TYK2 inhibitors

Abstract

The present invention relates to compounds of formula (I), which are inhibitors of TYK2. The inhibitors described herein may be useful in treating diseases or disorders associated with TYK2, such as autoimmune diseases. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit TYK2, methods of treating diseases or disorders associated with TYK2, and methods of synthesizing these compounds. JPEG2025539787001027.jpg64170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent No. 63 / 425,877, entitled "TYK2 Inhibitors," filed November 16, 2022, the disclosure of which is incorporated by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to inhibitors that target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. The inhibitors described herein may be useful for treating TYK2-related diseases or disorders, such as inflammatory diseases and lymphomas. These compounds are potent against human T-cell lines and primary immune cells, as well as human whole blood specimens. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit TYK2, methods for treating TYK2-related diseases or disorders, and methods for synthesizing these compounds.

[0003] (background) Cytokine signaling plays a critical role in controlling immune cell growth, differentiation, function, and communication. Multiple cytokine signaling pathways are tightly regulated by the action of receptor-bound JAKs and signal transducers and activators of transcription (STATs). Dysfunctional cytokine JAK / STAT activity has been demonstrated as a hallmark of many autoimmune and inflammatory diseases.

[0004] Tyrosine kinase 2 (TYK2), the first identified member of the Janus kinase (JAK) family, is crucial for mediating various cytokine signaling pathways, such as interleukin 23 (IL23), interleukin 12 (IL12), and type I interferon (IFN), which contribute to autoimmune diseases (e.g., psoriasis, lupus, inflammatory bowel disease).

[0005] Therefore, TYK2 represents an attractive target for developing small molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. To achieve a favorable therapeutic index in the development of TYK2 inhibitors, it is important to selectively inhibit TYK2 over other JAK isoforms.

[0006] The structure of TYK2 contains a complex architecture with multiple domains involved in inter- and intramolecular interactions that transduce cytokine receptor-mediated activation to its catalytic domain. TYK2 contains four distinct domains: (i) an N-terminal ezrin, radixin, and moesin (FERM) domain; (ii) an Src homology 2 (SH2) domain (which constitutes the receptor-binding module); followed by a C-terminal, (iii) JH2 pseudokinase domain; and (iv) a JH1 kinase domain. The JH2 pseudokinase domain possesses a canonical kinase fold but lacks catalytic activity. Rather than acting as a catalyst, the JH2 domain plays a key role in regulating receptor-mediated activation of the adjacent JH1 kinase domain through intermolecular autoinhibition. Evidence suggests that stabilizing the TYK2 JH2 pseudokinase domain induces a conformational change in the protein that prevents receptor-mediated activation and inhibits the activity of the TYK2 JH1 catalytic domain by blocking the relaxation of the intermolecular autoinhibitory interaction between the TYK2 JH2 pseudokinase and JH1 kinase domains. In the JAK family, it has been reported that the JAK2 pseudokinase and kinase domains co-immunoprecipitate, and coexpression of the JAK2 JH2 pseudokinase domain suppresses the activity of the isolated JH1 kinase domain. Furthermore, deletion of the pseudokinase domains of JAK2 and JAK3 increases basal kinase activity and signaling through their cognate receptors.

[0007] Designing small molecule inhibitors targeting the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the large structural homology of the catalytic domains of the JAK family. Another approach that targets the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein, which suppresses TYK2 catalytic activity through allosteric regulation, appears much more promising.

[0008] The TYK2 inhibitor duclavacitinib (BMS986165) is currently the most clinically advanced compound, selectively binding to the JH2 regulatory domain of TYK2 and suppressing the TYK2-related cytokine pathway. Duclavacitinib has demonstrated high efficacy and a favorable safety profile in phase 2 and 3 psoriasis trials. [ka]

[0009] The present invention relates to the development of a series of small molecule TYK2 ligands that selectively target the JH2 pseudokinase regulatory domain of TYK2. The TYK2 JH2 pseudokinase ligands inhibit the activity of the TYK2 JH1 catalytic domain via the intermolecular JH2-JH1 interaction. The mechanistic approach adopted for the TYK2 JH2 ligands differs from previously designed JAK and TYK2 inhibitors that target the ATP-binding site in the JH1 domain. The new series of TYK2 JH2 ligands specifically bind to the JH2 pseudokinase regulatory domain of TYK2, thereby maintaining TYK2 in an inactive conformation and inhibiting its kinase activity.

[0010] Due to serious side effects observed during clinical trials, the FDA did not approve higher-dose versions of tofacitinib and baricitinib, which are more effective for the treatment of rheumatoid arthritis (RA). Additionally, baricitinib and upadacitinib each carry a boxed warning, the most serious warning issued by the FDA, for the risk of serious infections, malignancies, and thrombosis. Side effects of these drugs may be related to a lack of specificity or selectivity. Given the shortcomings of current treatments, unmet medical need remains high for many patients suffering from autoimmune diseases. (overview)

[0011] A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein Ring Z is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; Ring G is selected from aryl, 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, or 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R 8 )2, wherein alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl; Alternatively, two R1's, together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heterocycle or heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 optionally substituted with one or more substituents independently selected from: each R2 is independently selected from hydrogen, C1-C6 alkyl; R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl; R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-N(R 8 )2, C1-C6 alkyl-OR 8 , heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 optionally substituted with one or more substituents independently selected from: R 5 is selected from H, C1-C6 alkyl; Alternatively, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 forming a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from R 6 -OR 8 , C1-C6 halogen alkyl; R 7is C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C 10 selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl; Alternatively, R 6 and R 7 together with the atom to which they are attached and any intervening atoms, form a 5-8 membered heterocyclic ring; Each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 14-membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

[0012] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0013] Another aspect of the present invention relates to a method of treating a disease or disorder associated with TYK2, comprising administering to a patient in need of treatment for a disease or disorder associated with TYK2 an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0014] Another aspect of the present invention relates to a method of treating a JAK2-associated disease or disorder, comprising administering to a patient in need of treatment for a JAK2-associated disease or disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0015] Another aspect of the present invention relates to a method of inhibiting TYK2, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0016] Another aspect of the present invention relates to a method of inhibiting JAK2, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0017] The present invention also provides methods for modulating IL-12, IL-23 and / or IFNa by inhibiting TYK-2-mediated signaling, the methods comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0018] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, the methods comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0019] A preferred embodiment is a method of treating inflammatory and autoimmune diseases. For purposes of this invention, inflammatory and autoimmune diseases or disorders include any disease that has an inflammatory or autoimmune component.

[0020] Another preferred embodiment is a method of treating metabolic diseases, including type 2 diabetes and atherosclerosis.

[0021] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting TYK2.

[0022] Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting JAK2.

[0023] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of diseases associated with the inhibition of TYK2.

[0024] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of diseases associated with the inhibition of JAK2.

[0025] Another aspect of the present invention pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0026] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0027] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0028] The present invention further provides a method for treating a disease or disorder associated with TYK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0029] The present invention provides inhibitors of TYK2 that are therapeutic agents in the treatment of diseases and disorders.

[0030] The present invention provides inhibitors of JAK2 that are therapeutic agents in the treatment of diseases and disorders.

[0031] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known inhibitors of TYK2. The present disclosure also provides agents with novel mechanisms of action that interact with TYK2 in the treatment of various types of diseases.

[0032] The present invention further provides a method for treating a disease or disorder associated with TYK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0033] The present invention provides inhibitors of TYK2 that are therapeutic agents in the treatment of diseases and disorders.

[0034] The present invention further provides a method of treating a disease, disorder, or condition selected from SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, atopic dermatitis; immunodeficiency disease 35 (IMD35); cancer; lymphoma; primary cutaneous anaplastic large cell lymphoma; X-linked lymphoproliferative syndrome 1 (XLP1); polycythemia vera (PV); autoimmune diseases including pneumonia, the method comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0035] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in General Procedures A, B, C, or D).

[0036] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparation Parts P1 to P120).

[0037] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0038] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0040] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0041] (Detailed explanation) The present disclosure provides methods for treating, preventing, or ameliorating diseases or disorders associated with the inhibition of TYK2 by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0042] Details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will become apparent from the specification and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. 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 and publications cited herein are incorporated herein by reference in their entirety. definition

[0043] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0044] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise stated.

[0045] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

[0046] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0047] As used herein, the term "unsubstituted" means that the particular group bears no substituents.

[0048] Unless otherwise defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0049] Unless otherwise defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic radicals can contain two or more fused rings and can further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Aromatic radicals may be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl ... lo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyridinyl Furo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl Lysinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] In addition, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described herein. In addition, when containing three or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring described herein may be optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyra pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0050] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0051] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neo-pentyl, and isohexyl.

[0052] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0053] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0054] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0055] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0056] "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3-18 carbon atoms. Polycyclic cycloalkyls may be fused bicyclic cycloalkyls, bridged bicyclic cycloalkyls, or spiro-fused bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0057] A "heterocyclyl," "heterocycle," or "heterocycloalkyl" containing 3-24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, is monocyclic or polycyclic, and wherein the ring is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents. Polycyclic heterocycloalkyls contain at least one non-aromatic ring. Polycyclic heterocyclic compounds can be bridged, fused, or spirofused. The substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, homotropanyl, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,6-diazaspiro[3.3]heptanyl.

[0058] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of linked p-orbitals with delocalized electrons, which may include lone pairs of electrons.

[0059] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0060] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0061] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0062] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced with a heteroatom.

[0063] The terms "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" are understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0064] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0065] As used herein, the term "alkyl-aryl" (and variations thereof, e.g., C1-C6 alkyl-aryl) refers to a chemical moiety comprising an alkyl group covalently bonded to an aryl group, where the bond to the rest of the molecule is on the first group described, i.e., the alkyl group. Similarly, alkyl-alkoxy refers to a chemical moiety comprising an alkyl group covalently bonded to an alkoxy group, where the bond to the rest of the molecule is on the alkyl group. This nomenclature can also be used for, e.g., alkenyl-aryl, alkenyl-heteroaryl, alkynyl-aryl, alkynyl-heteroaryl. As a non-limiting example, C1 alkyl-phenyl is [ka] C2 alkenyl-furanyl refers to [ka] C1 alkyl-C2 alkoxy refers to [ka] For example, it refers to

[0066] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0067] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0068] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble salts and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, and hydrochloride. , hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0069] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0070] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.

[0071] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0072] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0073] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0074] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0075] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0076] The term "salt" means a pharmaceutically acceptable salt.

[0077] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0078] As used herein, "TYK2 inhibitor" refers to a compound of Formula I and / or a composition comprising a compound of Formula I that inhibits TYK2.

[0079] The amount of the compound of the composition described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or an additional agent)) for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of the disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse symptoms of a disorder or disease.

[0080] For example, administration of a therapeutic agent to a subject suffering from an autoimmune disease provides a therapeutic benefit not only if the underlying condition is eradicated or ameliorated, but also if the subject reports a decrease in the severity or duration of symptoms associated with the disease. A therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is achieved. Compounds of the Disclosure

[0081] In one aspect, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G, Z, k, m, and n are as described herein.

[0082] For compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G, Z, k, m, and n can each be selected from groups described herein, where applicable; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Any group described herein for any of G, Z, k, m, and n may be selected from R 1、 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G, Z, k, m, and n may be combined with any of the groups described herein.

[0083] In some embodiments, Ring Z is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; Ring G is selected from aryl, 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, or 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R 8 )2, wherein alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl; Alternatively, two R1's, together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heterocycle or heteroaryl, wherein the heterocycle or heteroaryl is selected from the group consisting of halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 optionally substituted with one or more substituents independently selected from: each R2 is independently selected from hydrogen, C1-C6 alkyl; R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl; R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-N(R 8 )2, C1-C6 alkyl-OR 8 , heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, C1-C6 alkyl, C3-C6 alkyl, C6-C6 alkyl, C8-C8 alkyl, C9-C9 alkyl, C10-C11 alkyl, C12-C13 alkyl, C14-C15 alkyl, C16-C17 alkyl, C18-C19 alkyl, C19-C18 alkyl, C19-C19 alkyl, C20-C21 alkyl, C21-C22 alkyl, C22-C23 alkyl, C23-C24 alkyl, C24-C25 alkyl, C25-C26 alkyl, C26-C27 alkyl, C27-C28 alkyl, C28-C29 alkyl, C29-C30 alkyl, C29-C31 alkyl, C29-C32 alkyl, C29- 10 Cycloalkyl, -N(R 8 )2, -OR 8 optionally substituted with one or more substituents independently selected from: R 5 is selected from H, C1-C6 alkyl; Alternatively, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 forming a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from R 6 -OR 8 , C1-C6 halogen alkyl; R 7 is C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C 10 selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl; Alternatively, R 6 and R 7 together with the atom to which they are attached and any intervening atoms, form a 5-8 membered heterocyclic ring; Each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3.

[0084] In some embodiments, ring Z is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0085] In some embodiments, k is an integer selected from 0, 1, 2, and 3.

[0086] In some embodiments, k is 0.

[0087] In some embodiments, k is 1.

[0088] In some embodiments, k is 2.

[0089] In some embodiments, k is 3.

[0090] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0091] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0092] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing two heteroatoms selected from N, O, and S.

[0093] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing two nitrogen atoms as heteroatoms.

[0094] In some embodiments, ring Z is [ka] is selected from.

[0095] In some embodiments, ring Z is [ka] is.

[0096] In some embodiments, ring Z is [ka] is.

[0097] In some embodiments, ring Z is [ka] is.

[0098] In some embodiments, ring Z is [ka] is.

[0099] In some embodiments, ring Z is [ka] is selected from.

[0100] In some embodiments, ring Z is [ka] is.

[0101] In some embodiments, ring Z is [ka] is.

[0102] In some embodiments, ring Z is [ka] is.

[0103] In some embodiments, ring Z is [ka] is.

[0104] In some embodiments, ring Z is [ka] is selected from.

[0105] In some embodiments, ring Z is [ka] is.

[0106] In some embodiments, ring Z is [ka] is.

[0107] In some embodiments, ring Z is [ka] is.

[0108] In some embodiments, ring Z is [ka] is.

[0109] In some embodiments, ring Z is [ka] is selected from.

[0110] In some embodiments, ring Z is [ka] is.

[0111] In some embodiments, ring Z is [ka] is.

[0112] In some embodiments, ring Z is [ka] is.

[0113] In some embodiments, ring Z is [ka] is.

[0114] In some embodiments, ring Z is [ka] is selected from.

[0115] In some embodiments, ring Z is [ka] is.

[0116] In some embodiments, ring Z is [ka] is.

[0117] In some embodiments, ring Z is [ka] is.

[0118] In some embodiments, ring Z is [ka] is.

[0119] In some embodiments, ring Z is [ka] is selected from.

[0120] In some embodiments, ring Z is [ka] is.

[0121] In some embodiments, ring Z is [ka] is.

[0122] In some embodiments, ring Z is [ka] is.

[0123] In some embodiments, ring Z is [ka] is selected from.

[0124] In some embodiments, ring Z is [ka] is.

[0125] In some embodiments, ring Z is [ka] is.

[0126] In some embodiments, ring Z is [ka] is.

[0127] In some embodiments, ring Z is [ka] is.

[0128] In some embodiments, ring Z is [ka] is.

[0129] In some embodiments, ring Z is [ka] is.

[0130] In some embodiments, ring Z is [ka] is.

[0131] In some embodiments, ring Z is [ka] is.

[0132] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing two heteroatoms (one oxygen and one nitrogen).

[0133] In some embodiments, ring Z is [ka] is.

[0134] In some embodiments, ring Z is [ka] is.

[0135] In some embodiments, ring Z is [ka] is.

[0136] In some embodiments, ring Z is [ka] is.

[0137] In some embodiments, ring Z is [ka] is.

[0138] In some embodiments, ring Z is [ka] is.

[0139] In some embodiments, ring Z is [ka] is.

[0140] In some embodiments, ring Z is [ka] is.

[0141] In some embodiments, ring Z is [ka] is.

[0142] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing two heteroatoms (one sulfur and one nitrogen).

[0143] In some embodiments, ring Z is [ka] is.

[0144] In some embodiments, ring Z is [ka] is.

[0145] In some embodiments, ring Z is [ka] is.

[0146] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing 3 heteroatoms selected from N, O, and S.

[0147] In some embodiments, ring Z is a 5-membered monocyclic heteroaryl containing 4 heteroatoms selected from N, O, and S.

[0148] In some embodiments, ring Z is a 6-membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0149] In some embodiments, ring Z is a 6-membered monocyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0150] In some embodiments, ring Z is a 6-membered monocyclic heteroaryl containing one nitrogen as the heteroatom.

[0151] In some embodiments, ring Z is [ka] is selected from.

[0152] In some embodiments, ring Z is [ka] is.

[0153] In some embodiments, ring Z is [ka] is.

[0154] In some embodiments, ring Z is [ka] is.

[0155] In some embodiments, ring Z is [ka] are selected.

[0156] In some embodiments, ring Z is [ka] is.

[0157] In some embodiments, ring Z is [ka] is.

[0158] In some embodiments, ring Z is [ka] is.

[0159] In some embodiments, ring Z is [ka] is selected from.

[0160] In some embodiments, ring Z is [ka] is.

[0161] In some embodiments, ring Z is [ka] is.

[0162] In some embodiments, ring Z is [ka] is.

[0163] In some embodiments, ring Z is [ka] is.

[0164] In some embodiments, ring Z is [ka] is.

[0165] In some embodiments, ring Z is [ka] is selected from.

[0166] In some embodiments, ring Z is [ka] is.

[0167] In some embodiments, ring Z is [ka] is.

[0168] In some embodiments, ring Z is [ka] is.

[0169] In some embodiments, ring Z is [ka] is.

[0170] In some embodiments, ring Z is [ka] is.

[0171] In some embodiments, ring Z is [ka] is.

[0172] In some embodiments, ring Z is a 6-membered monocyclic heteroaryl containing two heteroatoms selected from N, O, and S.

[0173] In some embodiments, ring Z is a 6-membered monocyclic heteroaryl containing two nitrogen atoms as heteroatoms.

[0174] In some embodiments, ring Z is [ka] be.

[0175] In some embodiments, ring Z is [ka] is.

[0176] In some embodiments, ring Z is [ka] is.

[0177] In some embodiments, ring Z is [ka] is.

[0178] In some embodiments, ring Z is [ka] is.

[0179] In some embodiments, ring Z is a 9-membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0180] In some embodiments, ring Z is a 9-membered bicyclic heteroaryl containing 4 heteroatoms independently selected from N, O, and S.

[0181] In some embodiments, ring Z is a 9-membered bicyclic heteroaryl containing 4 nitrogen atoms as heteroatoms.

[0182] In some embodiments, ring Z is [ka] is selected from.

[0183] In some embodiments, ring Z is [ka] is.

[0184] In some embodiments, ring Z is [ka] is.

[0185] In some embodiments, ring Z is [ka] is.

[0186] In some embodiments, ring Z is [ka] is.

[0187] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0188] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 1 heteroatom independently selected from N, O, and S.

[0189] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing one nitrogen atom as the heteroatom.

[0190] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0191] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing two nitrogen atoms as heteroatoms.

[0192] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0193] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 3 nitrogen atoms as heteroatoms.

[0194] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 4 heteroatoms independently selected from N, O, and S.

[0195] In some embodiments, ring Z is a 10-membered bicyclic heteroaryl containing 4 nitrogen atoms as heteroatoms.

[0196] In some embodiments, [ka] is selected from Table 1.

[0197] JPEG2025539787000090.jpg229170JPEG2025539787000091.jpg58170

[0198] In some embodiments, ring G is selected from aryl, a 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0199] In some embodiments, ring G is aryl.

[0200] In some embodiments, ring G is a 6-membered monocyclic aryl.

[0201] In some embodiments, ring G is phenyl.

[0202] In some embodiments, ring G is [ka] is.

[0203] In some embodiments, ring G is [ka] is.

[0204] In some embodiments, ring G is [ka] and R 7 is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0205] In some embodiments, ring G is [ka] is selected from.

[0206] In some embodiments, ring G is [ka] is.

[0207] In some embodiments, ring G is [ka] is.

[0208] In some embodiments, ring G is a 10-membered bicyclic aryl.

[0209] In some embodiments, ring G is a 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S.

[0210] In some embodiments, ring G is a 5-membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, O, and S.

[0211] In some embodiments, ring G is a 6-membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, O, and S.

[0212] In some embodiments, ring G is a 6-membered monocyclic heterocyclyl containing one heteroatom selected from N, O, and S.

[0213] In some embodiments, ring G is a 6-membered monocyclic heterocyclyl containing a nitrogen atom as the heteroatom.

[0214] In some embodiments, ring G is [ka] is.

[0215] In some embodiments, ring G is [ka] is.

[0216] In some embodiments, ring G is a 7-membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S.

[0217] In some embodiments, ring G is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0218] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0219] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0220] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing two nitrogen atoms as heteroatoms.

[0221] In some embodiments, ring G is [ka] is selected from.

[0222] In some embodiments, ring G is [ka] is.

[0223] In some embodiments, ring G is [ka] is.

[0224] In some embodiments, ring G is [ka] is.

[0225] In some embodiments, ring G is [ka] is selected from.

[0226] In some embodiments, ring G is [ka] is.

[0227] In some embodiments, ring G is [ka] is.

[0228] In some embodiments, ring G is [ka] is.

[0229] In some embodiments, ring G is [ka] is selected from.

[0230] In some embodiments, ring G is [ka] is.

[0231] In some embodiments, ring G is [ka] is.

[0232] In some embodiments, ring G is [ka] is.

[0233] In some embodiments, ring G is [ka] is selected from.

[0234] In some embodiments, ring G is [ka] is.

[0235] In some embodiments, ring G is [ka] is.

[0236] In some embodiments, ring G is [ka] is.

[0237] In some embodiments, ring G is [ka] is.

[0238] In some embodiments, ring G is [ka] is.

[0239] In some embodiments, ring G is [ka] is selected from.

[0240] In some embodiments, ring G is [ka] is.

[0241] In some embodiments, ring G is [ka] is.

[0242] In some embodiments, ring G is [ka] is.

[0243] In some embodiments, ring G is [ka] is.

[0244] In some embodiments, ring G is [ka] is.

[0245] In some embodiments, ring G is [ka] is selected from.

[0246] In some embodiments, ring G is [ka] is.

[0247] In some embodiments, ring G is [ka] is.

[0248] In some embodiments, ring G is [ka] is.

[0249] In some embodiments, ring G is [ka] is.

[0250] In some embodiments, ring G is [ka] is.

[0251] In some embodiments, ring G is [ka] is.

[0252] In some embodiments, ring G is [ka] is.

[0253] In some embodiments, ring G is [ka] are selected.

[0254] In some embodiments, ring G is [ka] is.

[0255] In some embodiments, ring G is [ka] is.

[0256] In some embodiments, ring G is [ka] is.

[0257] In some embodiments, ring G is [ka] is.

[0258] In some embodiments, ring G is [ka] is.

[0259] In some embodiments, ring G is [ka] is.

[0260] In some embodiments, ring G is [ka] is.

[0261] In some embodiments, ring G is [ka] is selected from.

[0262] In some embodiments, ring G is [ka] is.

[0263] In some embodiments, ring G is [ka] is.

[0264] In some embodiments, ring G is [ka] is.

[0265] In some embodiments, ring G is [ka] is.

[0266] In some embodiments, ring G is [ka] is.

[0267] In some embodiments, ring G is [ka] is selected from.

[0268] In some embodiments, ring G is [ka] is.

[0269] In some embodiments, ring G is [ka] is.

[0270] In some embodiments, ring G is [ka] is.

[0271] In some embodiments, ring G is [ka] is.

[0272] In some embodiments, ring G is [ka] is.

[0273] In some embodiments, ring G is [ka] is selected from.

[0274] In some embodiments, ring G is [ka] is.

[0275] In some embodiments, ring G is [ka] is.

[0276] In some embodiments, ring G is [ka] is.

[0277] In some embodiments, ring G is [ka] is.

[0278] In some embodiments, ring G is [ka] is.

[0279] In some embodiments, ring G is [ka] is selected from.

[0280] In some embodiments, ring G is [ka] is.

[0281] In some embodiments, ring G is [ka] is.

[0282] In some embodiments, ring G is [ka] is.

[0283] In some embodiments, ring G is [ka] is.

[0284] In some embodiments, ring G is [ka] is.

[0285] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing one nitrogen atom and one oxygen atom as heteroatoms.

[0286] In some embodiments, ring G is [ka] is.

[0287] In some embodiments, ring G is [ka] is selected from.

[0288] In some embodiments, ring G is [ka] is selected from.

[0289] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0290] In some embodiments, ring G is [ka] and X 1 are independently selected from CH and N; 2 JPEG2025539787000168.jpg412X 3 is selected from a single bond and a double bond, while the bond X 2 JPEG2025539787000169.jpg412X 3 is a single bond (X 2 -X 3 ), then bond X 3 JPEG2025539787000170.jpg412X 4 is a double bond (X 3 =X 4 ) and X 2 is selected from O, S, and NH, and X 3 is selected from N and CH, and X 4 is selected from N and CH; 2 JPEG2025539787000171.jpg412X 3 is a double bond (X 2 =X 3 ), then bond X 3 JPEG2025539787000172.jpg412X 4 is a single bond (X 3 -X 4 ) and X 2 is selected from CH and N, and X 3 is selected from N and CH, and X 4 is selected from O, S, and NH.

[0291] In some embodiments, ring G is [ka] and X 1 are independently selected from CH and N; X 2 is selected from O, S and NH, and X 3 is selected from N and CH, and X 4 is selected from N and CH.

[0292] In some embodiments, ring G is [ka] and X 1 is independently selected from CH and N, and X 2 is selected from CH and N, and X 3 is selected from N and CH, and X 4 is selected from O, S, and NH.

[0293] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing 3 nitrogen atoms as heteroatoms.

[0294] In some embodiments, ring G is [ka] and X1 are independently selected from CH and N; 2 JPEG2025539787000176.jpg412X 3 is selected from a single bond and a double bond, while the bond X 2 JPEG2025539787000177.jpg412X 3 is a single bond (X 2 -X 3 ), then bond X 3 JPEG2025539787000178.jpg412X 4 is a double bond (X 3 =X 4 ) and X 2 is NH and X 3 is selected from N and CH, and X 4 is selected from N and CH; 2 JPEG2025539787000179.jpg412X 3 is a double bond (X 2 =X 3 ), then bond X 3 JPEG2025539787000180.jpg412X 4 is a single bond (X 3 -X 4 ) and X 2 is selected from CH and N, and X 3 is selected from N and CH, and X 4 is NH.

[0295] In some embodiments, ring G is [ka] and X 1 are independently selected from CH and N; X 3 is selected from N and CH, and X 4 is selected from N and CH.

[0296] In some embodiments, ring G is [ka] and X 1 are independently selected from CH and N; X 2 is selected from CH and N, and X 3 is selected from N and CH.

[0297] In some embodiments, ring G is [ka] are selected.

[0298] In some embodiments, ring G is [ka] is.

[0299] In some embodiments, ring G is [ka] is.

[0300] In some embodiments, ring G is [ka] is.

[0301] In some embodiments, ring G is [ka] is.

[0302] In some embodiments, ring G is [ka] is selected from.

[0303] In some embodiments, ring G is [ka] is selected from.

[0304] In some embodiments, ring G is [ka] is selected from.

[0305] In some embodiments, ring G is [ka] is selected from.

[0306] In some embodiments, ring G is [ka] is selected from.

[0307] In some embodiments, ring G is [ka] is selected from.

[0308] In some embodiments, ring G is [ka] is selected from.

[0309] In some embodiments, ring G is [ka] is selected from.

[0310] In some embodiments, ring G is [ka] is selected from.

[0311] In some embodiments, ring G is [ka] is selected from.

[0312] In some embodiments, ring G is a 5-membered monocyclic heteroaryl containing two nitrogen atoms and one oxygen atom as heteroatoms.

[0313] In some embodiments, ring G is [ka] is selected from.

[0314] In some embodiments, ring G is [ka] is.

[0315] In some embodiments, ring G is [ka] is.

[0316] In some embodiments, ring G is [ka] is.

[0317] In some embodiments, ring G is [ka] is selected from.

[0318] In some embodiments, ring G is [ka] is selected from.

[0319] In some embodiments, ring G is [ka] is selected from.

[0320] In some embodiments, ring G is [ka] is selected from.

[0321] In some embodiments, ring G is [ka] is.

[0322] In some embodiments, ring G is [ka] is.

[0323] In some embodiments, ring G is [ka] is.

[0324] In some embodiments, ring G is [ka] is.

[0325] In some embodiments, ring G is [ka] is.

[0326] In some embodiments, ring G is [ka] is.

[0327] In some embodiments, ring G is [ka] is.

[0328] In some embodiments, ring G is [ka] is.

[0329] In some embodiments, ring G is [ka] is.

[0330] In some embodiments, ring G is [ka] is.

[0331] In some embodiments, ring G is [ka] is.

[0332] In some embodiments, ring G is [ka] is.

[0333] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0334] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing one nitrogen atom as the heteroatom.

[0335] In some embodiments, ring G is [ka] is selected from.

[0336] In some embodiments, ring G is [ka] is selected from.

[0337] In some embodiments, ring G is [ka] is selected from.

[0338] In some embodiments, ring G is [ka] is.

[0339] In some embodiments, ring G is [ka] is.

[0340] In some embodiments, ring G is a 6-membered monocyclic heteroaryl containing two nitrogen atoms as heteroatoms.

[0341] In some embodiments, ring G is [ka] is selected from.

[0342] In some embodiments, ring G is [ka] is selected from.

[0343] In some embodiments, ring G is [ka] is selected from.

[0344] In some embodiments, ring G is [ka] is selected from.

[0345] In some embodiments, ring G is [ka] is.

[0346] In some embodiments, ring G is [ka] is.

[0347] In some embodiments, ring G is an 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0348] In some embodiments, ring G is an 8-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0349] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0350] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 1 heteroatom selected from N, O, and S.

[0351] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing two heteroatoms independently selected from N, O, and S.

[0352] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing one oxygen atom and one nitrogen atom as heteroatoms.

[0353] In some embodiments, ring G is [ka] is.

[0354] In some embodiments, ring G is [ka] is.

[0355] In some embodiments, ring G is [ka] is.

[0356] In some embodiments, ring G is [ka] is.

[0357] In some embodiments, ring G is [ka] is.

[0358] In some embodiments, ring G is [ka] is.

[0359] In some embodiments, ring G is a 9-membered bicyclic heteroaryl containing 3 heteroatoms independently selected from N, O, and S.

[0360] In some embodiments, ring G is a 10-membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S.

[0361] In some embodiments, [ka] is selected from Table 2.

[0362] JPEG2025539787000236.jpg182170

[0363] In some embodiments, each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R 8 )2, wherein alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0364] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and C1-C6 alkyl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0365] In some embodiments, R 1 is C1-C6 alkyl.

[0366] In some embodiments, each R 1 are independently selected from methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, sec-butyl, and tert-butyl.

[0367] In some embodiments, R 1 is methyl.

[0368] In some embodiments, R 1 is ethyl.

[0369] In some embodiments, R 1 is propyl.

[0370] In some embodiments, R 1 is n-propyl.

[0371] In some embodiments, R 1 is i-propyl.

[0372] In some embodiments, R 1 is butyl.

[0373] In some embodiments, R 1 is n-butyl.

[0374] In some embodiments, R 1 is i-butyl.

[0375] In some embodiments, R 1 is sec-butyl.

[0376] In some embodiments, R 1 is tert-butyl.

[0377] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10and C1-C6 alkoxy optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0378] In some embodiments, R 1 is C1-C6 alkoxy.

[0379] In some embodiments, R 1 is -OCH3.

[0380] In some embodiments, R 1 is halogen, OH, N(R 8 )2, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Aryl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0381] In some embodiments, R 1 teeth, [ka] is.

[0382] In some embodiments, each R 2 are independently selected from hydrogen, C1-C6 alkyl.

[0383] In some embodiments, R 2 is hydrogen.

[0384] In some embodiments, R 2 is C1-C6 alkyl.

[0385] In some embodiments, R 2 is methyl.

[0386] In some embodiments, m is an integer selected from 0, 1, 2, and 3.

[0387] In some embodiments, m is an integer selected from 1, 2, and 3.

[0388] In some embodiments, m is 0.

[0389] In some embodiments, m is 1.

[0390] In some embodiments, m is 2.

[0391] In some embodiments, m is 3.

[0392] In some embodiments, R 3 is hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl.

[0393] In some embodiments, R 3 is H.

[0394] In some embodiments, R 3 is C1-C6 alkyl.

[0395] In some embodiments, R 3 is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0396] In some embodiments, R 3 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0397] In some embodiments, R 3 is methyl.

[0398] In some embodiments, R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 Cycloalkyl, C1-C6 alkyl-N(R 8 )2, C1-C6 alkyl-OR 8 , heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, —N(R 8 )2, -OR 8 and optionally substituted with one or more substituents independently selected from:

[0399] In some embodiments, R 4 is hydrogen.

[0400] In some embodiments, R 4 is a halogen, -N(R 8 )2, -OR 8 and C1-C6 alkyl optionally substituted with one or more substituents independently selected from:

[0401] In some embodiments, R 4 is C1-C6 alkyl.

[0402] In some embodiments, R 4 is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0403] In some embodiments, R 4 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0404] In some embodiments, R 4 is methyl.

[0405] In some embodiments, R 4 is C1-C6 alkyl-N(R 8 )2.

[0406] In some embodiments, R4 is -CH2N(R8)2.

[0407] In some embodiments, R 4 is -CH2CH2N(R8)2.

[0408] In some embodiments, R 4 is -CH2CH2CH2N(R8)2.

[0409] In some embodiments, R 4 is -CH2CH2CH2CH2N(R8)2.

[0410] In some embodiments, R 4 is -CH2CH2CH2CH2CH2N(R8)2.

[0411] In some embodiments, R 4 is -CH2CH2CH2CH2CH2CH2N(R8)2.

[0412] In some embodiments, R 4 is selected from —C1-C6 alkyl-NH2, —C1-C6 alkyl-N(H)CH3, —C1-C6 alkyl-N(CH3)2.

[0413] In some embodiments, R 4 is C1-C6 alkyl-NH2.

[0414] In some embodiments, R 4 is -CH2NH2.

[0415] In some embodiments, R 4 is -CH2CH2NH2.

[0416] In some embodiments, R 4 is -CH2CH2CH2NH2.

[0417] In some embodiments, R 4is -CH2CH2CH2CH2NH2.

[0418] In some embodiments, R 4 is -CH2CH2CH2CH2CH2NH2.

[0419] In some embodiments, R 4 is -CH2CH2CH2CH2CH2CH2NH2.

[0420] In some embodiments, R 4 is -C1-C6 alkyl-N(H)CH3.

[0421] In some embodiments, R 4 is -CH2N(H)CH3.

[0422] In some embodiments, R 4 is -CH2CH2N(H)CH3.

[0423] In some embodiments, R 4 is -CH2CH2CH2N(H)CH3.

[0424] In some embodiments, R 4 is -CH2CH2CH2CH2N(H)CH3.

[0425] In some embodiments, R 4 is -CH2CH2CH2CH2CH2N(H)CH3.

[0426] In some embodiments, R 4 is -CH2CH2CH2CH2CH2CH2N(H)CH3.

[0427] In some embodiments, R 4 is -C1-C6 alkyl-N(CH3)2.

[0428] In some embodiments, R 4is -CH2N(CH3)2.

[0429] In some embodiments, R 4 is -CH2CH2N(CH3)2.

[0430] In some embodiments, R 4 is -CH2CH2CH2N(CH3)2.

[0431] In some embodiments, R 4 is -CH2CH2CH2CH2N(CH3)2.

[0432] In some embodiments, R 4 is -CH2CH2CH2CH2CH2N(CH3)2.

[0433] In some embodiments, R 4 is -CH2CH2CH2CH2CH2CH2N(CH3)2.

[0434] In some embodiments, R 4 is C1-C6 alkyl-OR 8 is.

[0435] In some embodiments, R 4 is -CH2-OR 8 is.

[0436] In some embodiments, R 4 is -CH2-CH2-OR 8 is.

[0437] In some embodiments, R 4 is -CH2-CH2-CH2-OR 8 is.

[0438] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-OR 8 is.

[0439] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-CH2-OR 8 is.

[0440] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-CH2-CH2-OR 8 is.

[0441] In some embodiments, R 4 is C1-C6 alkyl-OH.

[0442] In some embodiments, R 4 is -CH2-OH.

[0443] In some embodiments, R 4 is -CH2-CH2-OH.

[0444] In some embodiments, R 4 is -CH2-CH2-CH2-OH.

[0445] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-OH.

[0446] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-OH.

[0447] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-CH2-OH.

[0448] In some embodiments, R 4 is C1-C6 alkyl-OCH3.

[0449] In some embodiments, R 4 is -CH2-OCH3.

[0450] In some embodiments, R 4 is -CH2-CH2-OCH3.

[0451] In some embodiments, R 4 is -CH2-CH2-CH2-OCH3.

[0452] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-OCH3.

[0453] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-OCH3.

[0454] In some embodiments, R 4 is -CH2-CH2-CH2-CH2-CH2-CH2-OCH3.

[0455] In some embodiments, R 4 is halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 C3-C optionally substituted with one or more substituents independently selected from 10 It is cycloalkyl.

[0456] In some embodiments, R 4 is C3-C 10 It is cycloalkyl.

[0457] In some embodiments, R 4 is cyclopropyl.

[0458] In some embodiments, R 5 is selected from H, C1-C6 alkyl.

[0459] In some embodiments, R 5 is hydrogen.

[0460] In some embodiments, R 5 is halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 and C1-C6 alkyl optionally substituted with one or more substituents independently selected from:

[0461] In some embodiments, R 5 is C1-C6 alkyl.

[0462] In some embodiments, R 5 is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0463] In some embodiments, R 5 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0464] In some embodiments, R 5 is methyl.

[0465] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 Forms a 3- to 14-membered heterocyclic ring optionally substituted with one or more substituents independently selected from:

[0466] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8Forms a 3-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0467] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 Forms a 4-membered heterocyclic ring optionally substituted with one or more substituents independently selected from:

[0468] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 Forms a 5-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0469] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 and R 1 and R 2 form a 6-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0470] In some embodiments, R 4 and R 5 together with the atom to which they are attached and any intervening atoms, represent halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, -N(R 8 )2, -OR 8 and R 1 and R 2 form a 7-membered heterocycle optionally substituted with one or more substituents independently selected from:

[0471] In some embodiments, R 6 -OR 8 and C1-C6 halogen alkyl.

[0472] In some embodiments, R 6 -OR 8 is.

[0473] In some embodiments, R 6 is -OH.

[0474] In some embodiments, R 6 is —OC1-C6 alkyl.

[0475] In some embodiments, R 6 is selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.

[0476] In some embodiments, R 6 is -OCH3.

[0477] In some embodiments, R 6 is C1-C6 halogen alkyl.

[0478] In some embodiments, R 6 is monofluoro-C1-C6 alkyl.

[0479] In some embodiments, R 6 is difluoro-C1-C6 alkyl.

[0480] In some embodiments, R 6 is trifluoro-C1-C6 alkyl.

[0481] In some embodiments, R 6 is -CH2F.

[0482] In some embodiments, R 6is -CHF2.

[0483] In some embodiments, R 6 is -CF3.

[0484] In some embodiments, n is an integer selected from 0, 1, 2, and 3.

[0485] In some embodiments, n is 0.

[0486] In some embodiments, n is 1.

[0487] In some embodiments, n is 2.

[0488] In some embodiments, n is 3.

[0489] In some embodiments, R 7 is C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C 10 and selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0490] In some embodiments, R 7 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0491] In some embodiments, R 7 is C1-C6 alkyl.

[0492] In some embodiments, R 7 is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0493] In some embodiments, R 7 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

[0494] In some embodiments, R 7 is methyl.

[0495] In some embodiments, R 7 is i-propyl.

[0496] In some embodiments, R 7 is i-butyl.

[0497] In some embodiments, R 7 is oxo.

[0498] In some embodiments, R 7 is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0499] In some embodiments, R 7 is C1-C6 alkoxy.

[0500] In some embodiments, R 7 is methoxy.

[0501] In some embodiments, R 7 is -OCH2CH3.

[0502] In some embodiments, R 7 is -O(CH2)2CH3.

[0503] In some embodiments, R 7 is -O(CH2)3CH3.

[0504] In some embodiments, R 7 is -O(CH2)4CH3.

[0505] In some embodiments, R 7 is -O(CH2)5CH3.

[0506] In some embodiments, R 7 is -O(CH2)6CH3.

[0507] In some embodiments, R 7 is -O(CH2)7CH3.

[0508] In some embodiments, R 7 teeth, [ka] is.

[0509] In some embodiments, R 7 is a C3-C alkyl optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and cycloalkyl; 10 There is a cycloalkyl.

[0510] In some embodiments, R 7 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0511] In some embodiments, R 7 is cyclohexyl.

[0512] In some embodiments, R 7 is methyl, i-propyl, i-butyl, oxo, methoxy, -O(CH2)7CH3, [ka] cyclohexyl.

[0513] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocyclic ring.

[0514] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms, form a 5-membered heterocyclic ring.

[0515] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms, form a 6-membered heterocyclic ring.

[0516] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms, form a 7-membered heterocyclic ring.

[0517] In some embodiments, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms, form an 8-membered heterocyclic ring.

[0518] In some embodiments, each R 8 are independently H, C1-C6 alkyl, C3-C 10 cycloalkyl.

[0519] In some embodiments, R 8 is H.

[0520] In some embodiments, each R 8 is H.

[0521] In some embodiments, R 8 is C1-C6 alkyl.

[0522] In some embodiments, each R 8 is C1-C6 alkyl.

[0523] In some embodiments, each R 8 are independently selected from H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0524] In some embodiments, R 8 is methyl.

[0525] In some embodiments, R 8 is ethyl.

[0526] In some embodiments, R 8 is propyl.

[0527] In some embodiments, R 8 is butyl.

[0528] In some embodiments, R 8 is pentyl.

[0529] In some embodiments, R 8 is hexyl.

[0530] In some embodiments, each R 8 are independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl.

[0531] In some embodiments, R 8 is n-propyl.

[0532] In some embodiments, R 8 is -propyl.

[0533] In some embodiments, R 8 is n-butyl.

[0534] In some embodiments, R 8 is sec-butyl.

[0535] In some embodiments, R 8 is i-butyl.

[0536] In some embodiments, R 8 is tert-butyl.

[0537] In some embodiments, R 8 is n-pentyl.

[0538] In some embodiments, R 8 is n-hexyl.

[0539] In some embodiments, R 8 is C3-C 10 It is cycloalkyl.

[0540] In some embodiments, R 8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0541] In some embodiments, R 8 is cyclopropyl.

[0542] In some embodiments, R 8 is cyclobutyl.

[0543] In some embodiments, R 8 is cyclopentyl.

[0544] In some embodiments, R 8 is cyclohexyl.

[0545] In some embodiments, R 8 is cycloheptyl.

[0546] In some embodiments, the compound is of formula (C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0547] In some embodiments, the compound is of formula (C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0548] In some embodiments, the compound is of formula (C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0549] In some embodiments, the compound is of formula (C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0550] In some embodiments, the compound is of formula (I-AE): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N, and one to three X are N, and all other variables are as defined herein.

[0551] In some embodiments, the compound is of formula (I-AE-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N, and one to three X are N, and all other variables are as defined herein.

[0552] In some embodiments, the compound is of formula (I-AE-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N, and one to three X are N, and all other variables are as defined herein.

[0553] In some embodiments, the compound is of formula (IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0554] In some embodiments, the compound is of formula (IA-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0555] In some embodiments, the compound is of formula (IA-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0556] In some embodiments, the compound is of formula (IA-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0557] In some embodiments, the compound is of formula (IA-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0558] In some embodiments, the compound is of formula (IA-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0559] In some embodiments, the compound is of formula (IA-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0560] In some embodiments, the compound is of formula (IA-0-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0561] In some embodiments, the compound is of formula (IA-0-H-C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0562] In some embodiments, the compound is of formula (IA-0-H-C1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0563] In some embodiments, the compound is of formula (IA-0-H-C1-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0564] In some embodiments, the compound is of formula (IA-0-H-C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0565] In some embodiments, the compound is of formula (IA-0-H-C2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0566] In some embodiments, the compound is of formula (IA-0-H-C2-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0567] In some embodiments, the compound is of the formula (IA-0-H-C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0568] In some embodiments, the compound is of formula (IA-0-H-C3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0569] In some embodiments, the compound is of formula (IA-0-H-C3-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0570] In some embodiments, the compound is of formula (IA-0-HM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0571] In some embodiments, the compound is of formula (IA-0-HM-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0572] In some embodiments, the compound is of formula (IA-0-HM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0573] In some embodiments, the compound is of formula (IA-0-HM-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0574] In some embodiments, the compound is of formula (IA-0-HM-4-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0575] In some embodiments, the compound is of formula (IA-0-HM-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0576] In some embodiments, the compound is of formula (IA-0-HM-5-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0577] In some embodiments, the compound is of formula (IA-0-HM-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0578] In some embodiments, the compound is of formula (IA-0-HM-6-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0579] In some embodiments, the compound is of formula (IA-0-HM-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0580] In some embodiments, the compound is of formula (IA-0-HM-7-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0581] In some embodiments, the compound is of formula (IA-0-HM-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0582] In some embodiments, the compound is of formula (IA-0-HM-8-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0583] In some embodiments, the compound is of formula (IA-0-HM-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0584] In some embodiments, the compound is of formula (IA-0-HM-9-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0585] In some embodiments, the compound is of the formula (IA-0-HH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0586] In some embodiments, the compound is of formula (IA-0-HH-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0587] In some embodiments, the compound is of formula (IA-0-HH-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0588] In some embodiments, the compound is of formula (IA-0-HH-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0589] In some embodiments, the compound is of formula (IA-0-HH-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0590] In some embodiments, the compound is of formula (IA-0-HH-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0591] In some embodiments, the compound is of formula (IA-0-HH-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0592] In some embodiments, the compound is of formula (IA-0-HH-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0593] In some embodiments, the compound is of formula (IA-0-HH-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0594] In some embodiments, the compound is of formula (IA-0-HH-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0595] In some embodiments, the compound is of formula (IA-0-HH-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0596] In some embodiments, the compound is of the formula (IA-0-HF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0597] In some embodiments, the compound is of formula (IA-0-HF-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0598] In some embodiments, the compound is of formula (IA-0-HF-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0599] In some embodiments, the compound is of formula (IA-0-HF-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0600] In some embodiments, the compound is of formula (IA-0-HH-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0601] In some embodiments, the compound is of formula (IA-0-HH-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0602] In some embodiments, the compound is of formula (IA-0-HH-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0603] In some embodiments, the compound is of formula (IA-0-HH-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0604] In some embodiments, the compound is of formula (IA-0-HH-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0605] In some embodiments, the compound is of formula (IA-0-HH-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0606] In some embodiments, the compound is of formula (IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0607] In some embodiments, the compound is of formula (IB-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0608] In some embodiments, the compound is of formula (IB-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0609] In some embodiments, the compound is of the formula (IB-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0610] In some embodiments, the compound is of formula (IB-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0611] In some embodiments, the compound is of formula (IB-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0612] In some embodiments, the compound is of formula (IB-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0613] In some embodiments, the compound is of formula (IB-0-HM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0614] In some embodiments, the compound is of formula (IB-0-HM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0615] In some embodiments, the compound is of formula (IB-0-HM-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0616] In some embodiments, the compound is of formula (IB-0-HM-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0617] In some embodiments, the compound is of formula (IB-0-HM-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0618] In some embodiments, the compound is of formula (IB-0-HM-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0619] In some embodiments, the compound is of formula (IB-0-HM-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0620] In some embodiments, the compound is of formula (IB-0-HM-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0621] In some embodiments, the compound is of the formula (IB-0-HH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0622] In some embodiments, the compound is of formula (IB-0-HH-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0623] In some embodiments, the compound is of formula (IB-0-HH-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0624] In some embodiments, the compound is of formula (IB-0-HH-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0625] In some embodiments, the compound is of formula (IB-0-HH-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0626] In some embodiments, the compound is of formula (IB-0-HH-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0627] In some embodiments, the compound is of formula (IB-0-HH-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0628] In some embodiments, the compound is of formula (IB-0-HH-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0629] In some embodiments, the compound is of formula (IB-0-HH-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0630] In some embodiments, the compound is of formula (IB-0-HH-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0631] In some embodiments, the compound is of the formula (IB-0-HF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0632] In some embodiments, the compound is of formula (IB-0-HF-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0633] In some embodiments, the compound is of formula (IB-0-HF-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0634] In some embodiments, the compound is of the formula (IB-0-HF-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0635] In some embodiments, the compound is of formula (IB-0-HF-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0636] In some embodiments, the compound is of formula (IB-0-HF-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0637] In some embodiments, the compound is of formula (IB-0-HF-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0638] In some embodiments, the compound is of formula (IB-0-HF-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0639] In some embodiments, the compound is of formula (IB-0-HF-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0640] In some embodiments, the compound is of formula (IB-0-HF-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0641] In some embodiments, the compound is of formula (IC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0642] In some embodiments, the compound is of formula (IC-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0643] In some embodiments, the compound is of formula (IC-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0644] In some embodiments, the compound is of the formula (IC-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0645] In some embodiments, the compound is of formula (IC-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0646] In some embodiments, the compound is of formula (IC-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0647] In some embodiments, the compound is of formula (IC-0-HM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0648] In some embodiments, the compound is of formula (IC-0-HM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0649] In some embodiments, the compound is of formula (IC-0-HM-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0650] In some embodiments, the compound is of formula (IC-0-HM-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0651] In some embodiments, the compound is of formula (IC-0-HM-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0652] In some embodiments, the compound is of formula (IC-0-HM-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0653] In some embodiments, the compound is of formula (IC-0-HM-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0654] In some embodiments, the compound is of formula (IC-0-HM-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0655] In some embodiments, the compound is of the formula (IC-0-HH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0656] In some embodiments, the compound is of formula (IC-0-HH-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0657] In some embodiments, the compound is of formula (IC-0-HH-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0658] In some embodiments, the compound is of formula (IC-0-HH-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0659] In some embodiments, the compound is of formula (IC-0-HH-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0660] In some embodiments, the compound is of formula (IC-0-HH-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0661] In some embodiments, the compound is of formula (IC-0-HH-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0662] In some embodiments, the compound is of formula (IC-0-HH-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0663] In some embodiments, the compound is of formula (IC-0-HH-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0664] In some embodiments, the compound is of formula (IC-0-HH-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0665] In some embodiments, the compound is of the formula (IC-0-HF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0666] In some embodiments, the compound is of formula (IC-0-HF-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0667] In some embodiments, the compound is of formula (IC-0-HF-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0668] In some embodiments, the compound is of formula (IC-0-HF-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0669] In some embodiments, the compound is of formula (IC-0-HF-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0670] In some embodiments, the compound is of formula (IC-0-HF-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0671] In some embodiments, the compound is of formula (IC-0-HF-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0672] In some embodiments, the compound is of formula (IC-0-HF-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0673] In some embodiments, the compound is of formula (IC-0-HF-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0674] In some embodiments, the compound is of formula (IC-0-HF-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0675] In some embodiments, the compound is of formula (ID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0676] In some embodiments, the compound is of formula (ID-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0677] In some embodiments, the compound is of formula (ID-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0678] In some embodiments, the compound is of the formula (ID-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0679] In some embodiments, the compound is of formula (ID-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0680] In some embodiments, the compound is of formula (ID-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0681] In some embodiments, the compound is of formula (IE): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0682] In some embodiments, the compound is of formula (IE-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0683] In some embodiments, the compound is of formula (IE-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0684] In some embodiments, the compound is of the formula (IE-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0685] In some embodiments, the compound is of formula (IE-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0686] In some embodiments, the compound is of formula (IE-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0687] In some embodiments, the compound is of formula (IE-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0688] In some embodiments, the compound is of formula (IE-0-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0689] In some embodiments, the compound is of formula (I-FH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0690] In some embodiments, the compound is of formula (I-FH-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0691] In some embodiments, the compound is of formula (I-FH-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0692] In some embodiments, the compound is of the formula (I-FH-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0693] In some embodiments, the compound is of formula (I-FH-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0694] In some embodiments, the compound is of formula (I-FH-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH, and all other variables are as defined herein.

[0695] In some embodiments, the compound is of formula (IF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0696] In some embodiments, the compound is of formula (IF-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0697] In some embodiments, the compound is of formula (IF-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0698] In some embodiments, the compound is of the formula (IF-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0699] In some embodiments, the compound is of formula (IF-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0700] In some embodiments, the compound is of formula (IF-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0701] In some embodiments, the compound is of formula (IF-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0702] In some embodiments, the compound is of formula (IG): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0703] In some embodiments, the compound is of formula (IG-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0704] In some embodiments, the compound is of formula (IG-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0705] In some embodiments, the compound is of the formula (IG-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0706] In some embodiments, the compound is of the formula (IG-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0707] In some embodiments, the compound is of formula (IG-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0708] In some embodiments, the compound is of formula (IG-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0709] In some embodiments, the compound is of formula (IG-0-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0710] In some embodiments, the compound is of formula (IH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0711] In some embodiments, the compound is of formula (IH-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0712] In some embodiments, the compound is of formula (IH-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0713] In some embodiments, the compound is of the formula (IH-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0714] In some embodiments, the compound is of formula (IH-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0715] In some embodiments, the compound is of formula (IH-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0716] In some embodiments, the compound is of formula (I-IK): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, and all other variables are as defined herein.

[0717] In some embodiments, the compound is of formula (I-IK-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, and all other variables are as defined herein.

[0718] In some embodiments, the compound is of formula (I-IK-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, and all other variables are as defined herein.

[0719] In some embodiments, the compound is of formula (I-IK-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, and all other variables are as defined herein.

[0720] In some embodiments, the compound is of formula (I-IK-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, and all other variables are as defined herein.

[0721] In some embodiments, the compound is of formula (I-IK-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, NCH3, and all other variables are as defined herein.

[0722] In some embodiments, the compound is of formula (I-IK-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, NCH3, and all other variables are as defined herein.

[0723] In some embodiments, the compound is of formula (I-IK-0-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, NCH3, and all other variables are as defined herein.

[0724] In some embodiments, the compound is of formula (I-IK-0-HM-1-d): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, NCH3, and all other variables are as defined herein.

[0725] In some embodiments, the compound is of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0726] In some embodiments, the compound is of formula (II-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0727] In some embodiments, the compound is of formula (II-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0728] In some embodiments, the compound is of formula (II-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0729] In some embodiments, the compound is of formula (II-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0730] In some embodiments, the compound is of formula (II-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0731] In some embodiments, the compound is of formula (II-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0732] In some embodiments, the compound is of formula (IJ): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0733] In some embodiments, the compound is of formula (IJ-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0734] In some embodiments, the compound is of formula (IJ-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0735] In some embodiments, the compound is of formula (IJ-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0736] In some embodiments, the compound is of formula (IJ-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0737] In some embodiments, the compound is of formula (IJ-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0738] In some embodiments, the compound is of formula (IJ-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0739] In some embodiments, the compound is of formula (IK): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0740] In some embodiments, the compound is of formula (IK-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0741] In some embodiments, the compound is of formula (IK-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0742] In some embodiments, the compound is of the formula (IK-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0743] In some embodiments, the compound is of formula (IK-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0744] In some embodiments, the compound is of formula (IK-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0745] In some embodiments, the compound is of formula (IK-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0746] In some embodiments, the compound is of formula (IK-0-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0747] In some embodiments, the compound is of formula (IL): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0748] In some embodiments, the compound is of the formula (IL-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0749] In some embodiments, the compound is of the formula (IL-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0750] In some embodiments, the compound is of the formula (IL-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0751] In some embodiments, the compound is of the formula (IL-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0752] In some embodiments, the compound is of the formula (IL-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0753] In some embodiments, the compound is of the formula (IL-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0754] In some embodiments, the compound is of the formula (IL-1H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0755] In some embodiments, the compound is of the formula (IL-1H-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0756] In some embodiments, the compound is of the formula (IL-1H-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0757] In some embodiments, the compound is of the formula (IL-1-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0758] In some embodiments, the compound is of the formula (IL-1-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0759] In some embodiments, the compound is of the formula (IL-1H-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0760] In some embodiments, the compound is of the formula (IL-1H-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0761] In some embodiments, the compound is of the formula (IL-1H-HM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0762] In some embodiments, the compound is of the formula (IL-1H-HM-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0763] In some embodiments, the compound is of the formula (IL-1M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0764] In some embodiments, the compound is of the formula (IL-1M-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0765] In some embodiments, the compound is of the formula (IL-1M-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0766] In some embodiments, the compound is of the formula (IL-1M-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0767] In some embodiments, the compound is of the formula (IL-1M-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0768] In some embodiments, the compound is of the formula (IL-1M-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0769] In some embodiments, the compound is of the formula (IL-1M-HM-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0770] In some embodiments, the compound is of the formula (IL-1H-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0771] In some embodiments, the compound is of the formula (IL-1H-MM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0772] In some embodiments, the compound is of the formula (IL-1H-MM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0773] In some embodiments, the compound is of the formula (IL-1H-MM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0774] In some embodiments, the compound is of the formula (IL-1H-MM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0775] In some embodiments, the compound is of formula (IM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0776] In some embodiments, the compound is of formula (IM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0777] In some embodiments, the compound is of the formula (IM-2HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0778] In some embodiments, the compound is of the formula (IM-2HM-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0779] In some embodiments, the compound is of the formula (IM-2HM-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0780] In some embodiments, the compound is of formula (IM-2HM-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0781] In some embodiments, the compound is of formula (IM-2HM-HM-1-a) [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0782] In some embodiments, the compound is of formula (IM-2HM-HM-1-b) [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0783] In some embodiments, the compound is of formula (IM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0784] In some embodiments, the compound is of formula (IM-3H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0785] In some embodiments, the compound is of formula (IM-3H-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0786] In some embodiments, the compound is of the formula (IM-3H-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0787] In some embodiments, the compound is of formula (IM-3H-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0788] In some embodiments, the compound is of formula (IM-3H-HM-1-a) [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0789] In some embodiments, the compound is of formula (IK): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0790] In some embodiments, the compound is of formula (IN-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0791] In some embodiments, the compound is of the formula (IN-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0792] In some embodiments, the compound is of the formula (IN-0-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0793] In some embodiments, the compound is of the formula (IN-0-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0794] In some embodiments, the compound is of formula (IN-0-HM-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0795] In some embodiments, the compound is of formula (IN-0-HM-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0796] In some embodiments, the compound is of formula (II-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0797] In some embodiments, the compound is of formula (II-AM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0798] In some embodiments, the compound is of formula (II-AM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0799] In some embodiments, the compound is of formula (II-AM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0800] In some embodiments, the compound is of formula (II-AM-1-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0801] In some embodiments, the compound is of formula (II-AM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0802] In some embodiments, the compound is of formula (II-AM-1-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0803] In some embodiments, the compound is of formula (II-AM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0804] In some embodiments, the compound is of formula (II-AM-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0805] In some embodiments, the compound is of formula (II-AM-2-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0806] In some embodiments, the compound is of formula (II-AM-2-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0807] In some embodiments, the compound is of formula (II-AM-2-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0808] In some embodiments, the compound is of formula (II-AM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0809] In some embodiments, the compound is of formula (II-AM-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0810] In some embodiments, the compound is of formula (II-AM-3-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0811] In some embodiments, the compound is of formula (II-AM-3-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0812] In some embodiments, the compound is of formula (II-AM-3-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0813] In some embodiments, the compound is of formula (II-AM-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0814] In some embodiments, the compound is of formula (II-AM-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0815] In some embodiments, the compound is of formula (II-AM-4-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0816] In some embodiments, the compound is of formula (II-AM-4-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0817] In some embodiments, the compound is of formula (II-AM-4-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0818] In some embodiments, the compound is of formula (II-AM-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0819] In some embodiments, the compound is of formula (II-AM-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0820] In some embodiments, the compound is of formula (II-AM-5-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0821] In some embodiments, the compound is of formula (II-AM-5-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0822] In some embodiments, the compound is of formula (II-AM-5-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0823] In some embodiments, the compound is of formula (II-AM-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0824] In some embodiments, the compound is of formula (II-AM-6-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0825] In some embodiments, the compound is of formula (II-AM-6-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0826] In some embodiments, the compound is of formula (II-AM-6-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0827] In some embodiments, the compound is of formula (II-AM-6-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0828] In some embodiments, the compound is of formula (II-AM-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0829] In some embodiments, the compound is of formula (II-AM-7-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0830] In some embodiments, the compound is of formula (II-AM-7-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0831] In some embodiments, the compound is of formula (II-AM-7-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0832] In some embodiments, the compound is of formula (II-AM-7-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0833] In some embodiments, the compound is of formula (II-AM-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0834] In some embodiments, the compound is of formula (II-AM-8-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0835] In some embodiments, the compound is of formula (II-AM-8-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0836] In some embodiments, the compound is of formula (II-AM-8-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0837] In some embodiments, the compound is of formula (II-AM-8-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0838] In some embodiments, the compound is of formula (II-BK): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R 7 is selected from C1-C6 alkyl, or two R 7 together with the atom to which they are attached and any intervening atoms form a 6-membered aryl, a 5-8 membered heterocycle or a 5-8 membered heteroaryl.

[0839] In some embodiments, the compound is of formula (II-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0840] In some embodiments, the compound is of formula (II-BM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0841] In some embodiments, the compound is of formula (II-BM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0842] In some embodiments, the compound is of formula (II-BM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0843] In some embodiments, the compound is of formula (II-BM-1-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0844] In some embodiments, the compound is of formula (II-BM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0845] In some embodiments, the compound is of formula (II-BM-1-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0846] In some embodiments, the compound is of formula (II-BM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0847] In some embodiments, the compound is of formula (II-BM-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0848] In some embodiments, the compound is of formula (II-BM-2-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0849] In some embodiments, the compound is of formula (II-BM-2-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0850] In some embodiments, the compound is of formula (II-BM-2-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0851] In some embodiments, the compound is of formula (II-BM-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0852] In some embodiments, the compound is of formula (II-BM-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0853] In some embodiments, the compound is of formula (II-BM-3-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0854] In some embodiments, the compound is of formula (II-BM-3-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0855] In some embodiments, the compound is of formula (II-BM-3-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0856] In some embodiments, the compound is of formula (II-BM-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0857] In some embodiments, the compound is of formula (II-BM-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0858] In some embodiments, the compound is of formula (II-BM-4-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0859] In some embodiments, the compound is of formula (II-BM-4-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0860] In some embodiments, the compound is of formula (II-BM-4-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0861] In some embodiments, the compound is of formula (II-BM-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0862] In some embodiments, the compound is of formula (II-BM-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0863] In some embodiments, the compound is of formula (II-BM-5-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0864] In some embodiments, the compound is of formula (II-BM-5-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0865] In some embodiments, the compound is of formula (II-BM-5-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0866] In some embodiments, the compound is of formula (II-BH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0867] In some embodiments, the compound is of formula (II-BH-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0868] In some embodiments, the compound is of formula (II-BH-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0869] In some embodiments, the compound is of formula (II-BH-1-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0870] In some embodiments, the compound is of formula (II-BH-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0871] In some embodiments, the compound is of formula (II-BH-1-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0872] In some embodiments, the compound is of formula (II-BH-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0873] In some embodiments, the compound is of formula (II-BH-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0874] In some embodiments, the compound is of formula (II-BH-2-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0875] In some embodiments, the compound is of formula (II-BH-2-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0876] In some embodiments, the compound is of formula (II-BH-2-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0877] In some embodiments, the compound is of formula (II-BH-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0878] In some embodiments, the compound is of formula (II-BH-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0879] In some embodiments, the compound is of formula (II-BH-3-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0880] In some embodiments, the compound is of formula (II-BH-3-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0881] In some embodiments, the compound is of formula (II-BH-3-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0882] In some embodiments, the compound is of formula (II-BH-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0883] In some embodiments, the compound is of formula (II-BH-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0884] In some embodiments, the compound is of formula (II-BH-4-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0885] In some embodiments, the compound is of formula (II-BH-4-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0886] In some embodiments, the compound is of formula (II-BH-4-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0887] In some embodiments, the compound is of formula (II-BH-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0888] In some embodiments, the compound is of formula (II-BH-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0889] In some embodiments, the compound is of formula (II-BH-5-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0890] In some embodiments, the compound is of formula (II-BH-5-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0891] In some embodiments, the compound is of formula (II-BH-5-Ma): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0892] In some embodiments, the compound is of formula (II-C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0893] In some embodiments, the compound is of formula (II-CM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0894] In some embodiments, the compound is of formula (II-BM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0895] In some embodiments, the compound is of formula (II-CM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0896] In some embodiments, the compound is of formula (II-CM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0897] In some embodiments, the compound is of formula (II-D): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0898] In some embodiments, the compound is of formula (II-DM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0899] In some embodiments, the compound is of formula (II-DM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0900] In some embodiments, the compound is of formula (II-DM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0901] In some embodiments, the compound is of formula (II-DM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0902] In some embodiments, the compound is of formula (II-DM-1-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0903] In some embodiments, the compound is of formula (II-DM-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0904] In some embodiments, the compound is of formula (II-DM-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0905] In some embodiments, the compound is of formula (II-DM-2-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0906] In some embodiments, the compound is of formula (II-DM-2-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0907] In some embodiments, the compound is of formula (II-E): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0908] In some embodiments, the compound is of formula (II-EM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0909] In some embodiments, the compound is of formula (II-EM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0910] In some embodiments, the compound is of formula (II-EM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0911] In some embodiments, the compound is of formula (II-EM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0912] In some embodiments, the compound is of formula (II-F): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0913] In some embodiments, the compound is of formula (II-FM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0914] In some embodiments, the compound is of formula (II-FM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0915] In some embodiments, the compound is of formula (II-FM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0916] In some embodiments, the compound is of formula (II-FM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0917] In some embodiments, the compound is of formula (II-G): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0918] In some embodiments, the compound is of formula (II-GF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0919] In some embodiments, the compound is of formula (II-GF-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0920] In some embodiments, the compound is of formula (II-GF-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0921] In some embodiments, the compound is of the formula (II-GF-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0922] In some embodiments, the compound is of formula (II-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0923] In some embodiments, the compound is of formula (II-HM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0924] In some embodiments, the compound is of formula (II-HM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0925] In some embodiments, the compound is of formula (II-HM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0926] In some embodiments, the compound is of formula (II-HM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0927] In some embodiments, the compound is of formula (II-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0928] In some embodiments, the compound is of formula (II-IM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0929] In some embodiments, the compound is of formula (II-IM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0930] In some embodiments, the compound is of formula (II-IM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0931] In some embodiments, the compound is of formula (II-IM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0932] In some embodiments, the compound is of formula (II-IM-1-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0933] In some embodiments, the compound is of formula (II-IM-1-Hc): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0934] In some embodiments, the compound is of formula (II-J): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0935] In some embodiments, the compound is of formula (II-JM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0936] In some embodiments, the compound is of formula (II-JM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0937] In some embodiments, the compound is of formula (II-JM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, and all other variables are as defined herein.

[0938] In some embodiments, the compound is of formula (II-JM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0939] In some embodiments, the compound is of formula (II-JM-1-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0940] In some embodiments, the compound is of formula (II-JM-1-Hc): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0941] In some embodiments, the compound is of formula (II-K): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0942] In some embodiments, the compound is of formula (II-KM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0943] In some embodiments, the compound is of formula (II-KM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0944] In some embodiments, the compound is of formula (II-KM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0945] In some embodiments, the compound is of formula (II-KM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0946] In some embodiments, the compound is of formula (II-KM-1-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0947] In some embodiments, the compound is of formula (II-L): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0948] In some embodiments, the compound is of formula (II-LM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0949] In some embodiments, the compound is of formula (II-LM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0950] In some embodiments, the compound is of formula (II-LM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0951] In some embodiments, the compound is of formula (II-LM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0952] In some embodiments, the compound is of formula (II-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0953] In some embodiments, the compound is of formula (II-MM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0954] In some embodiments, the compound is of formula (II-MM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0955] In some embodiments, the compound is of formula (II-MM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0956] In some embodiments, the compound is of formula (II-MM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0957] In some embodiments, the compound is of formula (II-N): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0958] In some embodiments, the compound is of formula (II-NM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0959] In some embodiments, the compound is of formula (II-NM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0960] In some embodiments, the compound is of formula (II-NM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0961] In some embodiments, the compound is of formula (II-NM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0962] In some embodiments, the compound is of formula (II-NM-1-Hb): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0963] In some embodiments, the compound is of formula (II-OP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Q is selected from CH and N, and all other variables are as defined herein.

[0964] In some embodiments, the compound is of formula (II-OP-M): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0965] In some embodiments, the compound is of formula (II-OP-M-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0966] In some embodiments, the compound is of formula (II-OP-M-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0967] In some embodiments, the compound is of formula (II-OP-M-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0968] In some embodiments, the compound is of formula (II-OP-C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0969] In some embodiments, the compound is of formula (II-OP-C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0970] In some embodiments, the compound is of formula (II-OP-C1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0971] In some embodiments, the compound is of formula (II-OP-C1-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0972] In some embodiments, the compound is of formula (II-OP-C1-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0973] In some embodiments, the compound is of formula (II-OP-C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0974] In some embodiments, the compound is of formula (II-OP-C2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0975] In some embodiments, the compound is of formula (II-OP-C2-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0976] In some embodiments, the compound is of formula (II-OP-C2-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0977] In some embodiments, the compound is of formula (II-OP-C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0978] In some embodiments, the compound is of formula (II-OP-C3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0979] In some embodiments, the compound is of formula (II-OP-C3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0980] In some embodiments, the compound is of formula (II-OP-C3-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0981] In some embodiments, the compound is of formula (II-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0982] In some embodiments, the compound is of formula (II-OM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0983] In some embodiments, the compound is of formula (II-OM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0984] In some embodiments, the compound is of formula (II-OM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0985] In some embodiments, the compound is of formula (II-OM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0986] In some embodiments, the compound is of formula (II-OC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0987] In some embodiments, the compound is of formula (II-O-C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0988] In some embodiments, the compound is of formula (II-O-C1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0989] In some embodiments, the compound is of formula (II-O-C1-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0990] In some embodiments, the compound is of formula (II-O-C1-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0991] In some embodiments, the compound is of formula (II-O-C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0992] In some embodiments, the compound is of formula (II-O-C2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0993] In some embodiments, the compound is of formula (II-O-C2-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0994] In some embodiments, the compound is of formula (II-O-C2-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0995] In some embodiments, the compound is of formula (II-O-C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0996] In some embodiments, the compound is of formula (II-O-C3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0997] In some embodiments, the compound is of formula (II-O-C3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0998] In some embodiments, the compound is of formula (II-O-C3-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0999] In some embodiments, the compound is of formula (II-P): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1000] In some embodiments, the compound is of formula (II-PM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1001] In some embodiments, the compound is of formula (II-PM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1002] In some embodiments, the compound is of formula (II-PM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1003] In some embodiments, the compound is of formula (II-PM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1004] In some embodiments, the compound is of formula (II-PC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[1005] In some embodiments, the compound is of formula (II-P-C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1006] In some embodiments, the compound is of formula (II-P-C1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1007] In some embodiments, the compound is of formula (II-P-C1-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1008] In some embodiments, the compound is of formula (II-P-C1-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1009] In some embodiments, the compound is of formula (II-P-C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1010] In some embodiments, the compound is of formula (II-P-C2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1011] In some embodiments, the compound is of formula (II-P-C2-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1012] In some embodiments, the compound is of formula (II-P-C2-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1013] In some embodiments, the compound is of formula (II-P-C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1014] In some embodiments, the compound is of formula (II-P-C3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1015] In some embodiments, the compound is of formula (II-P-C3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1016] In some embodiments, the compound is of formula (II-P-C3-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1017] In some embodiments, the compound is of formula (II-Q): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1018] In some embodiments, the compound is of formula (II-QM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1019] In some embodiments, the compound is of formula (II-QM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1020] In some embodiments, the compound is of formula (II-QM-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1021] In some embodiments, the compound is of formula (II-QM-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1022] In some embodiments, the compound is of formula (II-QC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[1023] In some embodiments, the compound is of formula (II-Q-C1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1024] In some embodiments, the compound is of formula (II-Q-C1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1025] In some embodiments, the compound is of formula (II-Q-C1-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1026] In some embodiments, the compound is of formula (II-Q-C1-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1027] In some embodiments, the compound is of formula (II-Q-C2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1028] In some embodiments, the compound is of formula (II-Q-C2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1029] In some embodiments, the compound is of formula (II-Q-C2-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1030] In some embodiments, the compound is of formula (II-Q-C2-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1031] In some embodiments, the compound is of formula (II-Q-C3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1032] In some embodiments, the compound is of formula (II-Q-C3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1033] In some embodiments, the compound is of formula (II-Q-C3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1034] In some embodiments, the compound is of formula (II-Q-C3-1-Ha): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[1035] In some embodiments, the compound is selected from the compounds set forth in Table 3, and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[1036] In some embodiments, the compound is selected from the compounds set forth in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[1037] In some embodiments, the compound is selected from the compounds set forth in Table 3, and pharmaceutically acceptable salts thereof.

[1038] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[1039] In some embodiments, the compound is selected from the compounds set forth in Table 3. JPEG2025539787000729.jpg246170JPEG2025539787000730.jpg216170JPEG20255397870 00731.jpg226170JPEG2025539787000732.jpg195170JPEG2025539787000733.jpg229170 JPEG2025539787000734.jpg192170JPEG2025539787000735.jpg230170JPEG20255397870 00736.jpg238170JPEG2025539787000737.jpg232170JPEG2025539787000738.jpg198170 JPEG2025539787000739.jpg201170JPEG2025539787000740.jpg196170JPEG20255397870 00741.jpg190170JPEG2025539787000742.jpg211170JPEG2025539787000743.jpg192170 JPEG2025539787000744.jpg177170JPEG2025539787000745.jpg195170JPEG20255397870 00746.jpg229170JPEG2025539787000747.jpg242170JPEG2025539787000748.jpg217170

[1040] In some embodiments, the compound is the neutral form (ie, not a salt) of any one of the compounds listed in Table 3.

[1041] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 3.

[1042] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 3.

[1043] In some embodiments, the compound is the sodium or potassium salt of any one of the compounds listed in Table 3.

[1044] In some embodiments, the compound is the sodium salt of any one of the compounds listed in Table 3.

[1045] In some embodiments, the compound is the potassium salt of any one of the compounds listed in Table 3.

[1046] In some embodiments, the compound is a salt of any acid shown in Table 4 with any one of the compounds listed in Table 3. JPEG2025539787000749.jpg131170

[1047] In some embodiments, the compound is a salt of acetic acid and any one of the compounds listed in Table 3.

[1048] In some embodiments, the compound is a salt of adipic acid and any one of the compounds listed in Table 3.

[1049] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds listed in Table 3.

[1050] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds listed in Table 3.

[1051] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds listed in Table 3.

[1052] In some embodiments, the compound is a salt of citric acid and any one of the compounds listed in Table 3.

[1053] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds listed in Table 3.

[1054] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds listed in Table 3.

[1055] In some embodiments, the compound is a salt of formic acid and any one of the compounds listed in Table 3.

[1056] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds listed in Table 3.

[1057] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[1058] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3, as well as prodrugs and pharmaceutically acceptable salts thereof.

[1059] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[1060] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 3 and pharmaceutically acceptable salts thereof.

[1061] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[1062] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[1063] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[1064] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[1065] The term "isotopic derivative" as used herein refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched or labeled with respect to one or more atoms selected from S). 2 H).

[1066] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[1067] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 3, and pharmaceutically acceptable salts thereof.

[1068] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds listed in Table 3 and pharmaceutically acceptable salts thereof.

[1069] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 3.

[1070] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

[1071] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation in each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio of deuterium abundance to the natural abundance of deuterium.

[1072] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[1073] Compounds of the present disclosure containing the above-mentioned deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2Substitution with H) can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[1074] In some embodiments, the compound is 18 F-labeled compound.

[1075] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof.

[1076] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[1077] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds generally utilize S-labeled compounds in place of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36S-labeled reagents can be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein.

[1078] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure containing one or more S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[1079] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the broadest definition appearing first, as well as each and every specific definition associated with that group.

[1080] The various functional groups and substituents that make up the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, for example, 550 daltons or less.

[1081] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[1082] It will be understood that compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[1083] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[1084] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[1085] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Substituents attached to the chiral center are ranked according to the rules of Cahn, Ingold, and Prelog ordering. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[1086] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate groups on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[1087] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers have the same level of activity.

[1088] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers have the same level of activity.

[1089] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist because of restricted rotation of large groups around a central bond, which prevents rotation. Such atropic isomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropic isomers in selected cases.

[1090] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) of a sugar molecule reacts with one of the hydroxyl groups (-OH) of the same molecule to give a cyclic (ring-shaped) form, as shown in glucose.

[1091] It should be understood that the compounds of the present disclosure can be represented as different tautomers. When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[1092] Compounds of any one of the formulas disclosed herein can exist in many different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro. [ka]

[1093] A non-limiting example of a tautomer of a compound of formula (I) can be shown in compound 23. [ka]

[1094] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are not superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1095] The compounds of the present disclosure may have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[1096] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

[1097] It should be understood that the compounds of any formula described herein include, if applicable, the compounds themselves, as well as their salts and solvates.For example, salts can be formed between an anion on the substituted compounds disclosed herein and a positively charged group (e.g., amino).Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[1098] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[1099] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1100] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a certain molar ratio of solvent molecules in crystalline solid state to form solvates.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.Hydrate is formed by the combination of one molecule of a substance with one or more molecules of water, with water retaining its molecular state as H2O.

[1101] As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (for example, the replacement of one atom with an atom of a different element, or the replacement of one atom with the presence of a specific functional group, or the replacement of one functional group with another functional group).Thus, an analog is a compound that is similar or equivalent in function and appearance, but different in structure or origin from the reference compound.

[1102] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[1103] As used herein, the term "bioisomer" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to generate a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[1104] It should also be understood that any one particular compound of formula disclosed herein can exist in solvated form and unsolvated form, for example, hydrated form.Suitable pharmaceutically acceptable solvate is, for example, hydrate such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[1105] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be measured by Karl Fischer analysis.

[1106] Compounds of any one of the formulas disclosed herein containing an amine functional group can also form N-oxides. Herein, a reference to a compound of formula (I) or (II) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[1107] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is broken down in the human or animal body to release the disclosed compound.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.When the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed.Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain an alkyl or acyl substituent that can be cleaved in vivo on the ester or amide group.

[1108] Thus, the present disclosure includes those compounds of any of the above-defined formulas disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes those compounds of any of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[1109] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein are those that are based on sound medical judgment and are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1110] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers containing a hydroxy group of compounds of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 Examples of the ring substituents of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[1111] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, 1-4 alkylamines, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or its esters.

[1112] Suitable pharmaceutically acceptable prodrugs of any compound of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of ring substituents for the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[1113] The in vivo effects of a compound of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of a compound of any of the formulas disclosed herein. As mentioned above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug). Compound synthesis method

[1114] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[1115] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of stereocenters in compounds of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, an intermediate, or a starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[1116] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[1117] The compounds of the present invention can be prepared in many ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthetic chemistry, or modifications thereof that will be understood by those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in General Procedures A, B, C, or D, which involve assembling intermediates or compounds of different sequences. The starting materials are commercially available or can be prepared by any of the known procedures reported in the literature, or as shown below. General Procedure

[1118] In general, compounds of formula (I) may be prepared using Procedures A, B, C and D described herein.

[1119] According to the first possibility (A), compounds of formula (I) can be prepared using the reaction sequence shown below: [ka]

[1120] Alternative (B) for preparing compounds of formula (I) shown below: [ka]

[1121] Alternative (C) for preparing compounds of formula (I) shown below: [ka]

[1122] Alternative (D) for preparing compounds of formula (I) shown below: [ka]

[1123] Substituent R 1-R 7 It is understood that any of the following may be altered at any stage in the synthetic route.

[1124] All reagents may be commercially available compounds themselves or synthesized from commercially available reagents. All intermediates may be prepared using single- or multi-step synthetic procedures, including but not limited to those described in the preparative section of this specification.

[1125] It should be understood that any compound of formula (I) prepared according to any of procedures AD can be further modified to provide other compounds of formula (I). Biological assays

[1126] Once compounds designed, selected, and / or optimized by the above methods are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[1127] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay technologies, including but not limited to those described below.

[1128] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical Composition

[1129] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 3.

[1130] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[1131] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[1132] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspension agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[1133] Any suitable solubility enhancer can be used, including cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[1134] Any suitable chelating agent can be used, and examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[1135] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[1136] In some embodiments, exemplary preservatives include quaternary ammonium salts, such as those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[1137] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[1138] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[1139] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, the mixture can be adjusted to the desired pH range by simply adding either an acid or a base.

[1140] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or a salt thereof including disodium tetraborate), citrate buffer (such as citric acid or a salt thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[1141] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[1142] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can also be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, and the like.

[1143] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[1144] In some embodiments, the pharmaceutical compositions described herein can further comprise one or more additional pharmaceutically active agents.

[1145] The compositions of the disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by inhalation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[1146] The compositions of the present disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[1147] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a TYK2-associated condition referred to herein.

[1148] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with a TYK2-associated condition referred to herein.

[1149] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. How to use

[1150] In some aspects, the present disclosure provides methods of inhibiting TYK2 (e.g., in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[1151] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1152] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1153] In some embodiments, the disease or disorder is associated with TYK2.

[1154] The compounds of the present invention are inhibitors of TYK2. In some embodiments, the present invention relates to methods for inhibiting TYK2 by contacting TYK2 with a compound of the present invention. Contacting can be performed in vitro or in vivo. In some embodiments, the compounds of the present invention can bind to the JH2 domain of TYK2. In some embodiments, the present invention provides methods for inhibiting the activity of TYK2. In further embodiments, the present invention provides methods for inhibiting TYK2, comprising contacting TYK2 with a compound of the present invention.

[1155] The compounds of the present invention are also useful for treating diseases associated with TYK2. For example, diseases and conditions treatable by the methods of the present invention include autoimmune diseases, including SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, atopic dermatitis; immunodeficiency syndrome 35 (IMD35); cancer; lymphoma; primary cutaneous anaplastic large cell lymphoma; X-linked lymphoproliferative syndrome 1 (XLP1); polycythemia vera (PV); pneumonia, and other diseases or disorders mediated by TYK2.

[1156] In some embodiments, the disease or disorder is selected from the group consisting of autoimmune diseases, including SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, atopic dermatitis; immunodeficiency syndrome 35 (IMD35); cancer; lymphoma; primary cutaneous anaplastic large cell lymphoma; X-linked lymphoproliferative syndrome 1 (XLP1); polycythemia vera (PV); and pneumonia.

[1157] In some embodiments, the disease or disorder is an autoimmune disease.

[1158] In some embodiments, autoimmune diseases include SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis.

[1159] In some aspects, the present disclosure provides a method of treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1160] In some aspects, the present disclosure provides a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1161] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting TYK2 (eg, in vitro or in vivo).

[1162] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[1163] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[1164] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an autoimmune disease in a subject in need thereof.

[1165] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an autoimmune disease in a subject in need thereof.

[1166] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TYK2 (eg, in vitro or in vivo).

[1167] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or ameliorating a disease or disorder disclosed herein.

[1168] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[1169] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, or ameliorating an autoimmune disease in a subject in need thereof.

[1170] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject in need thereof.

[1171] The present disclosure provides compounds that function as inhibitors of TYK2 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides methods of inhibiting TYK2 in vitro or in vivo, the methods comprising contacting a cell with a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof.

[1172] In some embodiments, the TYK2 inhibitor is a compound of the present disclosure.

[1173] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models as described in the art and as found in the current general knowledge.

[1174] The present disclosure also provides a method for treating a disease or disorder in which TYK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[1175] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Administration route

[1176] The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[1177] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using aerosols, e.g., inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.;

[1178] Abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2025539787000756.jpg227170JPEG2025539787000757.jpg32170Example General Synthetic Procedures and Examples of Compound Preparation. Building Block Synthesis Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P5) [ka]

[1179] Preparation 1. Ethyl 2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (P1) [ka] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (490 mg, 2.22 mmol) in MeCN (5 mL) was added 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (450 mg, 2.20 mmol) and DIPEA (1.0 mL) at room temperature. The reaction was stirred for 3 h, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:DCM=3:2) to afford P1 (785 mg, 92% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 11.22 (s, 1H), 8.85 (s, 1H), 8.67 (dd, J = 8.0, 1.6 Hz, 1H), 8.12 (s, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[1180] Preparation 2. Ethyl 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P2) [ka] To a solution of P1 (780 mg, 2.00 mmol) in dioxane (10 mL, degassed) was added 2-aminopyridine (227 mg, 2.41 mmol), potassium phosphate (1.28 g, 6.04 mmol), Xantphos (116 mg, 0.20 mmol), and tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.10 mmol) at room temperature under an argon atmosphere. The solution was stirred at 100 °C overnight, and the mixture was cooled and filtered through a pad of Celite®. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 95:5) to give P2 (213 mg, 24% yield) as a white solid. 1H NMR (400 MHz, CDCl3), δ: 10.88 (br. s, 1H), 8.90 (s, 1H), 8.49 (d, J = 6.8 Hz, 1H), 8.35-8.30 (m, 2H), 8.12-8.06 (m, 3H), 7.75-7.73 (m, 1H), 7.64-7.62 (m, 1H), 7.43-7.41 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.97-6.95 (m, 1H), 6.66-6.64 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.21-4.37 (m, 3H), 4.02 (s, 3H), 3.87 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[1181] Preparation 3. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P3) [ka] To a solution of P2 (165 mg, 0.37 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (18 mg, 0.75 mmol) at room temperature. The mixture was stirred for 12 h, concentrated, and then purified by C18 reverse-phase column chromatography (5–100% MeOH in water with 1% TFA) to give P3 (160 mg, quantitative yield) as a yellow solid. 1 H NMR (400 MHz, MeOD-d4), δ: 8.96 (s, 1H), 8.78 (dd, J = 8.4, 1.6 Hz, 1H), 8.53 (s, 1H), 8.42-8.40 (m, 1H), 8.14-8.12 (m, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (d, J = 8.8 Hz,1H), 7.38-7.36 (m, 2H), 4.04 (s, 3H), 3.79 (s, 3H). Synthesis of 4-(2-methoxy-3-(pyrimidin-2-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P9) [ka]

[1182] Preparation 4. 2-(2-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (P4) [ka] 1-Bromo-2-methoxy-3-nitrobenzene (4.0 g, 17.24 mmol), bis(pinacolato)diboron (6.5 g, 25.86 mmol), potassium acetate (5.1 g, 51.72 mmol), and Pd(dppf)2Cl2 (995 mg, 0.86 mmol) were stirred in 50 mL of dioxane under reflux for 18 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:4) to give P4 (2.08 g, 41% yield). 1 H NMR (400 MHz, CDCl3), δ: 7.91 (dd, J = 8.6, 2.5 Hz, 1H), 7.82 (dd, J = 8.1, 1.6 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 3.98 (s, 3H), 1.37 (s, 12H).

[1183] Preparation 5. 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (P5) [ka] Compound P4 (3.3 g, 11.8 mmol) was placed in a two-necked round-bottom flask, 100 mL of ethanol was added, and the system was purged with argon. Pd / C (10%, 1.25 g, 1.18 mmol) was added, and hydrogen was bubbled through the solution for 24 hours. The solution was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. Product P5 (2.9 g, 93%) was used in the next step without purification.

[1184] Preparation 6. 2-Methoxy-3-(pyrimidin-2-yl)aniline (P6) [ka] 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline P5 (2.80 g, 11.24 mmol), 2-bromopyrimidine (1.77 g, 11.24 mmol), Cs2CO3 (10.96 g, 33.72 mmol), and Pd(PPh3)4 (649 mg, 0.56 mmol) were stirred in 50 mL of dioxane under reflux for 18 h under an argon atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (100% EtOAc) to give P6 (769 mg, 34%). 1 H NMR (400 MHz, DMSO-d6), δ: 8.84 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 8.2 Hz, 1H), 6.92-6.90 (m, 1H), 6.82-6.80 (m, 2H), 5.00 (s, 2H), 3. 61 (s, 3H).

[1185] Preparation 7. Ethyl 2-chloro-4-(2-methoxy-3-(pyrimidin-2-yl)phenylamino)pyrimidine-5-carboxylate (P7) [ka] A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (831 mg, 3.78 mmol) in ACN (20 mL) was mixed with 2-methoxy-3-(pyrimidin-2-yl)aniline (P6, 760 mg, 3.78 mmol) and DIPEA (1.3 mL) at room temperature. The reaction mixture was stirred for 20 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:1) to give P7 (866 mg, 59% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.96 (s, 1H), 8.97 (m, 2H), 8.86 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.33 (t, J = 7.2 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[1186] Preparation 8. Ethyl 4-(2-methoxy-3-(pyrimidin-2-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P8) [ka] Pyridin-2-amine (316 mg, 3.37 mmol), cesium carbonate (2184 mg, 6.72 mmol), Xantphos (13 mg, 0.22 mmol), and palladium acetate (50 mg, 0.22 mmol) were added to a solution of P7 (866 mg, 2.24 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give P8 (402 mg, 40% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.86 (s, 1H), 10.41 (s, 1H), 8.96-8.95 (m, 2H), 8.83 (s, 1H), 8.38-8.35 (m, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.47 (dd, J = 7.8, 1.5 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.10-7.06 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H).

[1187] Preparation 9. 4-(2-Methoxy-3-(pyrimidin-2-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P9) [ka] A solution of P8 (180 mg, 0.41 mmol) in THF (10 mL) was mixed with water (10 mL) and lithium hydroxide (49 mg, 2.03 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P9 (103 mg, 63%) as a yellow solid. LCMS (C18 column 20 × 2 mm, 2.5 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min, retention time 4.19 min). MS (ESI) m / z 416.35 [M−H] + . Synthesis of 4-(2-methoxy-3'-(octyloxy)biphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P15) [ka]

[1188] Preparation 10. 2-Ethynyl-4-methyl-1-[2-(2-oxoimidazolidin-1-yl)ethyl]-1H-indole-5-carbaldehyde (P10) [ka] 1-Bromo-2-methoxy-3-nitrobenzene (1.0 g, 4.32 mmol), 3-hydroxyphenylboronic acid (0.711 g, 5.19 mmol), a 2N solution of KCO (1.21 g, 8.64 mmol), and Pd(PPh) (200 mg, 0.17 mmol) were stirred under reflux in 50 mL of a 50:50 toluene / ethanol mixture for 18 h. The reaction mixture was filtered and concentrated. The product P10 was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6), δ: 9.62 (s, 1H), 7.85 (dd, J = 8.1, 1.6 Hz, 1H), 7.63 (dd, J = 9.4, 1.6 Hz, 1H), 7.38 (t, J = 8.22 Hz, 1H), 7.29(t, J = 8.22 Hz, 1H), 6.97-6.95 (m, 2H), 6.84 (dd, J = 7.9, 1.4 Hz, 1H), 3.46 (s, 3H).

[1189] Preparation 11. 2-Methoxy-3-nitro-3'-(octyloxy)biphenyl (P11) [ka] A solution of compound P10 (1 g, 4 mmol) and octyl bromide (0.866 g, 4.4 mmol) in acetonitrile was stirred with 1.14 g of K2CO3 (8 mmol) under reflux for 24 h. After cooling to room temperature, the inorganic compounds were filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:4) to give P11 (1410 mg, 97% yield). 1H NMR (400 MHz, DMSO-d6), δ: 7.85 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 8.22 Hz, 2H), 7.12-7.09 (m, 2H), 7.01 (dd, J = 7.9, 1.4 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.46 (s, 3H), 1.75-1.68 (m, 2H), 1.44-1.38 (m, 2H), 1.31-1.26 (m, 8H), 0.85 (t, J = 6.9Hz, 3H).

[1190] Preparation 12. 2-Methoxy-3'-(octyloxy)biphenyl-3-amine (P12) [ka] Compound P11 (1.4 g, 4 mmol) was placed in a two-necked round-bottom flask, 100 mL of ethanol was added, and the system was purged with argon. Pd / C (10%, 400 mg, 0.4 mmol) was added, and hydrogen was bubbled through the solution for 24 hours. The solution was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. Product P12 (1.3 g, 99%) was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6), δ: 7.33 (t, J = 8.22 Hz, 1H), 7.06-7.03 (m, 2H), 6.89-6.84 (m, 2H), 6.69 (dd, J = 7.9, 1.4 Hz, 1H), 6.49 (dd, J = 7.6, 1.4 Hz, 1H), 4.96 (s, 2H), 3.99 (t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 1.73-1.68 (m, 2H), 1.43-1.38 (m, 2H), 1.33-1.26 (m, 8H), 0.86 (t, J = 6.9 Hz, 3H).

[1191] Preparation 13. Ethyl 2-chloro-4-(2-methoxy-3'-(octyloxy)biphenyl-3-ylamino)pyrimidine-5-carboxylate (P13) [ka] Ethyl 2,4-dichloropyrimidine-5-carboxylate (793 mg, 3.6 mmol) in ACN (10 mL) was mixed with 2-methoxy-3'-(octyloxy)biphenyl-3-amine (P12, 830 mg, 3.6 mmol) and DIPEA (2.0 mL) at room temperature. The reaction mixture was stirred for 20 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to give P13 (1120 mg, 73% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 11.22 (s, 1H), 8.86 (s, 1H), 8.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.33 (t, J = 8.22 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.18-7.12 (m, 3H), 6.90 (dd, J = 7.9, 2.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.51 (s, 3H), 1.84-1.77 (m, 2H), 1.49-1.43 (m, 5H), 1.35-1.29 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H).

[1192] Preparation 14. Ethyl 4-(2-methoxy-3'-(octyloxy)biphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P14) [ka] Pyridin-2-amine (912 mg, 9.4 mmol), cesium carbonate (1261 mg, 3.88 mmol), Xantphos (70 mg, 0.1 mmol), and palladium acetate (25 mg, 0.1 mmol) were added to a solution of P13 (500 mg, 0.97 mmol) in dioxane (10 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give P14 (380 mg, 68% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.95 (s, 1H), 10.37 (s, 1H), 8.85-8.82 (m, 2H), 8.38 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 8.22 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.13-7.07 (m, 4H), 6.92 (dd, J = 7.9, 2.2 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.42 (s, 3H), 1.75-1.69 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.22 (m, 11H), 0.86 (t, J = 6.9 Hz, 3H).

[1193] Preparation 15. 4-(2-Methoxy-3'-(octyloxy)biphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P15) [ka] A solution of P14 (380 mg, 0.66 mmol) in THF (8.5 mL) was mixed with water (8.5 mL) and lithium hydroxide (84 mg, 2.0 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P15 (360 mg, quantitative yield) as a yellow solid. LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min, retention time 7.25 min). MS (ESI) m / z 542.3 [M−H] + . Synthesis of 4-(2-methoxy-3-(6-methoxypyridin-3-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P20) [ka]

[1194] Preparation 16. 2-Methoxy-5-(2-methoxy-3-nitrophenyl)pyridine (P16) [ka] 1-Bromo-2-methoxy-3-nitrobenzene (1.0 g, 4.32 mmol), 6-methoxypyridin-3-ylboronic acid (0.86 g, 5.63 mmol), a 2N solution of KCO (1.21 g, 8.64 mmol), and Pd(PPh) (20 mg, 0.02 mmol) were stirred under reflux in 50 mL of a 50:50 toluene / ethanol mixture for 18 h. The reaction mixture was filtered and concentrated. The product P16 was used without further purification. 1H NMR (400 MHz, DMSO-d6), δ: 8.37 (d, J = 2.3 Hz 1H), 7.93 (dd, J = 8.6, 2.5 Hz, 1H), 7.90 (dd, J = 8.1, 1.6 Hz, 1H), 7.72 (dd, J = 7.7, 1.6 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.49 (s, 3H).

[1195] Preparation 17. 2-Methoxy-3-(6-methoxypyridin-3-yl)aniline (P17) [ka] Compound P16 (1.01 g, 3.88 mmol) was placed in a two-necked round-bottom flask, 100 mL of ethanol was added, and the system was purged with argon. Pd / C (10%, 400 mg, 0.38 mmol) was added, and hydrogen was bubbled through the solution for 24 hours. The solution was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The product P17 (0.83 g, 93%) was used without further purification. 1 H NMR (400 MHz, DMSO-d6), δ: 8.28 (d, J = 2.3 Hz 1H), 7.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.90-6.86 (m, 2H), 6.71 (dd, J = 7.9, 1.5 Hz, 1H), 6.50 (dd, J = 7.6, 1.5 Hz, 1H), 5.01 (s, 2H), 3.89 (s, 3H), 3.31 (s, 3H).

[1196] Preparation 18. Ethyl 2-chloro-4-(2-methoxy-3-(6-methoxypyridin-3-yl)phenylamino)pyrimidine-5-carboxylate (P18) [ka] A solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (793 mg, 3.6 mmol) in ACN (10 mL) was mixed with 2-methoxy-3-(6-methoxypyridin-3-yl)aniline (P17, 830 mg, 3.6 mmol) and DIPEA (2.0 mL) at room temperature. The reaction mixture was stirred for 20 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to give P18 (1101 mg, 73% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.01(s, 1H), 8.86 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H),7.93 (dd, J = 8.5, 2.3 Hz, 1H), 7.31 (t, J = 8.22 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 3.8 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.91(s, 3H), 3.43 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H).

[1197] Preparation 19. Ethyl 4-(2-methoxy-3-(6-methoxypyridin-3-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P19) [ka] Pyridin-2-amine (912 mg, 9.7 mmol), cesium carbonate (1300 mg, 4.0 mmol), Xantphos (56 mg, 0.097 mmol), and palladium acetate (21 mg, 0.097 mmol) were added to a solution of P18 (400 mg, 0.97 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give P19 (108 mg, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.90 (s, 1H), 10.37 (s, 1H), 8.85-8.83 (m, 2H), 8.38-8.35 (m, 2H), 8.08 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.5, 2.4 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.13-7.07 (m, 2H), 6.94 (d, J = 7.9 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.43 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H).

[1198] Preparation 20. 4-(2-Methoxy-3-(6-methoxypyridin-3-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P20) [ka] A solution of P19 (108 mg, 0.22 mmol) in THF (10 mL) was mixed with water (10 mL) and lithium hydroxide (29 mg, 0.69 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P20 (73 mg, 72%) as a yellow solid. LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min, retention time 5.01 min). MS (ESI) m / z 445.3 [M−H] + . Synthesis of 4-(3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P25) [ka]

[1199] Preparation 21. 3'-(Cyclohexylmethoxy)-2-methoxy-3-nitrobiphenyl (P21) [ka] A solution of compound P10 (1 g, 4 mmol) and (methylbromo)cyclohexane (0.78 g, 4.4 mmol) in acetonitrile was stirred with 1.14 g of K2CO3 (8 mmol) under reflux for 24 h. After cooling to room temperature, the inorganic compounds were filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to give P21 (1.3 g, 97% yield). 1H NMR (400 MHz, DMSO-d6), δ: 7.85 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.41-7.37 (m, 2H), 7.12-7.09 (m, 2H), 6.99 (dd, J = 7.9, 1.4 Hz, 1H), 3.81 (d, J = 6.3 Hz, 2H), 3.46 (s, 3H), 1.83-1.46 (m, 5H), 1.29-1.14 (m, 4H), 1.08-0.99 (m, 2H).

[1200] Preparation 22. 3'-(Cyclohexylmethoxy)-2-methoxybiphenyl-3-amine (P22) [ka] Compound P21 (1.3 g, 3.8 mmol) was placed in a two-necked round-bottom flask, 100 mL of ethanol was added, and the system was purged with argon. Pd / C (10%, 500 mg, 0.4 mmol) was added, and hydrogen was bubbled through the solution for 24 hours. The solution was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The product P22 (0.80 g, 67%) was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6), δ: 7.30 (t, J = 8.22 Hz, 1H), 7.06-7.02 (m, 2H), 6.88-6.84 (m, 2H), 6.68 (dd, J = 7.9, 1.4 Hz, 1H), 6.49 (dd, J = 7.6, 1.4 Hz, 1H), 4.98 (s, 2H), 3.78 (d, J = 6.3 Hz, 2H), 3.32 (s, 3H), 1.73-1.63 (m, 5H), 1.27-1.16 (m, 4H), 1.08-0.99 (m, 2H).

[1201] Preparation 23. Ethyl 2-chloro-4-(3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-ylamino)pyrimidine-5-carboxylate (P23) [ka] Ethyl 2,4-dichloropyrimidine-5-carboxylate (565 mg, 2.6 mmol) in ACN (10 mL) was mixed with 2-3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-amine (P22, 830 mg, 2.6 mmol) and DIPEA (2.0 mL) at room temperature. The reaction mixture was stirred for 20 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:3) to give P23 (1101 mg, 73% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 11.24 (s, 1H), 8.87 (s, 1H), 8.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 (t, J = 8.22 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.19-7.14 (m, 3H), 6.92 (dd, J = 7.9, 2.2 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 3.80 (d, J = 7.2 Hz, 2H), 3.52 (s, 3H), 1.92-1.75 (m, 5H), 1.43 (t, 3H), 1.37-1.22 (m, 4H), 1.13-1.05 (m, 2H).

[1202] Preparation 24. Ethyl 4-(3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P24) [ka] Pyridin-2-amine (759 mg, 8.1 mmol), cesium carbonate (1050 mg, 3.23 mmol), Xantphos (46 mg, 0.08 mmol), and palladium acetate (18 mg, 0.08 mmol) were added to a solution of P23 (400 mg, 0.81 mmol) in dioxane (10 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give P24 (220 mg, 49% yield) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 11.00 (s, 1H), 8.96 (s, 1H), 8.51-8.36 (m, 3H), 7.68 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 8.22 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.92 (dd, J = 7.9, 2.2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.80 (d, J = 6.6 Hz, 2H), 3.54 (s, 3H), 1.92-1.70 (m, 5H), 1.43 (t, J = 7.2 Hz, 3H), 1.34-1.22 (m, 4H), 1.13-1.04 (m, 2H).

[1203] Preparation 25. 4-(3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-ylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P25) [ka] A solution of P24 (210 mg, 0.38 mmol) in THF (8.5 mL) was mixed with water (8.5 mL) and lithium hydroxide (47 mg, 1.14 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting solid was centrifuged and dried to give P25 (214 mg, quantitative yield) as a yellow solid. LCMS (C18 column 20 x 2 mm, particle size 2.5 μm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.77 min). MS (ESI) m / z 526.5 [M-H]+. Synthesis of 1-(2,7-diazaspiro[3.5]non-2-yl)-7-(2,2,2-trifluoroethyl)phthalazine (P27) [ka]

[1204] Preparation 26. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylate (P26) [ka] (1-Methyl-1H-pyrazol-4-yl)methanamine (1086 mg, 6.0 mmol), cesium carbonate (1.00 g, 3.08 mmol), Xantphos (40 mg, 0.07 mmol), and palladium acetate (18 mg, 0.07 mmol) were added to a solution of P1 (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:THF 50:50) to afford P26 (275 mg, 24% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (br. s, 1H), 8.67 (d, J = 6.8 Hz, 1H), 8.62 (s, 1H), 8.55 (s, 1H), 8.21 (t, J = 5.8 Hz, 1H), 7.51-7.49 (m, 2H), 7.35 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.78-3.75 (m, 6H), 1.32 (t, J = 7.2 Hz, 3H).

[1205] Preparation 27. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylic acid (P27) [ka] A solution of P26 (250 mg, 0.54 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (226 mg, 5.4 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting solid was centrifuged and dried to give P27 (230 mg, 92% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z C 20 H 21 Calculated for N9O3 435.44; Found 436.2 [M + H] + , t R = 4.15 minutes. Synthesis of 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylic acid (P29) [ka]

[1206] Preparation 28. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylate (P28) [ka] 1-(1,3,5-Trimethyl-1H-pyrazol-4-yl)ethanamine (118 mg, 0.77 mmol), cesium carbonate (292 g, 0.89 mmol), Xantphos (22 mg, 0.04 mmol), and palladium acetate (8 mg, 0.04 mmol) were added to a solution of P1 (150 mg, 0.38 mmol) in dioxane (20 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:THF 50:50) to afford P28 (88 mg, 45% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.89 (br. s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 5.11-5.04 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 3.57 (s, 3H), 3.55 (s, 3H), 2.19-2.17 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H)

[1207] Preparation 29. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylic acid (P29) [ka] A solution of P28 (194 mg, 0.39 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (163 mg, 3.8 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P29 (100 mg, 55% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min) m / z 479.8 [M + H] + , t R = 4.17 minutes. Synthesis of 2-((1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P31) [ka]

[1208] Preparation 30. Ethyl 2-((1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P30) [ka] (1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methanamine (118 mg, 0.77 mmol), cesium carbonate (292 g, 0.89 mmol), Xantphos (22 mg, 0.04 mmol), and palladium acetate (8 mg, 0.04 mmol) were added to a solution of P1 (150 mg, 0.38 mmol) in dioxane (20 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:THF 50:50) to afford P30 (88 mg, 45% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.94 (s, 1H), 8.93 (d, J = 8.9 Hz, 1H), 8.72 (d, J = 5.0 Hz, 1H), 8.62 (s,1H), 8.56 (s, 1H), 7.92 (t, J = 5.1 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 4.31 (q, J = Hz, 2H), 3.95-3.91 (m, 5H), 3.79 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.226-1.20 (m, 5H).

[1209] Preparation 31. 2-((1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P31) [ka] A solution of P30 (140 mg, 0.277 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (35 mg, 0.831 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P31 (130 mg, 98% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 478.3 [M + H] + , t R = 4.18 minutes. Synthesis of 2-(1-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P33) [ka]

[1210] Preparation 32. Ethyl 2-(1-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P32) [ka] (1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methanamine (118 mg, 0.77 mmol), cesium carbonate (292 g, 0.89 mmol), Xantphos (22 mg, 0.04 mmol), and palladium acetate (8 mg, 0.04 mmol) were added to a solution of P1 (150 mg, 0.38 mmol) in dioxane (20 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:THF 50:50) to give P32 (108 mg, 55% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.90 (s, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.61 (s,1H), 8.56 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.25-7.23 (m, 1H), 5.70 (s, 1H), 4.57-5.46 (m, 1H), 4.26 (d, 2H), 4.13 (q, J = Hz, 2H), 4.02 (s, 3H), 3.78 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.20-1.14 (m, 3H).

[1211] Preparation 33. 2-(1-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ylamino)-4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P33) [ka] A solution of P32 (108 mg, 0.21 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (55 mg, 1.3 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P33 (100 mg, 98% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 478.5 [M + H] + , t R = 4.21 minutes. Synthesis of 2-{[1-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P36) [ka]

[1212] Preparation 34. Ethyl 2-chloro-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino} pyrimidine-5-carboxylate (P34) [ka] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (490 mg, 2.22 mmol) in ACN (5 mL) was added 2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (P59, 450 mg, 2.20 mmol) and DIPEA (1.0 mL) at room temperature. The reaction was stirred for 3 h, and then the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:DCM=3:2) to give P34 (785 mg, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.99 (s, 1H), 8.88 (s, 1H), 8.59 (dd, J = 8.2, 1.3 Hz, 1H), 7.66 (dd, J = 7.9, 1.4 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.61 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[1213] Preparation 35. Ethyl 2-{[1-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P35) [ka] To a solution of P34 (500 mg, 1.28 mmol) in dioxane (10 mL, degassed) was added 1-(1,3-dimethyl-1H-pyrazol-4-yl)ethanamine (300 mg, 2.15 mmol), cesium carbonate (0.85 g, 2.6 mmol), Xantphos (80 mg, 0.13 mmol), and palladium acetate (30 mg, 0.13 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH = 95:5) to give P35 (568 mg, 89% yield) as a white solid. LCMS (ESI) 493.5 [M + H] + , t R = 1.25 minutes.

[1214] Preparation 36. 2-{[1-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P36) [ka] To a solution of P35 (568 mg, 1.15 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (240 mg, 5.72 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give P36 (0.52 g, 98%) as a yellow solid. LCMS (ESI) 465.5 [M + H] + , t R = 1.13 minutes. Synthesis of ethyl 2-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-methylethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P38) [ka]

[1215] Preparation 37. Ethyl 2-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-methylethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P37) [ka] To a solution of P34 (500 mg, 1.28 mmol) in dioxane (10 mL, degassed) was added 1-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-amine (350 mg, 2.28 mmol), cesium carbonate (0.85 g, 2.6 mmol), Xantphos (80 mg, 0.13 mmol), and palladium acetate (30 mg, 0.13 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH = 95:5) to give P37 (420 mg, 64% yield) as a white solid. LCMS (ESI) 507.4 [M + H] + , t R = 1.28 minutes.

[1216] Preparation 38. 2-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-methylethyl]amino}-4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P38) [ka] To a solution of P37 (420 mg, 1.15 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (170 mg, 4.05 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give P38 (0.38 g, 95%) as a yellow solid. LCMS (ESI) 479.3 [M + H] + , t R = 1.06 minutes. Synthesis of 4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrimidine-5-carboxylic acid (P40) [ka]

[1217] Preparation 39. Ethyl 4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrimidine-5-carboxylate (P39) [ka] To a solution of P34 (200 mg, 0.51 mmol) in dioxane (10 mL, degassed) was added [(1-methyl-1H-pyrazol-4-yl)methyl]amine dihydrochloride (100 mg, 0.54 mmol), cesium carbonate (0.80 g, 2.4 mmol), Xantphos (80 mg, 0.05 mmol), and palladium acetate (11 mg, 0.05 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH = 95:5) to give P39 (230 mg, 96% yield) as a white solid. LCMS (ESI) 465.4 [M + H] + , t R = 1.18 minutes.

[1218] Preparation 40. 4-{[2-methoxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]amino}-2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrimidine-5-carboxylic acid (P40) [ka] To a solution of P39 (230 mg, 0.49 mmol) in THF (8.5 mL) was added water (8.5 mL) and lithium hydroxide (100 mg, 2.38 mmol) at room temperature. After stirring overnight, the mixture was concentrated and then acidified with dilute HCl. The precipitated solid was filtered and air-dried to give P40 as a yellow solid (0.11 g, 51%). LCMS (ESI) 437.4 [M + H] + , t R= 1.15 minutes. Synthesis of 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-methyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P42) [ka]

[1219] Preparation 41. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-methyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (P41) [ka] 1-Methyl-1H-pyrazol-3-amine (240 mg, 2.47 mmol), cesium carbonate (600 mg, 1.85 mmol), Xantphos (44 mg, 0.07 mmol), and palladium acetate (16 mg, 0.07 mmol) were added to a solution of P1 (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:THF 50:50) to give P41 (180 mg, 67% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.95 (br. s, 1H), 8.67 (d, J = 6.8 Hz, 1H), 8.55 (s, 1H), 7.87 (d, 1H), 7.66-7.59 (m, 3H), 7.32 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[1220] Preparation 42. 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-2-(1-methyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P42) [ka] A solution of P41 (180 mg, 0.40 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (50 mg, 1.2 mmol) at room temperature. The reaction mixture was stirred overnight, concentrated, and acidified to pH = 6 with 1 M HCl. The resulting precipitate was centrifuged and dried to give P42 (115 mg, 68% yield) as a yellow solid. LCMS (ESI) (C18 column 100 × 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5 to 87%, 10 min) m / z 422.0 [M + H] + , t R = 4.27 minutes. Synthesis of 4-(2-methoxy-3-(piperidin-1-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P47) [ka]

[1221] Preparation 43. 1-(2-Methoxy-3-nitrophenyl)piperidine (P43) [ka] 1-Bromo-2-methoxy-3-nitrobenzene (0.5 g, 2.16 mmol), piperidine (0.368 g, 4.32 mmol), CsCO (1.40 g, 4.32 mmol), Pd(dba) (99 mg, 0.108 mmol), and XantPhos (62 mg, 0.108 mmol) were stirred in 50 mL of dioxane under reflux for 24 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:3) to give P43 (150 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6), δ: 7.35 (dd, J = 7.9, 1.3 Hz, 1H), 7.25-7.17 (m, 2H), 3.89 (s, 3H), 3.01 (t, J = 5.2 Hz, 4H), 1.71-1.65 (m, 4H), 1.57-1.53 ​​(m, 2H).

[1222] Preparation 44. 2-Methoxy-3-(piperidin-1-yl)aniline (P44) [ka] Compound P43 (210 mg, 0.88 mmol) was placed in a two-necked round-bottom flask, 100 mL of ethanol was added, and the system was purged with argon. Pd / C (10%, 200 mg, 0.20 mmol) was added, and hydrogen was bubbled through the solution for 24 hours. The solution was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The product P44 (145 mg, 79%) was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6), δ: 6.66 (t, J = 7.9 Hz, 1H), 6.32 (dd, J = 7.9, 1.3 Hz, 1H), 6.14 (dd, J = 7.9, 1.1 Hz, 1H), 4.68 (br. s, 2H), 3.70 (s, 3H), 2.91 (t, J = 5.2 Hz, 4H), 1.66-1.61 (m, 4H), 1.53-1.48 (m, 2H).

[1223] Preparation 45. Ethyl 2-chloro-4-(2-methoxy-3-(piperidin-1-yl)phenylamino)pyrimidine-5-carboxylate (P45) [ka] Ethyl 2,4-dichloropyrimidine-5-carboxylate (242 mg, 1.1 mmol) in ACN (10 mL) was mixed with 2-methoxy-3-(piperidin-1-yl)aniline (P44, 280 mg, 1.35 mmol) and DIPEA (2.0 mL) at room temperature. The reaction was stirred for 20 hours, and then the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:hexane = 1:1) to give P45 (420 mg, 97% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 10.99 (s, 1H), 8.82 (s, 1H), 7.27-7.23 (m, 1H), 7.18-7.15 (m, 1H), 4.39 (q, J = 6.9 Hz, 2H), 3.89 (s, 3H), 2.98 (t, J = 5.2 Hz, 4H), 1.72-1.63 (m, 4H), 1.57-1.51 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H).

[1224] Preparation 46. Ethyl 4-(2-methoxy-3-(piperidin-1-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P46) [ka] Pyridin-2-amine (482 mg, 5.1 mmol), cesium carbonate (734 mg, 2.26 mmol), Xantphos (29 mg, 0.05 mmol), and palladium acetate (11 mg, 0.05 mmol) were added to a solution of P45 (200 mg, 0.51 mmol) in dioxane (40 mL, degassed) at room temperature under an argon atmosphere. After stirring the solution at 85 °C overnight, the mixture was cooled and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give P46 (71 mg, 31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.90 (s, 1H), 10.37 (s, 1H), 8.38-8.35 (m, 2H), 8.08 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.5, 2.4 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.13-7.07 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.72-1.63 (m, 4H), 1.57-1.51 (m, 2H),1.35 (t, J = 6.9 Hz, 3H).

[1225] Preparation 47. 4-(2-Methoxy-3-(piperidin-1-yl)phenylamino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P47) [ka] A solution of P46 (71 mg, 0.14 mmol) in THF (10 mL) was mixed with water (10 mL) and lithium hydroxide (17 mg, 0.41 mmol) at room temperature. After stirring overnight, the mixture was concentrated and acidified. The resulting solid was centrifuged and dried to give P47 (60 mg, 72%) as a yellow solid. LCMS (C18 column 20 × 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5–87%, 10 min, retention time 4.91 min). MS (ESI) m / z 421.1 [M−H] + . Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P49) [ka]

[1226] Preparation 48. Ethyl 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P48) [ka] A solution of P1 (780 mg, 2.00 mmol), 2-aminopyridine (227 mg, 2.41 mmol), cesium carbonate (1.28 g, 6.04 mmol), Xantphos (116 mg, 0.20 mmol), and palladium acetate (92 mg, 0.10 mmol) in dioxane (10 mL, degassed) was purged with argon. The reactio...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. Ring Z is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, and S; Ring G is selected from aryl, 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S, or 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, S; Each R １ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R ８ ) ２ wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, N(R ８ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ optionally substituted with one or more substituents independently selected from alkynyl, heterocycle, aryl, heteroaryl; Or, two R １ together with the atom to which they are attached and any intervening atoms form a 5-6 membered heterocycle or heteroaryl, the heterocycle or heteroaryl being free of halogen, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl, —N(R ８ ) ２ , -OR ８ optionally substituted with one or more substituents independently selected from Each R ２ are independently hydrogen, C １ -C ６ alkyl; R ３ is hydrogen, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl; R ４ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl-N(R ８ ) ２ , C １ -C ６ Alkyl-OR ８ , heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl, —N(R ８ ) ２ , -OR ８ optionally substituted with one or more substituents independently selected from R ５ is H, C １ -C ６ alkyl; Or, R ４ and R ５ together with the atoms to which they are attached and any intervening atoms, represent halogen, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl, —N(R ８ ) ２ , -OR ８ forming a 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from R ６ is -OR ８ , C １ -C ６ selected from halogenalkyl; R ７ is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, oxo, C ３ -C １０ cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy, cycloalkyl; Or, R ６ and R ７ together with the atom to which they are attached and any intervening atoms, form a 5-8 membered heterocyclic ring; Each R ８ are independently H, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl; k is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

2. The compound has the formula (I-AE): 【Chemistry 2】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein each X is independently selected from CH and N, and one to three X are N.

3. The compound has the formula (I-FH): 【Transformation 3】 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, and Y is selected from O, S, and NH.

4. The compound has the formula (I-IK): 【Chemistry 4】 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, and W is selected from O, S, and NH.

5. The compound has the formula (IL): 【Transformation 5】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

6. The compound has the formula (I-M): 【Transformation 6】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

7. The compound has the formula (I-N): 【Transformation 7】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

8. The compounds are of formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q): 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

9. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

10. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

11. 11. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active agents.

12. 12. A method of inhibiting TYK2 in a cell, comprising contacting said cell with a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11.

13. The method of claim 12 , wherein the contacting is in vitro or in vivo.

14. A method for treating or preventing a disease or disorder associated with TYK2, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 or 11.

15. 15. The method of claim 14, wherein the disease or disorder is selected from the group consisting of a proliferative disease, a metabolic disease, an allergic disease, an autoimmune disease, and an inflammatory disease.

16. 15. The method of claim 14, wherein the disease or disorder is selected from the group consisting of immunodeficiency, cancer, lymphoma, X-linked lymphoproliferative syndrome 1 (XLP1), polycythemia vera (PV), and pneumonia.

17. 16. The method of claim 15, wherein the autoimmune disease is selected from the group consisting of SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis.

18. The method of any one of claims 12 to 17, wherein the subject is a mammal.

19. 20. The method of claim 18, wherein the subject is a human.

20. A compound selected from:

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