from the group consisting of carbocyclyl, 3- to 6-membered heterocyclyl, 3- to 6-membered aryl optionally substituted with halogen, and 3- to 6-membered heteroaryl. a , Ab , and A1, taken together,

[0169] [ka] Any one of the preceding structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the structure.

[0170] In some embodiments, A2 is selected from the group consisting of optionally substituted 5-6 membered heteroaryl or optionally substituted 5-6 membered heterocyclyl. 2 contains 1, 2, or 3 heteroatoms. In some embodiments, A 2 The heteroatoms in are N and / or S. In some embodiments, A2 is

[0171] [ka] Any one of the preceding structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the structure.

[0172] In some embodiments, A c is -O- or absent. In some embodiments, A3 is C 1~5 alkyl, phenyl optionally substituted with -F, C1-C3 alkamino, optionally substituted 5-12 membered heteroaryl, optionally substituted C 3~10 It is selected from the group consisting of carbocyclyl, and optionally substituted 3- to 12-membered heterocyclyl.

[0173] In some embodiments, A c and A3, taken together,

[0174] [ka] Any one of the preceding structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the structure.

[0175] In some embodiments, A c is C 1~3 In some embodiments, A3 is phenyl optionally substituted with -F and optionally substituted C 3~7 In some embodiments, A is selected from the group consisting of carbocyclyl. c and A3, taken together,

[0176] [ka] This results in a structure selected from the group consisting of:

[0177] In some embodiments, formula (I) is the following compound (or others):

[0178] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Any one of the immediately preceding structures may be optionally further substituted by replacing one or more -H atoms with any carbon or nitrogen atom present in the structure.

[0179] In some embodiments, the triazine compound having the structure of Formula (I) is a compound selected from one or more of the following: Ethyl 3-((4-(1H-pyrazol-1-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4,6-di(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(1H-pyrazol-1-yl)-6-(pyridin-2-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(1H-benzo[d]imidazol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(indolin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-pentyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-ethoxy-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(4,4-difluoropiperidin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(1H-pyrazol-1-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(ethylamino)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(1,4-diazepan-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-((4-fluorobenzyl)amino)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(cycloheptyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; Ethyl 3-((4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate; 2-((4-(4-fluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)acetamide; 3-((4-(cycloheptyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide; N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(indolin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cycloheptyloxy)-N-(morpholinomethyl)-6-(pyridin-2-yl)-1,3,5-triazin-2-amine; (S)—N-(1-(4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)ethyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(2-(1H-tetrazol-1-yl)ethyl)-4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(1H-Benzo[d]imidazol-1-yl)-N-(3-ethoxypropyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propan-1-ol; 4-Ethoxy-N-(2-methoxyethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(4,4-difluoropiperidin-1-yl)-6-(1H-pyrazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-amine; 1-(((4-(1H-pyrazol-1-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)amino)methyl)urea; 1-Ethyl-3-(((4-(ethylamino)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)methyl)urea; 4-((4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)butan-2-one; 3-((4-(1,4-diazepan-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)-1-(pyrrolidin-1-yl)propan-1-one; 1-(aziridin-1-yl)-3-((4-((4-fluorobenzyl)amino)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propan-1-one; 3-((4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)-1-(1H-pyrrol-1-yl)propan-1-one; 3-((4-(cycloheptyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)-1-(1H-pyrrol-2-yl)propan-1-one; 1-(oxazol-2-yl)-3-((4-pentyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propan-1-one; 4-(cyclohexyloxy)-N-isopropyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-isobutyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 1-((4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)ethan-1-ol; N-butyl-4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-cyclopropyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; N-cyclobutyl-4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexylmethyl)-6-(1H-pyrazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-amine; 4-(cyclohexylmethyl)-6-(1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-(piperidin-4-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexylmethyl)-6-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)-1,3,5-triazin-2-amine; Ethyl (4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)glycinate; 2-((4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)acetamide; 4-(cyclohexyloxy)-N-(morpholinomethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-(piperidin-4-ylmethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-N-(1H-pyrrol-2-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-N-(trifluoromethyl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-(2,3-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-N-(thiophen-2-yl)-1,3,5-triazin-2-amine; 8-(4-(1H-pyrazol-1-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4,6-di(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-pyrazol-1-yl)-6-(pyridin-2-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-benzo[d]imidazol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(indolin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-pentyl-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-ethoxy-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(4,4-difluoropiperidin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-pyrazol-1-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; N-ethyl-4-(1H-pyrazol-1-yl)-6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)-1,3,5-triazin-2-amine; 8-(4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1,4-diazepan-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; N-(4-fluorobenzyl)-4-(1H-pyrazol-1-yl)-6-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)-1,3,5-triazin-2-amine; 8-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(cycloheptyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(cyclohexyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-indol-1-yl)-6-(pyridin-2-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-indol-1-yl)-6-(1H-1,2,3-triazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-indol-1-yl)-6-(2H-1,2,3-triazol-2-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 8-(4-(1H-indol-1-yl)-6-(thiazol-2-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane; 2-(4-methylpiperazin-1-yl)-4-(1H-pyrazol-1-yl)-6-(pyridin-2-yl)-1,3,5-triazine; 2-(4-methylpiperazin-1-yl)-4,6-di(1H-pyrazol-1-yl)-1,3,5-triazine; 3-(4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine; 2-(3,5-difluorophenyl)-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 1-(4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-benzo[d]imidazole; 1-(4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)indoline; 1-(4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole; 2-(4,4-difluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 2-Butyl-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 2-Ethoxy-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 2-(4-methylpiperazin-1-yl)-4-(1H-pyrazol-1-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazine; N-Ethyl-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(1H-indol-1-yl)-N-(2-methoxyethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 1-(4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole; 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide; 4-(4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine; 2-(azetidin-1-yl)-4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 4-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine; 1-(4-(cyclopentyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole; 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide; 4-(1H-indol-1-yl)-N-(3-methoxypropyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(1H-indol-1-yl)-N-(methoxymethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 2-(3,5-difluorophenyl)-4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine; 4-(azetidin-1-yl)-N-(3,5-difluorobenzyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; N-(3,5-difluorobenzyl)-4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; N-(3,5-difluorobenzyl)-4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; N 2 -(3,5-difluorobenzyl)-N 4 -(Morpholinomethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diamine; 4-(cycloheptyloxy)-N-(morpholinomethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; 4-(cyclohexyloxy)-N-(morpholinomethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine; and 8-(4-(1H-indol-1-yl)-6-(pyridin-2-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane.

[0180] In some embodiments, as disclosed elsewhere herein, a variable defined for one structural formula may also be used in any other formula having the same variable. For example, if a variable has the same alphanumeric designation (e.g., A2) for one formula (e.g., formula (Id) or (I), etc.), the definition of that variable may be used in other formulas (e.g., formula (Ic), (Ie), etc.) even if the variable is not specifically defined for those other formulas.

[0181] Genus and compounds of formula (Ia) Some exemplary embodiments of the structure of formula (I) can be represented by aminotriazines that are structures of formula (Ia), where L is -NR 1 - and R 1 is -H, and A a is C1-C3 alkylene, A b is -C(=O)-, and A cis absent (e.g., is a single bond), n is an integer equal to 1, 2, or 3, and each other variable is as defined elsewhere herein.

[0182] [ka] Formula (Ia) may be represented by any one of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 26, 36, 91, 96, or others.

[0183] Genus and compounds of formula (Ib) In some embodiments, the compound of formula (I) (or formula (Ia)) is further represented by the structure of formula (Ib), where L is -NR 1 - and R 1 is -H, and A a is C1-C3 alkylene, A b is -C(=O)-, and A c is a single bond, A2 is pyrazole, and each of the other variables is as defined elsewhere herein.

[0184] [ka]

[0185] Some embodiments of the structure of Formula (I) (or Formula (Ib)) are represented by Formula (Ib-i), where L is -NR 1 - and R 1 is -H, and A a is ethylene, and A b is -C(=O)-, and A c is a single bond, A1 is ethoxy, and each of the other variables is as defined elsewhere herein.

[0186] [ka] A3,

[0187] [ka] In some embodiments of formula (Ib-i) selected from, formula (Ib-i) may be represented by any one of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or others.

[0188] Some embodiments of the structure of formula (I) are represented by formula (Ib-ii), where L is -NR 1 - and R 1 is -H, and A a is ethylene, and A b is -C(=O)-, and A c is a single bond (other variables are as disclosed elsewhere herein).

[0189] [ka] A1,

[0190] [ka] A3 is selected from

[0191] [ka] and each other variable is as defined elsewhere herein, formula (Ib-ii) may be represented by any one of compounds 20, 31, 32, 33, 34, 35, 36, or others.

[0192] Genus and compounds of formula (Ic) A2 is the symbol

[0193] [ka] In some embodiments, Formula (I) is further represented by the structure of Formula (Ic):

[0194] [ka] Formula (Ic) may be represented by any one of compounds 41, 42, 45, 51, 53, 54, 89, 97, or others.

[0195] Some embodiments of the structure of formula (I) (or formula (Ic)) are further represented by formula (Ic-i), wherein A c is -O-, A2 is pyrazole, A3 is cyclohexane, and each of the other variables is as defined elsewhere herein.

[0196] [ka]

[0197] L is -NR 1 - and R 1 is -H, and A a and A b does not exist, and A1 is

[0198] [ka] and each other variable is as defined elsewhere herein, formula (Ic-i) may be represented by any one of compounds 41, 42, 45, 51, 53, 54, or others.

[0199] L is -NR 1 - and R 1 is -H, and A a and A bIn some embodiments of formula (Ic-i), where is absent and A is selected from (CH)CH-, (CH)CHCH-, CH(CH)-, CH(HO)CH-, and CF, and each other variable is as defined elsewhere herein, formula (Ic-i) may be represented by any one of compounds 37, 38, 39, 40, 52, or others.

[0200] L is -NR 1 - and R 1 is -H, and A a is methylene, and A b does not exist, and A1 is

[0201] [ka] and each other variable is as defined elsewhere herein, formula (Ic-i) may be represented by any one of compounds 49, 50, or others.

[0202] L is -NR 1 - and R 1 is -H, and A a is methylene, and A b In some embodiments of formula (Ic-i), where A is -C(=O)-, A is selected from CHCHO- and NH-, and each other variable is as defined elsewhere herein, formula (Ici) may be represented by any one of compounds 47, 48, or others.

[0203] Some embodiments of the structure of formula (I) are represented by formula (Ic-ii), wherein A c is -CH2-, A2 is pyrazole, A3 is cyclohexane, and each of the other variables is as defined elsewhere herein.

[0204] [ka]

[0205] L is -NR 1 - and R 1 is -H, and A a and A b does not exist, and A1 is

[0206] [ka] and each other variable is as defined elsewhere herein, formula (Ic-ii) may be represented by any one of compounds 43, 44, 46, or others.

[0207] Some embodiments of the structure of formula (I) are represented by formula (Ic-iii), where L is -NR 1 - and R 1 is -H, and A a is ethylene, and A b and A c is absent, A2 is pyrazole, and each of the other variables is as defined elsewhere herein.

[0208] [ka]

[0209] A1,

[0210] [ka] A3 is selected from

[0211] [ka] and each other variable is as defined elsewhere herein, formula (Ic-iii) may be represented by any one of compounds 21, 24, 25, 26, 27, or others.

[0212] Some embodiments of the structure of formula (I) are represented by formula (Ic-iv), where L is -NR 1 - and R 1 is -H, and A a is methylene, and A b and A c is absent, A2 is pyrazole, and each of the other variables is as defined elsewhere herein.

[0213] [ka]

[0214] A1 is selected from NH2C(=O)CH2-, NH2C(=O)NH-, CH3CH2NHC(=O)NH-, and CH3O-; A3 is

[0215] [ka] and each other variable is as defined elsewhere herein, formula (Ic-iv) may be represented by any one of compounds 19, 29, 30, 98, or others.

[0216] Some embodiments of the structure of formula (I) are represented by formula (Ic-v), where A a and A c is absent, A1 is tetrahydropyran, A2 is pyrazole, and each of the other variables is as defined elsewhere herein.

[0217] [ka]

[0218] L is -NR 1 - and R 1 is -H, and A b does not exist, and A3 is

[0219] [ka] and each of the other variables is as defined elsewhere herein, formula (Ic-v) may be represented by compound 28, or else.

[0220] L is -CR 1 - and R 1 is CH3 and A b is -N(CH3)- and A3 is

[0221] [ka] and each of the other variables is as defined elsewhere herein, formula (Ic-v) may be represented by compound 23 or others.

[0222] [ka]

[0223] Some embodiments of the structure of formula (I) are represented by formula (Ic-vi), where L is -O- and A a , A b , and A c is absent and A2 is a pyrazole.

[0224] [ka]

[0225] In some embodiments of formula (Ic-vi), A1 is

[0226] [ka] and A3 is

[0227] [ka] and each of the other variables is as defined elsewhere herein, and formula (Ic-vi) may be represented by compound 95 or others.

[0228] Some embodiments of the structure of formula (I) are represented by pyridinyl triazines of formula (Ic-vii), where L is -NR 1 - and R 1 is -H, and A b and A c is absent and A2 is pyridine.

[0229] [ka] A a is methylene, and A1 is

[0230] [ka] and A3 is

[0231] [ka] and each of the other variables is as defined elsewhere herein, formula (Ic-vii) may be represented by compound 22, or otherwise.

[0232] Genus and compounds of formula (Id) In some embodiments, the compound of formula (I) is further represented by the structure of formula (Id), wherein A a and A b is absent and L is heterocyclyl (e.g., L and N(R 1 )2), A1 is as defined elsewhere herein. In some embodiments, R 1 In each case, C 1~6 In some embodiments, R1 In some cases, C 1~6 is alkyl, R 1 In some cases, C1-C6 alkamino, C 1~6 alkoxy, or C1-C6 alkylthio. In some embodiments, L forms a ring with X. In other words, L is tethered to X by two independent linkages that contain alkylene groups, where the number of alkylene groups in the linkages is an integer represented by m and o.

[0233] [ka] In some embodiments, X is selected from the group consisting of -CH2-, -NH-, N (when A1 is a substituent of X), -O-, and -S-, m is an integer equal to 1, 2, 3, or 4, o is an integer equal to 1, 2, 3, or 4, and A1 is a heterocyclyl group. In this case, formula (Id) may be represented by any one of compounds 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 101, or others.

[0234] Alternatively, in some embodiments, X is N, m is an integer equal to 2, o is an integer equal to 2, and A1 is an alkyl group substituted on X. In this case (or otherwise), formula (Id) may be represented by any one of compounds 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or others.

[0235] In some embodiments, the compound of formula (Id-i) is A a , A b and A1 is absent and L is optionally substituted N(R 1 )2, and R 1 But in each case, C 1~6and L is alkyl, and L together with X forms a ring, and each of the other variables are as disclosed elsewhere herein. In some embodiments, L (e.g., X or the methylene of L) is optionally substituted with C1-C6 alkyl. In this (or other) case, formula (Id-i) may be represented by any one of compounds 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or others.

[0236] [ka]

[0237] In some embodiments of formula (Id-i), X is selected from the group consisting of -CH2-, -NH-, and -O-, m is an integer equal to 1, 2, 3, or 4, and o is an integer equal to 1, 2, 3, or 4. In this case (or otherwise), formula (Id-1) may be represented by any one of compounds 92, 93, 94, 99, or others.

[0238] Some embodiments of the structure of formula (I) are represented by formula (Id-i), wherein A a , A b , and A1 is absent, A2 is pyrazole, and A3 is 3,5-difluorophenyl.

[0239] [ka] A c In some embodiments of formula (Id-ii), where is absent, X is selected from -NH- or -O-, m is 2, o is 2, and each other variable is as defined elsewhere herein, formula (Id-i) may be represented by compounds 92, 99, (or others).

[0240] A cIn some embodiments of formula (Id-i), where is absent, X is selected from -CH2-, m is 1, o is 1, and each other variable is as defined elsewhere herein, formula (Id-i) may be represented by compound 93, or others.

[0241] A c In some embodiments of formula (Id-ii), where X is selected from -NH- or -O-, m is 2, o is 2, and each other variable is as defined elsewhere herein, formula (Id-i) may be represented by compounds 101, 102, or others.

[0242] A c In some embodiments of formula (Id-ii), where X is selected from -CH-, m is 1, o is 1, and each other variable is as defined elsewhere herein, formula (Id-i) may be represented by compound 100, or otherwise.

[0243] Genus and compounds of formula (Ie) In some embodiments, the compound of formula (I) is further represented by the structure of formula (Ie), where L is -NR 1 - and R 1 is -H, and A a is methylene, and A b and A c is absent, A1 is morpholine, and A2 is pyrazole.

[0244] [ka] A3,

[0245] [ka] and each other variable is as defined elsewhere herein, formula (Ie) may be represented by compound 103, 104, 105, or others.

[0246] Methods for Making Compounds of Formula (I) The compounds disclosed herein can be synthesized by the methods described below or by modifying these methods. The manner of modifying the methods includes, among others, temperatures, solvents, reagents, etc., known to those skilled in the art. In general, during any of the methods for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be accomplished by using conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (JFW MacOmie, ed., Plenum Press, 1973) and PGM Green, TW Hutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. The protecting groups can be removed at a subsequent convenient stage using methods known in the art. Synthetic chemical transformations useful for synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are merely exemplary and are not intended to, and should not be construed as, limiting the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and will be able to devise alternative routes based on the disclosures herein. All such modifications and alternative routes are within the scope of the claims.

[0247] In the schemes that follow, protecting groups are selected for their compatibility with the synthetic steps required, and for the compatibility of the installation and deprotection steps with the overall synthetic scheme (PGM Green, TW Futts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0248] When the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are within the scope of the present technology, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0249] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0250] Some exemplary embodiments relate to methods of synthesizing compounds of formula (I) and / or intermediates of compounds of formula (I) (as shown in Figures 1A-2). Figure 1A provides some possible routes to compounds of formula (I). In some embodiments, the variables in Figure 1A are as disclosed elsewhere herein, and X1, X2, and X3 are each halogen (e.g., -Cl). In some embodiments, compounds of formula (I) can be prepared as shown in Figures 1A or 1B. In some embodiments referring to either Figure 1A or 1B, the method can include any one or more of steps (i), (ii), (iii), or any combination of the foregoing. In some embodiments, any one of steps (i), (ii), (iii) can be omitted. For example, in some embodiments, the method can include step i, but not ii or iii. In some embodiments, the method can include steps i and ii, but not iii. In some embodiments, the method can include steps i, ii, and iii. In some embodiments, the method may include steps ii and iii, but not step i. The method may include step ii, but not step i or iii. The method may include step iii, but not step i or ii.

[0251] In some embodiments, step (i) includes the step of adding a reagent that replaces one of X1, X2, or X3 (e.g., H-LA a A b A1, H-A2, or HA c A3 (e.g., 1.0 equivalent). In some embodiments, step (i) is performed in the presence of a base (e.g., DIPEA, 1.5 equivalents). In some embodiments, step (i) is performed in the presence of a polar aprotic solvent (e.g., THF). In some embodiments, step (i) is performed at room temperature or lower (e.g., −78° C. to RT).

[0252] In some embodiments, step (ii) comprises the step of adding a reagent (e.g., H-LA) that replaces one of the remaining X groups (e.g., X1, X2, or X3). a A b A1, A2, or A c A3 (e.g., 1.0 equivalent). In some embodiments, the reagent replaces the remaining X groups. In some embodiments, step (ii) is performed in the presence of a base (e.g., DIPEA, 1.5 equivalents). In some embodiments, step (ii) is performed in the presence of a polar aprotic solvent (e.g., THF). In some embodiments, step (ii) is performed at room temperature or higher (e.g., 50° C.).

[0253] In some embodiments, step (iii) comprises adding a reagent (e.g., H-LA) to replace the last remaining X group (e.g., X1, X2, or X3). a A b A1, A2, or A c A3 (e.g., 1.0 equivalent). In some embodiments, step (iii) is performed in the presence of a base (e.g., NaH or DIPEA, 2.0 equivalents). In some embodiments, step (iii) is performed in the presence of a polar aprotic solvent (e.g., THF). In some embodiments, step (iii) is performed at room temperature or higher (e.g., 90° C.).

[0254] In some embodiments, the compound of formula (I) can be prepared via any one of routes A, B, or C, where any one of steps i, ii, iii can be omitted. In some embodiments, the variables (and reagents and / or reactants) in FIG. 1B (or FIG. 1A or FIG. 2) can be defined as follows: (i) NHA a A b A1, A2, or A c A3 (e.g., 1.0 equivalent), a base (e.g., DIPEA, 1.5 equivalent), a solvent (e.g., THF, −78° C. to RT), (ii) NHA a A bA1, A2, or A c A3 (1.0 eq.), a base (e.g., DIPEA, 1.5 eq.), a solvent (e.g., THF) at a controlled temperature (e.g., 50° C.), (iii) NHA a A b A1, A2, or A c A3 (3-5 eq.), NaH or DIPEA (2 eq.), THF, 90° C. In some embodiments, as disclosed elsewhere herein, the method of preparation can include or omit any of the steps provided in FIG. 1B. In some embodiments, any one of routes A, B, or C can be used. In some embodiments, the method can include some steps of A, B, or C of FIG. 1A, but not others.

[0255] Figure 2 provides more specific reaction pathways as disclosed in Figures 1A and 1B. In some embodiments, the manufacturing method may include some steps from any of the three pathways in Figure 2, but not others. For example, in some embodiments, the method may include step i, but not ii or iii. In some embodiments, the method may include steps i and ii, but not iii. In some embodiments, the method may include steps i, ii, and iii. In some embodiments, the method may include steps ii and iii, but not step i. The method may include step ii, but not step i or iii. The method may include step iii, but not step i or ii.

[0256] Some exemplary embodiments relate to intermediate compounds (e.g., compounds used to provide compounds of formula (I)). In some embodiments, the intermediate compounds include those of formula (IX) shown in FIG. 1A. 1,2,3 ), (IX 2,3 ), (IX 3 ), (IX 1,3 ), (IX 1 ), (IX 1,2 ), (IX 2 ), and (IX 1,2,3), where X 1 is a halogen.

[0257] Administration and Pharmaceutical Compositions The compounds are administered in therapeutically effective dosages. Human dosage levels have not yet been optimized for the compounds described herein, but in general, the daily dose can be from about 0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg of body weight, from about 1.0 mg / kg to about 50 mg / kg of body weight, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, the dosage range for administration to a 70 kg human should be from about 17 mg / day to about 8000 mg / day, from about 35 mg / day or less to about 7000 mg / day or more, from about 70 mg / day to about 6000 mg / day, from about 100 mg / day to about 5000 mg / day, or from about 200 mg / day to about 3000 mg / day. The amount of active compound administered will, of course, be dependent on the subject and the condition being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician.

[0258] Administration of the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, can be by any of the accepted modes of administration for drugs that serve similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or ocular. Oral and parenteral administration are conventional in the treatment of the indications covered by the preferred embodiments.

[0259] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating these conditions.Standard pharmaceutical formulation techniques can be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams&Wilkins (2005), which is incorporated by reference in its entirety.Thus, some embodiments include pharmaceutical compositions that include (a) a safe therapeutically effective amount of the compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0260] Some embodiments include compositions that contain a pharma- ceutically acceptable carrier in addition to the selected compound useful as described above. The term "pharma- ceutically acceptable carrier" or "pharma- ceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, and the like. The use of such media and agents for pharma- ceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0261] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents, such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0262] The choice of a pharma- ceutically acceptable carrier to be used in conjunction with the subject compounds is basically determined by the way the compound is to be administered.

[0263] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration in a single dose to an animal, preferably a mammalian subject, in accordance with good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once during a course of treatment. Such dosage forms are contemplated to be administered once, twice, three times or more per day, and may be administered as an infusion or as a continuous infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), and may be given more than once during a course of treatment, although a single administration is not specifically excluded. Those skilled in the art will recognize that the formulations are not specifically intended for the entire course of treatment, and such a determination is left to those skilled in the art of treatment, not formulation.

[0264] As mentioned above, the useful compositions may be in any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, subcutaneous, or other parental routes of administration. In some embodiments, the compositions may be in a form suitable for subcutaneous administration. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and made using available methods. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surfactants, and encapsulating materials. Optional pharmaceutically active materials may be included that do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used with the compound is an amount sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002), Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989), and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0265] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow agents, and melting agents can be compressed, triturated, enteric coated, sugar coated, film coated, or multiple-compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0266] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma-ceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of powder mixtures. Coloring agents such as FD&C dyes can be added for appearance. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents as previously disclosed. The selection of carrier components will depend on secondary considerations such as taste, cost, and shelf stability, but these are not critical and may be readily made by one of ordinary skill in the art.

[0267] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavorings and colorings disclosed above.

[0268] Such compositions can also be coated by conventional methods, typically using pH or time-dependent coatings, so that the subject compound is released in the gastrointestinal tract near the desired local application, or released at various times to extend the desired effect.Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coating, wax and shellac.

[0269] The compositions described herein may optionally contain other medicamentously active substances.

[0270] Other compositions useful for systemically delivering the subject compound include sublingual, oral buccal and nasal dosage forms.Such compositions typically include soluble filler, such as sucrose, sorbitol and mannitol, and binder, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.Also can include glidants, lubricants, sweeteners, colorants, antioxidants and flavorings as disclosed above.

[0271] The preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.Useful surfactants are, for example, Tween 80.Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0272] If necessary or convenient, osmolality adjusting agents may be added, including but not limited to salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable osmolality adjusting agent that is ophthalmically acceptable.

[0273] Various buffers and means for adjusting pH may be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used, if necessary, to adjust the pH of these preparations.

[0274] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0275] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as glucose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated by reference in their entireties. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0276] Compositions for intravenous administration may be provided to the caregiver in one more solid form that is reconstituted with a suitable diluent, such as sterile water, saline, or glucose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready for parenteral administration. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein with another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two drugs prior to administration, or the two agents may be administered separately.

[0277] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0278] The compounds and compositions described herein may be presented in a pack or dispenser device that contains one or more unit dosage forms that contain active ingredient as desired.Such a pack or device may include, for example, metal or plastic foil, such as blister pack, or glass and rubber stopper in vial and the like.The pack or dispenser device may be accompanied by instructions for administration.The compounds and compositions described herein that are formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0279] The amount of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains about 0.01-99.99 wt% of the compound according to the technology of the present invention on a weight percent (wt%) basis based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

[0280] In some embodiments, a "carboxyl ester," "carboxylate ester," or "carboxylic acid ester" can be used as a prodrug of a "carboxylic acid."

[0281] Formulation examples The following are representative pharmaceutical formulations containing a compound of formula (I):

[0282] Formulation Example 1 - Tablet formulation The following ingredients are thoroughly mixed and compressed into a single scored tablet.

[0283] [Table 1]

[0284] Formulation Example 2 - Capsule formulation The following ingredients are thoroughly mixed and loaded into a hard shell gelatin capsule:

[0285] [Table 2]

[0286] Formulation Example 3 - Suspension formulation The following ingredients are mixed to form a suspension for oral administration:

[0287] [Table 3]

[0288] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable formulation:

[0289] [Table 4]

[0290] Formulation Example 5 - Suppository formulation Suppositories with a total weight of 2.5 g are prepared by mixing a compound according to the present technology with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids, Riches-Nelson, Inc., New York), which have the following composition:

[0291] [Table 5]

[0292] Treatment The compounds of formula (I) disclosed herein or their tautomers and / or pharma- ceutically acceptable salts thereof can be effective as inhibitors of JMJD3. Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharma- ceutically acceptable excipient.

[0293] Some embodiments provide a method for preventing, treating or ameliorating one or more inflammatory or autoimmune diseases in a subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0294] Some embodiments provide methods of preventing, treating, or ameliorating inflammatory bowel disease (IBD). Some embodiments provide methods of preventing, treating, or ameliorating ulcerative colitis, Crohn's disease, atopic dermatitis, psoriasis, systemic lupus erythematosus, atherosclerosis, and type 1 diabetes. Some embodiments provide methods of preventing, treating, or ameliorating graft-versus-host disease (GVHD), type 1 diabetes (T1D), ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, Sjogren's syndrome, Hashimoto's thyroiditis, autoimmune hepatitis, Behcet's disease, Castleman's disease, allergic rhinitis, eczema, Dressler's syndrome, eosinophilic esophagitis, Guillain-Barre syndrome, juvenile arthritis, Kawasaki's disease, asthma, pulmonary allergies, and atopic dermatitis. In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the methods include administering one or more pharma- ceutically acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0295] In some embodiments, the method of administering one or more of the compounds disclosed herein prevents, treats, or improves inflammatory or autoimmune diseases.In some embodiments, the method of administering one or more of the compounds disclosed herein prevents, treats, or improves ulcerative colitis, Crohn's disease, atopic dermatitis, psoriasis, systemic lupus erythematosus, atherosclerosis, and type 1 diabetes.In some embodiments, the method comprises administering one or more pharmacologic acceptable salts of the compounds disclosed herein.

[0296] JMJD3 inhibitors have been implicated in the progression and / or metastatic potential of several cancer types, namely kidney, breast, prostate, skin, hematopoietic system, myelodysplastic syndrome (MDS), esophageal squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and ovarian cancer. High JMJD3 expression correlated with shorter overall survival in patients with gastric cancer (GC) and was an independent prognostic predictor. Importantly, JMJD3 inhibitors could halt the oncogenic effect of JMJD3 overexpression in human GC cell lines. In some embodiments, the disclosed compounds are used to treat cancer. In some embodiments, the cancer is selected from the group consisting of colorectal, gastric, stomach, esophageal, liver, pancreatic, breast, prostate, bladder, kidney, ovary, lung, melanoma, and multiple myeloma. In some embodiments, the cancer is selected from the group consisting of kidney cancer, breast cancer, castration-resistant prostate cancer, acute myeloid leukemia (AML), melanoma, Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS), esophageal squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and ovarian cancer. In some embodiments, the cancer is selected from the group consisting of prostate, skin, hematopoietic system, myelodysplastic syndrome (MDS), esophageal squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and ovarian cancer. In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering one or more pharma- ceutically acceptable salts thereof of the compounds disclosed herein to a subject in need thereof.

[0297] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the inhibition of the activity of JMJD3 in one or more organs of the subject. In some embodiments, the inhibition of the activity of JMJD3 suppresses the expression and / or activity of pro-inflammatory signals. In some embodiments, the pro-inflammatory signals can be one or more cytokines. In some embodiments, the cytokines include TNF-alpha (TNFA), interleukin 6 (IL6), interleukin 1 beta (IL1B), MCP1 and interleukin 8 (IL8). In some embodiments, the method includes the step of administering one or more pharma- ceutically acceptable salts thereof of the compounds disclosed herein.

[0298] Some embodiments include co-administration of the compounds, compositions, and / or pharmaceutical compositions described herein with additional pharmaceutical agents. By "co-administration" is meant that two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is achieved by combining the agents into a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, e.g., orally. In another embodiment, the agents are administered via different routes, e.g., one is administered subcutaneously, another is administered orally, and another is administered iv.

[0299] The following examples are provided for the purpose of illustrating various embodiments of the present disclosure, and are not meant to limit the present disclosure in any way. Those skilled in the art will easily understand that the present disclosure is fully adapted to achieve the objects and obtain the ends and advantages mentioned, which are inherent in the present specification. Those modifications and other uses that are encompassed within the spirit of the present disclosure as defined by the claims will occur to those skilled in the art. EXAMPLES

[0300] Synthesis of triazines All reactions were carried out under an argon atmosphere. Reagents and solvents were used without further purification from commercial sources. Hydrogenation reactions were carried out under a balloon. Microwave reactions were carried out using a CEM Discover SP microwave synthesizer. Sample purification was carried out using commercially available prepacked silica gel columns on a Buchi Pureflash with an ELSD purification system. Thin layer chromatography (TLC) was carried out on aluminum plates using Merck Kiesegel 60 F254 (230-400 mesh) fluorescent treated silica visualized under ultraviolet light (254 nm) or by staining with potassium permanganate or ninhydrin solutions as appropriate. All nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance III HD 400 MHz NMR spectrometer. Chemical shifts are reported in ppm (δ). HPLC / MS was performed on a Sciex 5500 Qtrap mass spectrometer connected to a Shidmazu Nexera X2 UHPLC using a Phenomenex Luna C18 column (50 × 2.0 mm, 3 μm particle size) with the following method: Gradient mobile phase A contained 0.1% formic acid in water, and mobile phase B contained 0.1% formic acid in acetonitrile, with gradients of A / B (95:5) 0–0.9 min to A / B (5:95) 0.9–2.2 min, A / B (5:95) 2.2–4.14 min to A / B (95:5) 4.14–4.20 min, and A / B (95:5) 4.2–6 min. The flow rate was 0.4 mL / min, the column temperature was maintained at 35 °C, and the autosampler temperature was maintained at 4 °C. The ion spray voltage, drying gas temperature, ion source gas 1, and ion source gas 2 settings were 4500 V, 500 °C, 35 V, and 45 V, and the ESI was set in positive mode using full scan. The purity of all compounds was analyzed on an Agilent 1260 Infinity II Lab LC series HPLC (1260 Quatpum, 1260 Vial Autosampler, ICC column oven, 1260DAD WR detector). Samples were injected onto a Phenomenex Synergi Polar RP column (150 × 4.6 mm, 4 μm, 80 Å).A gradient mobile phase (A: water with 0.1% trifluoroacetic acid, B: acetonitrile with 0.1% trifluoroacetic acid, A / B (99:1) at 0 min, A / B (1:99) at 0–15 min, A / B (1:99) at 15–18 min, A / B (99:1) at 18–18.1 min, and A / B (99:1) at 18.1–20 min) was pumped at a flow rate of 1 mL / min. The UV detector was set at 254 nm with the column oven at 35 °C. The injection volume was 10 μL unless otherwise specified. All compounds evaluated in biological assays had a purity of 90% or higher and in animal studies had a purity of 95% or higher.

[0301] The compounds were generally prepared by three successive chloro substitutions of a triazine scaffold as illustrated in general Scheme 1 shown in Figure 2. In some embodiments, the conditions of Scheme 1 include: (i) NHR a , pyrazole, or NR b R c (1.0 equivalent), DIPEA (1.5 equivalent), THF, -78℃~RT, (ii) NHR a , pyrazole, or NR b R c (1.0 equivalent), DIPEA (1.5 equivalent), THF, 50℃, (iii) NHR a , pyrazole, or NR b R c (3-5 equiv.), NaH or DIPEA (2 equiv.), THF, 90 °C.

[0302] To investigate the propensity of pyrazole-triazine core to inhibit the activity of JMJD3, 6-(1H-pyrazol-1-yl)-1,3,5-triazine analogs were synthesized from commercially available cyanogen chloride. The structure-activity relationship (SAR) of 2,4 substitution of 6-(1H-pyrazol-1-yl)-1,3,5-triazine was studied with various groups using computational docking to further enhance potency. All structures disclosed herein were tested using available software SeeSAR v.10 by computational molecular docking. The publicly available crystal structure data of the compounds was used to estimate the affinity binding of JMJD3 inhibitor (6G8F-GSK-J1) bound to JMJD3 protein. The data generated using JMJD3 protein was used to evaluate compounds that have good affinity for JMJD3 protein binding pocket. Each of these compounds is disclosed herein.

[0303] The following provides representative methods for preparing the compounds disclosed herein. One of ordinary skill in the art would be able to prepare each of the structures disclosed herein given this guidance and the guidance provided by the remainder of this disclosure. EXAMPLES

[0304] Synthesis of ethyl 3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)propanoate (INT1)

[0305] [ka]

[0306] To a solution of cyanuric chloride (1.00 g, 5.42 mmol) in anhydrous THF (20 mL) cooled to -78°C under an argon atmosphere was added β-alanine ethyl ester hydrochloride (0.83 g, 5.42 mmol) and stirred for 5 min, followed by DIPEA (1.05 g, 8.13 mmol). The reaction mixture was stirred for 1 h for the addition, then slowly equilibrated to 0°C and maintained at that temperature overnight. The reaction was extracted with ethyl acetate (2 x 50 mL) and washed with saturated NaHCO3, followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (80 g) using 100% CH 2 Cl 2 to give ethyl 3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)propanoate (1.09 g, 76%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.45 (bs, 1H), 4.15 (q, 2H, J = 8.0 Hz), 3.74 (q, 2H, J = 8.0 Hz), 2.61 (t, 2H, J = 8.0 Hz), 1.25 (t, 3H, J = 8.0 Hz). MS (ESI): C8H 10 Calculated value for Cl2N4O2: 265, Found value: 265 (M) + EXAMPLES

[0307] Synthesis of ethyl 3-((4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (INT2)

[0308] [ka]

[0309] To a solution of ethyl 3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)propanoate (0.20 g, 0.75 mmol) in anhydrous THF (6 mL) was added DIPEA (0.16 g, 1.51 mmol) and pyrazole (0.05 g, 0.75 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 4 days. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 97:3 CH2Cl2:MeOH and 0.7 N ammonia to give ethyl 3-((4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.13 g, 60%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.50 (dd, 1H, J = 12.0, 4.0 Hz), 7.83 (dd, 1H, J = 16.0, 4.0 Hz), 6.51 (bs, 1H), 6.48 (m, 1H), 4.16 (q, 2H, J = 8.0 MS (ESI): C 11 H 13 Calculated value for ClN6O2: 296, Found value: 297 (M) + and 319 (M+23) + EXAMPLES

[0310] Synthesis of ethyl 3-((4-(1H-pyrazol-1-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-1,3,5-triazin-2-yl)amino)propanoate (Compound 1)

[0311] [ka]

[0312] To a solution of ethyl 3-((4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.11 g, 0.84 mmol) and 2,3,4,5-tetrahydro-1H-3-benzazepine (0.99 g, 0.67 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. overnight. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 97:3 CH2Cl2:MeOH and 0.7 N ammonia to give ethyl 3-((4-(1H-pyrazol-1-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.12 g, 86%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.50 (dd, 1H, J = 12.0, 4.0 Hz), 7.75 (dd, 1H, J = 12.0, 4.0 Hz), 7.14 (s, 4H), 6.41 (m, 1H), 5.80 (t, 1H, J = 4.0 Hz), 4.15 (q, 2H, J = 8.0 Hz), 4.02 (m, 4H), 3.76 (q, 2H, J = 8.0 Hz), 2.97 (m, 4H), 2.63 (t, 2H, J = 8.0 Hz), 1.25 (t, 3H, J = 8.0 Hz). MS (ESI): C 21 H 25 Calculated N7O2: 407, Measured 408 (M) + EXAMPLES

[0313] Synthesis of ethyl 3-((4,6-di(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (compound 2)

[0314] [ka]

[0315] To a solution of ethyl 3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)propanoate (0.15 g, 0.57 mmol) in anhydrous THF (3 mL) was added DIPEA (0.22 g, 1.70 mmol) and pyrazole (0.19 g, 2.82 mmol) under an argon atmosphere. The sealed tube was heated at 90 °C for 4 days. The cooled reaction was stripped of its solvent and immediately purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH and 0.7 N ammonia to give ethyl 3-((4,6-di(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.18 g, 99%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ 8.63 (dd, 2H, J = 12.0, 4.0 Hz), 7.84 (dd, 2H, J = 12.0, 2.0 Hz), 7.33 (bs, 0.5 H), 6.49 (m, 2H), 6.33 (t, 0.5 H, J = MS (ESI): C 14 H 16 Calculated N8O2: 328, Found 329 (M+1) + and 351 (M+23) + EXAMPLES

[0316] Synthesis of 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (INT3)

[0317] [ka]

[0318] To a solution of indole (2.54 g, 21.69 mmol) in anhydrous THF (30 mL) was added 60% sodium hydride (1.08 g, 27.11 mmol) in one portion under ice bath and stirred until no more bubbles were released. A separate flush was charged with cyanogen chloride (4.00 g, 21.69 mmol) in anhydrous THF (30 mL) under argon and cooled to -78°C. The indole / sodium hydride solution was cannulated slowly over 20 min at -78°C. The mixture was stirred for 90 min and monitored by LCMS (mass 265). After completion, DIPEA (5.61 g, 43.38 mmol) and pyrazole (1.55 g, 22.78 mmol) were added and then equilibrated to 0°C with stirring for 2 h. The mixture was then stirred at room temperature for 2 days. After completion, the mixture was filtered through a celite pad and washed thoroughly with ethyl acetate and dichloromethane. The organic layer was washed with brine (400 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (120 g) with 100% dichloromethane to give 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (1.30 g, 20%) as a light powdery yellow solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.87 (dd, 1H, J = 48, 4.0 Hz), 8.83 (dd, 1H, J = 44, 8.0 Hz), 8.33 (dd, 1H, J = 28, 2.0 Hz), 8.09 (dd, 1H, J = MS (ESI): C 14 Calculated for H9ClN6: 296, Found: 297 (M+1) + EXAMPLES

[0319] Synthesis of 4-(1H-indol-1-yl)-N-(2-methoxyethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (compound 89)

[0320] [ka]

[0321] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.09 g, 0.67 mmol) and 2-methoxyethylamine (0.13 g, 1.69 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 20 h. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) with 100% ethyl acetate to give 4-(1H-indol-1-yl)-N-(2-methoxyethyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (0.04 g, 39%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.88 (dd, 1H, J = 64.0, 8.0 Hz), 8.8 (dd, 1H, J = 28.0, 4.0 Hz), 8.63 (dt, 1H, J = 16.0, 4.0 Hz), 8.35 (dd, 1H, J = 32.0, 4.0 Hz), 7.95 (dd, 1H, J = 4.0, 2.0 Hz), 7.65 (m, 1H), 7.36 (m, 1H), 7.25 (m, 1H), 6.83 (dd, 1H, J = 8.0, 4.0 Hz, 6.66 (m, 1H), 3.67 (m, 2H), 3.59 (m, 2H), 3.31 (s, 3H). MS (ESI): C17 H 17 Calculated value for N7O: 335, Measured value: 336 (M) + and 358 (M+Na) + EXAMPLES

[0322] Synthesis of 1-(4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (compound 90)

[0323] [ka]

[0324] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added piperazine (0.17 g, 2.02 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 20 h. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 (2×20 mL) followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was precipitated in dichloromethane and collected by filtration to give 1-(4-(piperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.05 g, 47%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6 / MeOD): δ 8.72 (s, 1H), 8.37 (d, 1H, J = 4.0 Hz), 7.87 (s, 1H), 7.60 (d, 1H, J = 8.0 Hz), 7.37 (m, 1H), 7.25 (m, MS (ESI): C 18 H 18Calculated N8: 346, Measured: 347 (M) + EXAMPLES

[0325] Synthesis of 1-(4-(cyclopentyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (compound 95)

[0326] [ka]

[0327] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) cooled to -78 °C under argon was added pentanol (0.04 g, 0.40 mmol) and potassium tert-butoxide (0.04 g, 0.37 mmol) and stirred for 25 min. The mixture was then equilibrated to room temperature and stirred overnight (24 h). The reaction was quenched with water and then extracted with an 8:2 dichloromethane / isopropanol mixture (3 x 20 mL) and washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) with 100% dichloromethane to give 1-(4-(cyclopentyloxy)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.05 g, 42%) as a white solid. 11H-NMR (400 MHz, DMSO-d6): δ 8.85 (m, 2H), 8.35 (d, 1H, J = 4.0 Hz), 8.03 (d, 1H, J = 0.5 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.42 (dt, 1H, J = 8.0, 0.5 Hz), 7.30 (dt, 1H, J = 8.0, 0.5 Hz), 6.89 (dd, 1H, J = 4.0, 0.2 Hz), 6.71 (dd, 1H, J = 4.0, 4.0, Hz), 5.66 (m, 1H), 2.08 (m, 2H), 1.92 (m, 2H), 1.79 (m, 2H), 1.67 (m, 2H). MS (ESI): C 19 H 18 Calculated for C 19 H 18 N6O: 346, found 279 (hydrolyzed -OH product), unstable under acidic LCMS conditions.

Example

[0328] Synthesis of ethyl 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (compound 6)

[0329]

Chemical formula

[0330] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.43 g, 3.37 mmol) and beta-alanine ethyl ester hydrochloride (0.21 g, 1.35 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 20 h. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was precipitated in a minimum amount of methanol and collected by filtration to give ethyl 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.10 g, 77%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.87 (dd, 1H, J = 48.0, 8.0 Hz), 8.80 (dd, 1H, J = 20.0, 4.0 Hz), 8.63 (dt, 1H, J = 32.0, 4.0 Hz), 8.34 (dd, 1H, J = 36.0, 4.0 Hz), 7.94 (ddd, 1H, J = 16.0, 2.0, 2.0 Hz), 7.66 (t, 1H, J = 8.0 Hz), 7.36 (m, 1H), 7.26 (m, 1H), 6.84 (ddd, 1H, J = 8.0, 4.0, 2.0 Hz), 6.66 (m, MS (ESI): C 19 H 19 Calculated N7O2: 377, Measured 378 (M) + and 400 (M+Na) + EXAMPLES

[0331] Synthesis of 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide (compound 91)

[0332] [ka]

[0333] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.43 g, 3.37 mmol) and 3-amino-propionamide hydrochloride (0.21 g, 1.35 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 20 h. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was precipitated in a minimum amount of dichloromethane and collected by filtration to give 3-((4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide (0.11 g, 93%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.90 (dd, 1H, J = 44.0, 8.0 Hz), 8.80 (dd, 1H, J = 28.0, 4.0 Hz), 8.56 (dt, 1H, J = 16.0, 4.0 Hz), 8.35 (dd, 1H, J = 40.0, 4.0 Hz), 7.94 (ddd, 1H J = 8.0. 2.0, 2.0 Hz) 7.65 (m, 1H), 7.41 (bs, 1H), 7.35 (m, 1H), 7.26 (m, 1H), 6.91 (bs, 1H), 6.83 (ddd, 1H, J = 8.0, 4.0, 2.0 Hz, 6.66 (m, 1H), 3.68 (m, 2H), 2.49 (m, 2H). MS (ESI): C 17 H 16 Calculated N8O: 348, Measured: 349 (M) + and 371 (M+Na) + EXAMPLES

[0334] Synthesis of 4-(1H-indol-1-yl)-N-(3-methoxypropyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (compound 97)

[0335] [ka]

[0336] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.09 g, 0.67 mmol) and 3-methoxypropylamine (0.1 g, 1.72 mmol) under an argon atmosphere. The sealed tube was heated at 50° C. for 20 h. The cooled reaction was extracted with an 8:2 mixture of dichloromethane / isopropanol (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) with 100% ethyl acetate to give 4-(1H-indol-1-yl)-N-(3-methoxypropyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (0.06 g, 53%) as a white solid. 11H-NMR (400 MHz, DMSO-d6): δ 8.89 (dd, 1H, J = 52.0 8.0 Hz), 8.80 (dd, 1H, J = 12.0, 4.0 Hz), 8.60 (dt, 1H, J = 40.0, 8.0 Hz, 8.34 (dd, 1H, J = 36.0, 4.0 Hz), 7.94 (ddd, 1H, J = 8.0, 2.0, 2.0 Hz), 7.65 (dd, 1H, J = 8.0, 4.0 Hz), 7.36 (m, 1H), 7.26 (m, 1H), 6.82 (ddd, 1H, J = 8.0, 4.0, 2.0 Hz), 6.66 (m, 1H), 3.54 (m, 2H), 3.45 (q, 2H, J = 4.0 Hz), 3.26 (s, 3H), 1.87 (m, 2H). MS (ESI): C 18 H 19 Calculated value for C + N7O: 349, found 350 (M) +

Example

[0337] Synthesis of 4-(4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine (Compound 92)

[0338]

Chemical formula

[0339] To a solution of 2,4-dichloro-6-(3,5-difluorophenyl)-1,3,5-triazine (0.10 g, 0.38 mmol) in anhydrous THF (2 mL) was added pyrazole (0.03 g, 0.40 mmol) and DIPEA (0.10 g, 0.76 mmol) at 0° C. under argon atmosphere. The mixture was kept in a refrigerator at 4° C. overnight. After completion by monitoring with LCMS (mass 294), morpholine (0.04 g, 0.42 mmol) was then added via syringe. The sealed tube was stirred at room temperature for 1 h and a precipitate formed. The cooled reaction was extracted with 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) using 95:5 CH2Cl2:MeOH to give 4-(4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine (0.11 g, 82%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.95 (dd, 1H, J = 4.0, 2.0 Hz), 8.13 (m, 2H), 7.91 (dd, 1H, J = 4.0, 2.0 Hz), 7.56 (tt, 1H, J = 8.0, 4.0 Hz), 6.64 (dd, 1H, J = 4.0, 2.0 Hz), 4.03 (t, 2H, J = 4.0 Hz), 3.94 (t, 2H, J = 4.0 Hz), 3.73 (t, 4H, J = 4.0 Hz). MS (ESI): C 16 H 14 Calculated value for F2N6O: 344, Measured value: 345 (M) + and 367 (M+Na) + EXAMPLES

[0340] Synthesis of 2-(azetidin-1-yl)-4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine (compound 93)

[0341] [ka]

[0342] To a solution of 2,4-dichloro-6-(3,5-difluorophenyl)-1,3,5-triazine (0.10 g, 0.38 mmol) in anhydrous THF (2 mL) was added pyrazole (0.03 g, 0.40 mmol) and DIPEA (0.10 g, 0.76 mmol) at 0° C. under argon atmosphere. The mixture was kept in a refrigerator at 4° C. overnight. After completion by monitoring with LCMS (mass 294), azetidine (0.04 g, 0.42 mmol) was then added via syringe. The sealed tube was stirred at room temperature for 1 h and a precipitate formed. The cooled reaction was extracted with a 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (40 g) with 100% ethyl acetate to give 2-(azetidin-1-yl)-4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine (0.06 g, 50%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.89 (dd, 1H, J = 8.0, 1.0 Hz), 8.04 (m, 2H), 7.90 (dd, 1H, J = 4.0, 1.0 Hz), 7.55 (tt, 1H, J = 8.0, 4.0 Hz), 6.62 (dd, 1H, J = 4.0, 2.0 Hz), 4.26 (dt, 4H, J = 20.0, 8.0 Hz), 2.39 (p, 2H, J = 8.0 Hz). MS (ESI): C 15 H 12 Calculated F2N6 value: 314, Measured value: 315 (M) + and 337 (M+Na) + EXAMPLES

[0343] Synthesis of 2-(3,5-difluorophenyl)-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine (compound 80)

[0344] [ka]

[0345] To a solution of 2,4-dichloro-6-(3,5-difluorophenyl)-1,3,5-triazine (0.10 g, 0.38 mmol) in anhydrous THF (2 mL) was added pyrazole (0.03 g, 0.40 mmol) and DIPEA (0.10 g, 0.76 mmol) at 0° C. under argon atmosphere. The mixture was kept in a refrigerator at 4° C. overnight. After completion by monitoring with LCMS (mass 294), 1-methylpiperazine (0.05 g, 0.46 mmol) was then added via syringe. The sealed tube was stirred at room temperature for 1 h and a precipitate formed. The cooled reaction was extracted with 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) using 95:5 CH2Cl2:MeOH to give 2-(3,5-difluorophenyl)-4-(4-methylpiperazin-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine (0.11 g, 81%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.95 (dd, 1H, J = 4.0, 1.0 Hz), 8.12 (m, 2H), 7.91 (dd, 1H, J = 2.0, 1.0 Hz), 7.56 (tt, 1H, J = 8.0, 4.0 Hz), 6.64 (dd, 1H, J = 4.0, 2.0 Hz), 4.02 (bs, 2H), 3.94 (bs, 2H), 2.46 (m, 4H), 2.26 (s, 3H). MS (ESI): C 17 H 17 Calculated value of F2N7: 357, Measured value: 358 (M) + and 380 (M+Na)+ EXAMPLES

[0346] Synthesis of ethyl 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (compound 8)

[0347] [ka]

[0348] To a solution of 2,4-dichloro-6-(3,5-difluorophenyl)-1,3,5-triazine (0.10 g, 0.38 mmol) in anhydrous THF (2 mL) was added pyrazole (0.03 g, 0.40 mmol) and DIPEA (0.17 g, 1.34 mmol) at 0° C. under argon atmosphere. The mixture was kept in a refrigerator at 4° C. overnight. After completion by monitoring with LCMS (mass 294), beta-alanine ethyl ester hydrochloride (0.07 g, 0.46 mmol) was then added via syringe. The sealed tube was stirred at room temperature for 1 h and a precipitate formed. The cooled reaction was extracted with 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (24 g) with 100% ethyl acetate to give ethyl 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanoate (0.06 g, 42%) as a white solid. 11H-NMR (400 MHz, DMSO-d6): δ 8.91 (dt, 1H, J = 4.0, 1.0 Hz), 8.67 (dt, 1H, J = 52.0, 4.0 Hz), 8.13 (m, 1H), 8.02 (m, 1H), 7.91 (dq, 1H, J = 12.0, 4.0 Hz), 7.57 (m, 1H), 6.64 (dq, 1H, J = 4.0, 1.0 Hz), 4.05 (m, 2H), 3.72 (m, 2H), 2.67 (q, 2H, J = 8.0 Hz), 1.15 (t, 3H, J = 8.0 Hz). MS (ESI): C 17 H 16 Calculated for F2N6O2: 374, Found 375 (M) + and 397 (M+Na) +

Example

[0349] Synthesis of 4-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine (Compound 94)

[0350]

Chemical formula

[0351] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (2 mL) was added DIPEA (0.09 g, 0.67 mmol) and morpholine (0.12 g, 1.35 mmol) under an argon atmosphere. The reaction was stirred at room temperature for 3 h. The reaction was then extracted with an 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a silica gel cartridge (12 g) with 100% ethyl acetate to give 4-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)morpholine (0.11 g, 98%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.86 (dd,1H, J = 4.0, 1.0 Hz), 8.80 (d, 1H, J = 12.0 Hz), 8.38 (d, 1H, J = 4.0 Hz), 7.97 (dd, 1H, J = 4.0, 1.0 Hz), 7.66 (d, 1H, J = 8.0 Hz), 7.38 (dt, 1H, J = 8.0, 1.0 Hz), 7.26 (dt, 1H, J = 8.0, 0.5 Hz), 6.67 (dd, 1H, J = 4.0, 1.0 Hz), 3.97 (m, 4H), 3.75 (m, 4H). MS (ESI): C 18 H 17 Calculated value for N7O: 347, Measured value: 348 (M) + EXAMPLES

[0352] Synthesis of 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide (Compound 96)

[0353] [ka]

[0354] To a solution of 2,4-dichloro-6-(3,5-difluorophenyl)-1,3,5-triazine (0.10 g, 0.38 mmol) in anhydrous THF (2 mL) was added pyrazole (0.03 g, 0.40 mmol) and DIPEA (0.25 g, 1.91 mmol) at 0° C. under argon atmosphere. The mixture was kept in a refrigerator at 4° C. overnight. After completion by monitoring with LCMS (mass 294), 3-amino-propionamide hydrochloride (0.04 g, 0.42 mmol) and anhydrous isopropanol (2 mL) were then added. The sealed tube was heated at 50° C. for 3 hours, and a precipitate formed. The cooled reaction was extracted with a 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was precipitated in a minimum amount of dichloromethane and collected by filtration to give 3-((4-(3,5-difluorophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)amino)propanamide (0.89 g, 68%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 8.90 (ddd, 1H, J = 8.0, 2.0, 0.5 Hz), 8.60 (dt, 1H, 36.0, 4.0 Hz), 8.13 (dd, 1H, J = 8.0, 4.0 Hz), 8.03 (dd, 1H, J = 8.0, 4.0 Hz), 7.90 (ddd, 1H, J = 8.0, 1.0, 0.5 Hz), 7.57 (m, 1H), 7.40 (bs, 1H), 6.89 (bs, 1H), 6.63 (dq, 1H, J = 8.0, 1.0 Hz), 3.66 (m, 2H), 2.45 (t, 2H, J = 8.0 Hz). MS (ESI): C 15 H 13 Calculated value for F2N7O: 345, Measured value: 346 (M) + EXAMPLES

[0355] Synthesis of 8-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane (compound 60)

[0356] [ka]

[0357] To a solution of ethyl 1-(4-chloro-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1H-indole (0.10 g, 0.34 mmol) in anhydrous THF (3 mL) was added DIPEA (0.17 g, 1.35 mmol) and 2-oxa-5,8-diazaspiro[3.5]nonane (nonae) dihydrochloride (0.07 g, 0.37 mmol) under an argon atmosphere. The reaction was stirred at 50° C. for 24 h. The reaction was then extracted with an 8:2 dichloromethane / isopropanol mixture (3×20 mL) and washed with saturated NaHCO3 followed by brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Buchi Pureflash chromatography on a pre-neutralized silica gel cartridge (40 g) with 100% ethyl acetate to give 8-(4-(1H-indol-1-yl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-5,8-diazaspiro[3.5]nonane (0.13 g, 98%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.87 (dd,1H, J = 18, 2.4 Hz), 8.82 (dd, 1H, J = 29, 8.4 Hz), 8.39 (dd, 1H, J = 10.4, 3.6 Hz), 7.97 (dd, 1H, J = 6.8, 1.0 Hz), 7.66 (t, 1H, J = 7.2.0 Hz), 7.39 (t, 1H, J = 7.2 Hz), 7.26 (m, 1H), 6.84 (dd, 1H, J = 13.2, 4.0 Hz), 6.67 (ddd, 1H, J = 10.4, 2.4, 1.6 Hz), 4.42 (t, MS (ESI): C 20 H 20 Calculated N8O: 388, Measured: 389 (M) + EXAMPLES

[0358] Cellular assays for the anti-inflammatory properties of JMJD3 inhibitors The anti-inflammatory properties of five JMJD3 inhibitors (99, 92, 93, 98, and 95, in no particular order) were evaluated in immune cell assays targeting key pro-inflammatory cytokines involved in the pathogenesis of multiple autoimmune diseases. The JMJD3 inhibitors examined are shown in Table 1.

[0359] [Table 6]

[0360] In particular, THP-1 human monocytes were grown in 6-well plates (RPMI1640+10%FBS+1%P / S). After washing with PBS, THP-1 cells were differentiated into macrophages using 20nM phorbol 12-myristate 13-acetate (PMA) for 24 hours. 99, 92, 93, 98, and 95) (1μM) were added to the macrophages, which were then incubated for 4 hours, followed by the addition of 100ng / mL lipopolysaccharide (LPS) for either 4 or 24 hours. Macrophages were then collected by centrifugation at 1.2K rpm for 5 minutes, and their media were used to assess cytokine protein levels by using a Bio-rad Cytokine ELISA multiplex assay (catalog number M5000031YV). Supernatants were collected from macrophages treated with only LPS+PMA and used as negative controls. All JMJD3 inhibitors (99, 92, 93, 98, and 95) showed suppression of TNF-alpha (TNFA), interleukin 6 (IL6), interleukin 1beta (IL1B), interleukin 8 (IL8), interleukin 5 (IL5), and interleukin 13 (IL13).

[0361] The effects of JMJD3 inhibitors (99, 92, 93, 98, and 95) on TNFA, IL6, and IL1B suggest that they may be used in the treatment of autoimmune diseases, including ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, psoriasis, type 1 diabetes, graft-versus-host disease (GVHD), autoimmune encephalitis, Behcet's disease, Sjogren's syndrome, asthma, pulmonary allergy, and atopic dermatitis. Furthermore, the effects of JMJD3 inhibitors on IL5 and IL13 suggest that they may also be used in asthma, pulmonary allergy, and atopic dermatitis. EXAMPLES

[0362] Cellular assay for FoxP3-inducing activity of JMJD3 inhibitors CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress proinflammatory cells and signals and are crucial mediators of tolerance, inhibiting excessive inflammation and autoimmunity. Treatment of CD4+ T cells with interleukin-2 (IL-2) and transforming growth factor beta (TGF-β) signaling is also important for FOXP3 induction and Treg formation.

[0363] Naive CD4 + T human cells (catalog no. 2W-200, Lonza) were cultured and activated with artificial antigen presenting cells and soluble anti-CD3 (100 ng / ml) in the presence of IL-2 (300 U / ml) and TGF-β (10 ng / ml) for 5 days. On day 3, cells were transfected with antisense RNA against JMJD3 (catalog no. 1299001, Thermo) using Lipofectamine 2000 (catalog no. 11668027, Thermo). On day 5, RNA was extracted and qPCR analysis was performed to evaluate FoxP3 mRNA levels by using the following primers with a 217 bp product: F: 5'-TCC ACA ACA TGC GAC CCC CTT TCA-3' and R: 5'-ACA GCC CCC TTC TCG CTC TCC A-3'. All JMJD3 inhibitors (99, 92, 93, 98, and 95) in CD4+ T cells induced 7-fold FoxP3 expression levels, thus towards Treg differentiation and formation. The results of this study are shown in Figure 3 (FoxP3 induction). Thus, genetic or pharmacological inhibition of CD4+ T cells leads to the induction of FoxP3 activation and Treg formation. Based on this evidence, JMJD3 inhibitors (99, 92, 93, 98, and 95) could be used in autoimmune diseases where T regulatory cells have potential therapeutic potential. There is growing evidence and literature from human clinical studies (Arellano B et al., Regulatory T Cell-based Therapies for Autoimmunity, Discov Med, 22:73-80, 2016).

[0364] Therefore, the JMJD3 inhibitors 99, 92, 93, 98, and 95 compounds can be applied as treatments in graft-versus-host disease (GVHD), type 1 diabetes (T1D), ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, Sjogren's syndrome, Hashimoto's thyroiditis, autoimmune hepatitis, Behcet's disease, Castleman's disease, allergic rhinitis, eczema, Dressler's syndrome, eosinophilic esophagitis, Guillain-Barré syndrome, juvenile arthritis, Kawasaki disease, asthma, pulmonary allergy, and atopic dermatitis. EXAMPLES

[0365] Example of a cellular assay for the anti-inflammatory properties of JMJD3 inhibitors THP-1 cells were grown to confluence and seeded in 6-well plates. PMA (25 nM) was added to the medium and replaced with non-PMA containing medium after 24 h. ATH compounds (1 μM) or vehicle (0.1% DMSO) were added and incubated. After 4 h, LPS (50 ng / ml) was added without changing the medium and supernatants were collected after 4 h and 4 h. The medium was placed on ice for detection of cytokines using ELISA (Quantikine, R&D Systems).

[0366] JMJD3 inhibitors Compound 89, Compound 91 (Figure 4A, p<0.05), Compound 97, Compound 92, Compound 93 (Figure 4B, p<0.01), and Compound 94 (Figure 4C, p<0.01) show suppression of TNF-alpha (TNFA) expression following LPS treatment in THP-1 human monocytes (Figures 4A-C, p<0.05 for both). EXAMPLES

[0367] Exemplary JMJD3 Binding Assays Test compounds were prepared as 111x stocks in 100% DMSO. d Values ​​were determined using an 11-point 3-fold compound dilution series and three DMSO control points. dAll compounds for measurement were dispensed in 100% DMSO by acoustic transfer (non-contact dispensing). Compounds were then directly diluted for assay use so that the final concentration of DMSO was 0.9%. All reactions were carried out in polypropylene 384-well plates. Each was in a final volume of 0.02 ml. The assay plate was incubated for 1 hour at room temperature with shaking, and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. Kinase concentrations in the eluates were measured by qPCR. Binding constants were calculated with a standard dose-response curve using the Hill equation.

[0368]

number

[0369] Hill Slope was set to -1. Curves were fitted using a nonlinear least squares fit with the Levenberg-Marquardt algorithm. Binding data are summarized in Table 2, where A is <100 nM, B is 100-500 nM, and C is >500 nM.

[0370] [Table 7] EXAMPLES

[0371] Hypothetical example of in vivo anti-inflammatory efficacy of VNN1 inhibitors Inhibition of JMJD3 ameliorates colitis in studies using a dextran sulfate sodium (DSS)-induced colitis mouse model, and downregulation of JMJD3 reduces TNFα expression in mouse macrophages. Our data demonstrate that addition of the JMJD3 inhibitors disclosed herein to THP-1 human monocytes significantly inhibits TNFα release in response to the potent inflammatory inducer LPS.

[0372] C57BL / 6 mice (20-22 grams) are fed ad libitum and assigned to four different groups (n=8 mice / group). After a 72-hour acclimation period, the test group receives 25 mg / kg of the test compound in vehicle PO (gavage) daily. The control group receives vehicle only. After 24 hours, the mice are weighed and DSS is added to their drinking water. The mice are then treated with the test compound, weighed daily for 5 days, and replenished with DSS water every 72 hours, replacing it with regular drinking water on the 5th day. The mice are sacrificed on day 12 and clinical scores were assessed. Intestinal tissue and blood are also collected. Tissues are flash frozen and kept at -80°C for RNA and protein isolation or placed in 10% formalin solution for future histological analysis. Blood is spun at 5K rpm for 5 minutes and serum is collected and kept at -20°C for multiplex cytokine analysis. Combined with the central role of TNFα in IBD pathophysiology, the above data strongly predict the beneficial effect of JMJD3 inhibitors in improving inflammatory responses in animal models of colitis and subsequent IBD patients. Efficacy data are summarized in Table 3 below, where A is strong inhibition, B is moderate inhibition, and C is no inhibition.

[0373] [Table 8] EXAMPLES

[0374] Hypothetical Example of Treatment of an IBD Patient This is a hypothetical example. The JMJD3 inhibitors disclosed in Example 22 (compounds 1, 2, 89, 90, 6, 91, 97, 92, 93, 80, 8, 94, 96, and 95) are used to treat patients with ulcerative colitis and Crohn's disease patients with active disease who have been sensitive or resistant to previous anti-TNFA treatments. The inhibitors are administered orally daily for 12 weeks as capsules at doses of 50-200 mg. After completion of treatment, patients have both clinical and histological improvement as assessed by Mayo or CDAI clinical scores, endoscopic appearance, and histological evaluation. EXAMPLES

[0375] Hypothetical Example of Treating a Cancer Patient This is a hypothetical example. The JMJD3 inhibitors disclosed in Example 22 (compounds 1, 2, 89, 90, 6, 91, 97, 92, 93, 80, 8, 94, 96, and 95) are used to treat patients with kidney, breast, castration-resistant prostate cancer, acute myeloid leukemia (AML), melanoma, Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS), esophageal squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and ovarian cancer. The inhibitors are orally administered daily as capsules at a dose of 50-200 mg in patients with or without chemotherapy. After completion of treatment, patients have clinical improvement characterized by increased prognostic survival.

Claims

1. A compound having a structure represented by formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, L is -C(R １ ) ２ -, -N-, -NR １ -, -N(R １ ) ２ , optionally substituted amine (alkyl), -O-, - -C(=O)-, -OC(=O)-, -C(=O)O-, optionally substituted heterocyclyl, and a single bond; A ａ is an optionally substituted C １ ~C ６ Alkylene and C １ ~C ６ alkyl, or A ａ does not exist, A ｂ is -C(=O)- or -N(CH ３ )- or A ｂ does not exist, A １ is hydroxyl, amino, optionally substituted C １～１２ Alkyl, optionally substituted C １ ~C １２ Alkoxy, optionally substituted C １ ~C １２ Alkamino, optionally substituted carbamide, C-amide, optionally substituted C ６～１０ Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C ３～１０ carbocyclyl, and 3- to 12-membered heterocyclyl, or A １ does not exist, A ２ is selected from the group consisting of pyrazole and pyridine; A ｃ does not exist, A ３ is an optionally substituted C １～１２ Alkyl, optionally substituted C ６～１０ Aryl, optionally substituted 5-12 membered heteroaryl, and optionally substituted C ３～１０ carbocyclyl; R １ is, when present, independently at each occurrence, —H, halogen, hydroxy, C １～６ Alkyl, C １ ~C ６ Alkoxy, C １～６ Haloalkyl, and C ６～１０ aryl, or two R １ When the group is present, R １ The groups taken together form an optionally substituted 3- to 12-membered heterocycle or an optionally substituted C ３～１０ to form a carbocyclyl.

2. L is -N(R １ ) ２ and R １ The compound of claim 1, wherein the groups taken together form a 3- to 12-membered heterocyclyl group.

3. 3. The compound of claim 2, wherein L is a 6-membered heterocyclyl group containing 1 or 2 heteroatoms.

4. The compound of claim 3 , wherein the heteroatom of L is N.

5. A ａ and A ｂ The compound of claim 2 , wherein is not present.

6. A １ is a 3- to 12-membered heterocyclyl group; A １ 6. The compound of claim 5, wherein the ring of and the ring of L result in a spiro ring system.

7. L.A. ａ , A ｂ , and A １ But together, 【Chemistry 2】 The compound of claim 2, which results in a structure selected from the group consisting of:

8. The compound of claim 1 , wherein L is —NH—.

9. A ａ But, C １ ~C ６ The compound of claim 8 which is an alkylene.

10. A ａ But, C １ ~C ３ The compound of claim 1 which is an alkylene.

11. A ｂ The compound of claim 10, wherein is -C(=O)- or absent.

12. A １ Amino, hydroxyl, C １～３ carbamido optionally substituted with alkyl, methyl or ethyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heteroaryl, or C １ ~C ３ The compound of claim 10 which is alkoxy.

13. L.A. ａ , A ｂ , and A １ But together, 【Chemistry 3】 9. The compound of claim 8, which results in a structure selected from the group consisting of:

14. A ａ The compound of claim 8, wherein is absent.

15. A ｂ The compound of claim 14 , wherein is absent.

16. A １ is optionally substituted with hydroxyl or halogen; １～４ Alkyl, optionally substituted C ３～６ 15. The compound of claim 14 which is a carbocyclyl, a 3- to 6-membered heterocyclyl, a 3- to 6-membered aryl optionally substituted with halogen, or an optionally substituted 3- to 6-membered heteroaryl.

17. L.A. ａ , A ｂ , and A １ But together, 【Chemistry 4】 15. The compound of claim 14, which results in a structure selected from the group consisting of:

18. A ２ The compound according to claim 1, wherein is pyridine.

19. A ２ but, 【Chemistry 5】 2. The compound of claim 1,

20. A ３ The compound of claim 1 , wherein is phenyl optionally substituted with -F.

21. A ｃ and A ３ But together, 【Chemistry 6】 21. The compound of claim 20, which results in a structure:

22. A ３ is optionally substituted C ３～７ The compound of claim 1 which is carbocyclyl.

23. A ｃ and A ３ But together, 【Chemistry 7】 23. The compound of claim 22, which results in a structure:

24. A １ When a group is substituted with one or more optional substituents, the one or more optional substituents are independently selected from acyl, C １～６ Alkyl, C １～６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkoxy, C-amide, aryl, ester, halogen, heteroaryl, heterocyclyl, and hydroxy.

25. A ３ When a group is substituted with one or more optional substituents, the one or more optional substituents are independently selected from the group consisting of: １～６ Alkyl, C １～６ Cycloalkyl, C ６～１０ The compound of claim 1 , wherein the alkyl group is selected from the group consisting of aryl, halogen, and hydroxy.

26. A ａ , A ｂ , A １ , or A ３ is substituted with one or more optional substituents, each of the one or more optional substituents is independently selected from -OH, C １～３ Alkyl, C １～３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of alkoxy, or halogen.

27. The compound of formula (I) has the structure of formula (Ia) 【Chemistry 8】 and n is an integer equal to 1, 2, or 3.

28. 28. The compound of claim 27, wherein the structure of formula (Ia) is represented by a structure selected from the group consisting of compounds 4, 5, 6, 8, 26, 91, and 96.

29. The compound of formula (I) has the structure of formula (Ib) 【Chemistry 9】 2. The compound of claim 1 further represented by:

30. 30. The compound of claim 29, further represented by a structure selected from the group consisting of compounds 4, 5, 6, 8, 20, and 36.

31. The compound of formula (I) has the structure of formula (Id) 【Chemistry 10】 [In the formula, X is -CH ２ selected from the group consisting of -, -NH-, and -O-; m is an integer equal to 1, 2, 3, or 4; o is an integer equal to 1, 2, 3, or 4.

2. The compound of claim 1 further represented by:

32. 32. The compound of claim 31, further represented by a structure selected from the group consisting of compounds 58, 59, 60, 62, 73, 80, 81, 83, 92, 93, 94, and 99.

33. The compound of formula (I) has the structure of formula (Ie) 【Chemistry 11】 2. The compound of claim 1 further represented by:

34. A １ But, CH ３ -, CF ３ -, CH ３ (CH ２ ) ３ -, (CH ３ ) ２ CH-, (CH ３ ) ２ CHCH ２ -, CH ３ (CH ２ ) ３ -, CH ３ (HO)CH-, HOCH ２ -, CH ３ CH ２ OCH ２ -, NH ２ C(=O)CH ２ -, CH ３ O-, CH ３ CH ２ O-, NH ２ -, NH ２ C(=O)NH-, and CH ３ CH ２ 2. The compound of claim 1, selected from the group consisting of NHC(=O)NH-.

35. A １ but, 【Chemistry 12】 2. The compound of claim 1 selected from the group consisting of:

36. A ３ but, 【Chemistry 13】 2. The compound of claim 1 selected from the group consisting of:

37. 【Catalog 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound selected from the group consisting of:

38. 40. A compound according to any one of claims 1 to 37 for use in a method of treating a JMJD3 mediated condition.

39. 38. A method for producing a compound according to any one of claims 1 to 37, comprising the steps of: In the presence of a base, H-LA ａ A ｂ A １ and replacing the halogen group from the cyanuric chloride using The method includes:

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