Inhibitors of tyk2

Abstract

The present invention is directed to the compounds of Formula (I) inhibitors of TYK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with TYK2, such as an autoimmune decease. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting TYK2, methods of treating diseases or disorders associated with TYK2, and methods of synthesizing these compounds.

Description

INHIBITORS OF TYK2 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63 / 425,877 filed November 16, 2022, entitled “Inhibitors of TYK2” the disclosure of which are incorporated by reference in its entirety for all purposes.FIELD OF INVENTION

[0002] The present invention is directed to inhibitors targeting the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with TYK2, such as inflammatory diseases, Lymphoma. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting TYK2, methods of treating diseases or disorders associated with TYK2, and methods of synthesizing these compounds.BACKGROUND

[0003] Cytokine signaling transduction plays a pivotal role in controlling the growth, differentiation, function, and communication of immune cells. Multiple cytokine-signaling pathways are tightly regulated by the actions of receptor-bound JAKs and the signal transducers and activators of transcription (STATs). Dysfunctional cytokine-JAK / STAT activities have been demonstrated as hallmarks of numerous autoimmune disorders and inflammatory diseases.

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

[0005] Thus, TYK2 represents an attractive target to develop small -molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors.

[0006] The structure of TYK2 contains a complex architecture with multiple domains participating in both inter- and intramolecular interactions which transit cytokine receptor- mediated activation to its catalytic domain. TYK2 contains four distinct domains: (i) the A-terminal Ezrin, Radixin, Moesin (FERM), (ii) Src homology 2 (SH2) domains (which constitute the receptor-binding module) followed by C-terminal, (iii) JH2 pseudokinase and (iv) JH1 kinase domains. The JH2 pseudokinase domain has a canonical kinase fold but lacks catalytic activity. Rather than acting catalytically, the JH2 domain plays a pivotal role in regulating the receptor-mediated activation of the adjacent JH1 kinase domain through intermolecular autoinhibition. Evidence suggests that stabilizing the TYK2 JH2 pseudokinase domain led to a protein conformational change that prevents receptor- mediated activation and hinders activity of the TYK2 JH1 catalytic domain by blocking relief of intermolecular autoinhibitory interactions between the TYK2 JF12 pseudokinase and JH1 kinase domains. In the JAK family, it was reported that the pseudokinase and kinase domains in JAK2 coimmunoprecipitate and lead to co-expression of the JAK2 JH2 pseudokinase domain suppresses activity of the isolated JH1 kinase domain. Additionally, deletion of the pseudokinase domain in JAK2 and JAK3 elevates basal kinase activity and increases signaling through cognate receptors.

[0007] Designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Other approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein which suppress the TYK2 catalytic activity through allosteric regulation looks significantly more promising.

[0008] The TYK2 inhibitor, Deucravacitinib (BMS986165), is currently the compound most advanced clinically, which selectively binds to the JH2 regulatory domain of TYK2 and suppresses TYK2 associated cytokine pathways. Deucravacitinib was demonstrated to be highly efficacious in phase 2 and 3 psoriasis trials with good safety profiles.

[0009] The present invention is directed to develop a series of small-molecule TYK2 ligands that selectively target the JH2 pseudokinase regulatory domain of TYK2. The TYK2 JH2 pseudokinase ligands inhibit the TYK2 JH1 catalytic domain activity through the intermolecular JH2-JH1 interaction. The mechanistic approach adopted for the TYK2 JH2 ligands is distinct from traditionally designed JAK and TYK2 inhibitors which 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, leading to inhibition of its kinase activity.

[0010] Severe side effects observed during clinical studies prevented the FDA from approving more efficacious higher doses for tofacitinib and baricitinib for the treatment of rheumatoid arthritis (RA). Also, baricitinib and upadacitinib each carry a boxed warning, the most serious warning the FDA issues, for risks of serious infection, malignancy, and thrombosis. The adverse effects of these drugs may be linked to the lack of specificity or selectivity. Given the shortcomings of current therapeutics, the unmet medical need remains high for many patients suffering from autoimmune disorders.SUMMARY

[0011] A first aspect of the invention relates to compounds of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, whereinRing Z is 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, S;Ring G is selected from aryl, 5-10 membered heterocyclyl comprising 1-3 heteroatom selected from N, O, S or 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatom selected from N, O, S; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R8)2, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl; or two R1together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heterocycle or heteroaryl, wherein heterocycle or heteroaryl optionally substituted with one or more substituents independently selected from halogen, Ci-C6alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8each R2is independently selected from hydrogen, C1-C6 alkyl;R3is selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;R4is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkyl-N(R8)2, C1-C6 alkyl-OR8, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted withone or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R5is selected from H, C1-C6 alkyl; or R4and R3together with the atoms to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R6is selected from -OR8, C1-C6 halogenalkyl;R7is selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C10 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; or R6and R7together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle; each R8is independently selected from H, C1-C6 alkyl, C3-C10 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; wherein, cycloalkyl is a mono or polycyclic saturated carbon rings containing 3-18 carbon atoms; aryl is a cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7- 12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.

[0012] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0013] Another aspect of the invention relates to a method of treating a disease or disorder associated with TYK2. The method comprises administering to a patient in need of a treatment for diseases or disorders 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 invention relates to a method of treating a disease or disorder associated with JAK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with JAK2 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 invention is directed to a method of inhibiting of TYK2. The method involves 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 invention is directed to a method of inhibiting of JAK2. The method involves 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 a method for the modulation of IL-12, IL-23 and / or IFNa by inhibiting TYK-2-mediated signal transduction comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.

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

[0019] A preferred embodiment is a method for treating inflammatory and autoimmune diseases or diseases. For the purposes of this invention, an inflammatory and autoimmunedisease or disorder includes any disease having an inflammatory or autoimmune component.

[0020] An alternate preferred embodiment is a method for treating metabolic diseases, including type 2 diabetes and atherosclerosis.

[0021] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting TYK2.

[0022] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting JAK2.

[0023] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting of TYK2.

[0024] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting of JAK2.

[0025] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0026] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment 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 compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers,tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0028] The present invention further provides methods of 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 an improved efficacy and safety profile relative to known inhibitors of TYK2. The present disclosure also provides agents with novel mechanisms of action toward interaction of TYK2 in the treatment of various types of diseases.

[0032] The present invention further provides methods of 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 methods of treating a disease, disorder, or condition selected from 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 35 (IMD35); Cancer; Lymphoma; Primary Cutaneous Anaplastic Large Cell Lymphoma; Lymphoproliferative Syndrome X-Linked, 1 (XLP1); Polycythemia Vera (PV); Pneumonia 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 present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure A, B, C or D).

[0036] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g, the intermediate is selected from the intermediates described in Preparative part - P1-P120)

[0037] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0038] In some aspects, the present disclosure provides a method of preparing 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. In the specification, the singular forms also include 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 the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0040] Other features and advantages of the disclosure will be apparent from the following detailed description and claimsDETAILED DESCRIPTION

[0041] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which associated with the inhibition of TYK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0042] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, 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. All patents and publications cited in this specification are incorporated herein by reference in their entireties.Definitions

[0043] The articles "a" and "an" are used in this disclosure to refer to one or 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] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0045] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (z.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, - OH, -CN, -COOH, -CH2CN, -O-(CI-C6) alkyl, (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) haloalkyl, (C1-C6) haloalkoxy, -O-(C2-Ce) alkenyl, -O-(C2-Cs) alkynyl, (C2-Ce) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, - OC(O)O(C1-C6) alkyl, -NH2, -NH((CI-C6) alkyl), -N((CI-C6) alkyl)2, -NHC(O)(CI-C6) alkyl, -C(O)NH(CI-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and -S(0)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0046] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0047] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0048] Unless otherwise specifically defined, the term "aryl1' refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(Ci-Cfi)alkyl, (Ci-Cfi)alkyl, - O-(C2-C6)alkenyl, -O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, - OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, - NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -S(O)2-(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and - S(O)N((Ci-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0049] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwisespecifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaiyl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, 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[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[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][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,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[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro- 2H-l-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazo[l,2- a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazole, l,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fusedwith one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is 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-lH— isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[l,2- a]indol- 1 (2H)-onyl, benzo[c] [ 1 ,2]oxaborol- 1 (37 / )-olyl, 6,6a,7,8-tetrahydro-9 / f- pyrido[2,3-Z>]puyrrolo[l,2-<7][l,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H- spiro[cyclopropane-l,8’-pyrido[2,3-Z>]pyrrolo[l,2-d][l,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 a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, Ao-propyl, zso-butyl, .sec-butyl, tert -butyl, zso-pentyl, zzeo-pentyl, and zso-hexyl.

[0052] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0053] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “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, zso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

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

[0055] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1-C6 alkylene. An alkylene may 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-, -CH2CH2CH2CH2-, and the like.

[0056] “Cycloalkyl” means mono or polycyclic saturated or partially unsaturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbomyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3- dihydro-lH-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[l. l.l]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0057] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. A polycyclic heterocycloalkyl comprises at least one non-aromatic ring. Polycyclic heterocycles may be bridged, fused, or spiro- fused. The substituents can 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” means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[0059] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0060] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0061] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, z.e., C=N.

[0062] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0063] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” is understood to mean a spirocycle wherein 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 variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure 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 wherein 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 attached to an aryl group,wherein the linkage to the rest of the molecule is on the first group recited, i.e., the alkyl group. Similarly, alkyl-alkoxy refers to a chemical moiety comprising an alkyl group covalently attached to an alkoxy group wherein the linkage to the rest of the molecule is on the alkyl group. This nomenclature may also be used for, e.g. alkenyl-aryl, alkenylheteroaryl, alkynyl-aryl, alkynyl-heteroaryl. As non-limiting examples, Ci alkyl-phenylVsA / r°|l J refers to ; C2 alkenyl-furanyl refers to $Ci alky I-C2 alkoxy referson.

[0066] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (1) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0067] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with2H and14C). Deuterated (z.e.,2H or D) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0068] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water- soluble and water-insoluble salts, such as the 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, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, 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, subacetate, 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, such as a monkey, chimpanzee, baboon, or rhesus.

[0070] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing 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, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

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

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

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

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

[0076] The term “salt’ refers to pharmaceutically acceptable salts

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

[0078] “ TYK2 inhibitor” as used herein refer to compounds of Formula I and / or compositions comprising a compound of Formula I which inhibits TYK2.

[0079] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g., compounds or compositions of Formula I (and / or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.

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

[0081] In one aspect, the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereofwherein R1, R2, R3, R4, R5, R6, R7, G, Z, k, m, and n are as described herein.

[0082] It is understood that, for a compound of Formula (I), R1, R2, R3, R4, R5, R6, R7, G, Z, k, m, and n can each be, where applicable, selected from the groups described herein, and any group described herein for any of R1, R2, R3, R4, R5, R6, R7, G, Z, k, m, and n can be combined, where applicable, with any group described herein for one or more of the remainder of R1, R2, R3, R4, R5, R6, R7, G, Z, k, m, and n.

[0083] In some embodiments,Ring Z is 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, S;Ring G is selected from aryl, 5-10 membered heterocyclyl comprising 1-3 heteroatom selected from N, O, S or 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatom selected from N, O, S; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R8)2, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl; or two R1together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heterocycle or heteroaryl, wherein heterocycle or heteroaryl optionally substituted with one or more substituents independently selected from halogen, Ci-C6alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8each R2is independently selected from hydrogen, C1-C6 alkyl;R3is selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;R4is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkyl-N(R8)2, C1-C6 alkyl-OR8, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R5is selected from H, C1-C6 alkyl; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R6is selected from -OR8, C1-C6 halogenalkyl;R7is selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C10 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; or R6and R7together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle; each R8is independently selected from H, C1-C6 alkyl, C3-C10 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 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, 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 5 membered monocyclic heteroaryl comprising 1- 4 heteroatom selected from N, O, S.

[0091] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 1 heteroatom selected from N, O, S.

[0092] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 2 heteroatoms selected from N, O, S.

[0093] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 2 nitrogen atoms as heteroatoms.

[0094] In some embodiments, Ring Z is selected from,

[0096] In some embodiments, Ring Z is

[0097] In some embodiments, Ring

[0098] In some embodiments, Ring

[0099] In some embodiments, Ring Z is selected from,

[0101] In some embodiments, Ring Z is

[0102] In some embodiments, Ring

[0103] In some embodiments, RingR1

[0104] In some embodiments, Ring Z is selected from

[0106] In some embodiments, Ring

[0107] In some embodiments, Ring

[0108] In some embodiments, Ring

[0109] In some embodiments, Ring Z is selected fromw,

[0111] In some embodiments, Ring

[0112] In some embodiments, Ring

[0113] In some embodiments, Ring

[0114] In some embodiments, Ring Z is selected from,

[0119] In some embodiments, Ring Z is selected from,,

[0121] In some embodiments, Ring

[0124] In some embodiments, Ring

[0125] In some embodiments, Ring

[0126] In some embodiments, Ring

[0127] In some embodiments, Ring

[0128] In some embodiments, Ring

[0129] In some embodiments, Ring

[0130] In some embodiments, Ring

[0131] In some embodiments, Ring

[0132] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 2 heteroatoms, one - oxygen and one - nitrogen.

[0133] In some embodiments, Ring Z is

[0134] In some embodiments, Ring Z is

[0135] In some embodiments, Ring Z is

[0136] In some embodiments, Ring Z is

[0137] In some embodiments, Ring

[0138] In some embodiments, Ring

[0139] In some embodiments, Ring Z is

[0140] In some embodiments, Ring Z is

[0141] In some embodiments, Ring

[0142] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 2 heteroatoms, one - sulfur and one - nitrogen.

[0143] In some embodiments, Ring Z is

[0144] In some embodiments, Ring Z is

[0145] In some embodiments, Ring Z is

[0146] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 3 heteroatoms selected from N, O, S.

[0147] In some embodiments, Ring Z is 5 membered monocyclic heteroaryl comprising 4 heteroatoms selected from N, O, S.

[0148] In some embodiments, Ring Z is 6 membered monocyclic heteroaryl comprising 1 - 4 heteroatom selected from N, O, S.

[0149] In some embodiments, Ring Z is 6 membered monocyclic heteroaryl comprising 1 heteroatom selected from N, O, S.

[0150] In some embodiments, Ring Z is 6 membered monocyclic heteroaryl comprising one nitrogen as a heteroatom.

[0151] In some embodiments, Ring Z is selected from

[0152] In some embodiments, Ring Z is

[0153] In some embodiments, Ring Z is

[0154] In some embodiments, Ring Z is

[0155] In some embodiments, Ring Z is selected from

[0156] In some embodiments, Ring Z is

[0157] In some embodiments, Ring

[0158] In some embodiments, Ring Z is

[0159] In some embodiments, Ring Z is selected from

[0160] In some embodiments, Ring Z is

[0161] In some embodiments, Ring

[0162] In some embodiments, Ring Z is

[0163] In some embodiments, Ring Z is

[0164] In some embodiments, Ring Z is

[0165] In some embodiments, Ring Z is selected from

[0166] In some embodiments, Ring Z is

[0167] In some embodiments, Ring

[0168] In some embodiments, Ring

[0169] In some embodiments, Ring

[0170] In some embodiments, Ring Z is

[0171] In some embodiments, Ring Z is

[0172] In some embodiments, Ring Z is 6 membered monocyclic heteroaryl comprising 2 heteroatoms selected from N, O, S.

[0173] In some embodiments, Ring Z is 6 membered monocyclic heteroaryl comprising two nitrogen atoms as heteroatoms.

[0174] In some embodiments, Ring Z is

[0175] In some embodiments, Ring Z is

[0176] In some embodiments, Ring Z is

[0177] In some embodiments, Ring

[0178] In some embodiments, Ring

[0179] In some embodiments, Ring Z is 9 membered bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, S.

[0180] In some embodiments, Ring Z is 9 membered bicyclic heteroaryl comprising 4 heteroatoms independently selected from N, O, S.

[0181] In some embodiments, Ring Z is 9 membered bicyclic heteroaryl comprising 4 nitrogen atoms as heteroatoms.

[0182] In some embodiments, Ring Z is selected from

[0183] In some embodiments, Ring

[0184] In some embodiments, Ring Z is

[0185] In some embodiments, Ring

[0186] In some embodiments, Ring

[0187] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, S.

[0188] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 1 heteroatom independently selected from N, O, S.

[0189] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 1 nitrogen atom as heteroatom.

[0190] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 2 heteroatoms independently selected from N, O, S.

[0191] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 2 nitrogen atoms as heteroatoms.

[0192] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 3 heteroatoms independently selected from N, O, S.

[0193] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 3 nitrogen atoms as heteroatoms.

[0194] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 4 heteroatoms independently selected from N, O, S.

[0195] In some embodiments, Ring Z is 10 membered bicyclic heteroaryl comprising 4 nitrogen atoms as heteroatoms.

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

[0197] Table 1

[0198] In some embodiments, Ring G is selected from aryl, 5-10 membered heterocyclyl comprising 1-3 heteroatom selected fromN, O, S or 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatom selected from N, O, S.

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

[0200] In some embodiments, Ring G is 6 membered monocyclic aryl.

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

[0202] In some embodiments, Ring G iswherein R7is C1-C6 alkoxy, optionally substituted with one or more substituents independently selected from halogen, Ci-C6alkyl, C1-C6 alkoxy, cycloalkyl.

[0205] In some embodiments, Ring G is selected from

[0206] In some embodiments, Ring.

[0207] In some embodiments, Ring G is

[0208] In some embodiments, Ring G is 10 membered bicyclic aryl.

[0209] In some embodiments, Ring G is 5-10 membered heterocyclyl comprising 1-3 heteroatom selected from N, O, S.

[0210] In some embodiments, Ring G is 5 membered monocyclic heterocyclyl comprising 1-3 heteroatom selected from N, O, S.

[0211] In some embodiments, Ring G is 6 membered monocyclic heterocyclyl comprising 1-3 heteroatom selected from N, O, S.

[0212] In some embodiments, Ring G is 6 membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, S.

[0213] In some embodiments, Ring G is 6 membered monocyclic heterocyclyl comprising nitrogen atom as a heteroatom.-J-N AD ^2^(R7)n

[0214] In some embodiments, Ring G is ' - '

[0215] In some embodiments, Ring G is.

[0216] In some embodiments, Ring G is 7 membered monocyclic heterocyclyl comprising 1-3 heteroatom independently selected from N, O, S.

[0217] In some embodiments, Ring G is 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatom independently selected from N, O, S.

[0218] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising 1-3 heteroatom independently selected from N, O, S.

[0219] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising 2 heteroatoms independently selected from N, O, S.

[0220] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising two nitrogen atoms as heteroatoms.

[0221] In some embodiments, Ring G is selected from

[0222] In some embodiments, Ring G is

[0223] In some embodiments, Ring

[0224] In some embodiments, Ring

[0225] In some embodiments, Ring G is selected from

[0226] In some embodiments, Ring G is

[0227] In some embodiments, Ring

[0228] In some embodiments, Ring

[0229] In some embodiments, Ring G is selected from

[0230] In some embodiments, Ring G is

[0231] In some embodiments, Ring

[0232] In some embodiments, Ring

[0233] In some embodiments, Ring G is selected from

[0234] In some embodiments, Ring G is

[0235] In some embodiments, Ring G is R7

[0236] In some embodiments, Ring G is

[0237] In some embodiments, Ring

[0238] In some embodiments, Ring

[0239] In some embodiments, Ring G is selected from

[0240] In some embodiments, Ring G is

[0241] In some embodiments, Ring G is

[0242] In some embodiments, Ring G is

[0243] In some embodiments, Ring

[0244] In some embodiments, Ring

[0245] In some embodiments, Ring G is selected from

[0246] In some embodiments, Ring G is

[0247] In some embodiments, Ring

[0248] In some embodiments, Ring

[0249] In some embodiments, Ring

[0250] In some embodiments, Ring

[0251] In some embodiments, Ring

[0252] In some embodiments, Ring.

[0253] In some embodiments, Ring G is selected from

[0254] In some embodiments, Ring G is

[0255] In some embodiments, Ring

[0256] In some embodiments, Ring

[0257] In some embodiments, Ring

[0258] In some embodiments, Ring

[0259] In some embodiments, Ring

[0260] In some embodiments, Ring

[0261] In some embodiments, Ring G is selected from

[0262] In some embodiments, Ring

[0263] In some embodiments, Ring

[0264] In some embodiments, Ring

[0265] In some embodiments, Ring

[0268] In some embodiments, Ring

[0269] In some embodiments, Ring

[0270] In some embodiments, Ring

[0271] In some embodiments, Ring

[0272] In some embodiments, Ring

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

[0275] In some embodiments, Ring

[0276] In some embodiments, Ring

[0277] In some embodiments, Ring

[0278] In some embodiments, Ring

[0279] In some embodiments, Ring G is selected from,

[0281] In some embodiments, Ring

[0282] In some embodiments, Ring

[0283] In some embodiments, Ring

[0284] In some embodiments, Ring

[0285] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising one nitrogen atom and one oxygen atom as heteroatoms.Jr(R7)n

[0286] In some embodiments, Ring G is 0

[0287] In some embodiments, Ring G is selected from

[0288] In some embodiments, Ring G is selected from

[0289] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising 3 heteroatoms independently selected from N, O, S.

[0290] In some embodiments, Ring G is, wherein X1is independently selected from CH and N; bond X2X3selected from a single bond and double bond, provided that when bondis a single bond (X2-X3), bondis a double bond (X3=X4), X2is selected from O, S, and NH, X3is selected from N and CH, X4is selected from N and CH; and when bondis a double bond (X2=X3), bonda single bond (X3-X4), X2is selected from CH and N, X3is selected from N and CH, X4is selected from O, S, and NH.

[0291] In some embodiments, Ring G is, wherein X1is independently selected from CH and N; X2is selected from O, S, and NH, X3is selected from N and CH,X4is selected from N and CH.

[0292] In some embodiments, Ring G is, wherein X1is independently selected from CH and N; X2is selected from CH and N, X3is selected from N and CH, X4is selected from O, S, NH.

[0293] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising three nitrogen atoms as heteroatoms.X1^X2 “I \ " "T"(R7)n

[0294] In some embodiments, Ring G is X , wherein X1is independently selected from CH and N; bond X2X3selected from a single bond and double bond, provided that when bond X2X3is a single bond (X2-X3), bondis a double bond (X3=X4), X2is NH, X3is selected from N and CH, X4is selected from N and CH; and when bondis a double bond (X2=X3), bondis a single bond (X3-X4), X2is selected from CH and N, X3is selected from N and CH, X4is NH.

[0295] In some embodiments, Ring G is, wherein X1is independently selected from CH and N; X3is selected from N and CH, X4is selected from N and CH.

[0296] In some embodiments, Ring, wherein X1is independently selected from CH and N; X2is selected from CH and N, X3is selected from N and CH.

[0297] In some embodiments, Ring G is selected from

[0298] In some embodiments, Ring G is

[0299] In some embodiments, Ring G is H

[0300] In some embodiments, Ring G is

[0301] In some embodiments, Ring

[0302] In some embodiments, Ring G is selected from

[0304] In some embodiments, Ring G is selected from

[0305] In some embodiments, Ring G is selected from

[0307] In some embodiments, Ring G is selected from

[0308] In some embodiments, Ring G is selected from

[0309] In some embodiments, Ring G is selected from

[0312] In some embodiments, Ring G is 5 membered monocyclic heteroaryl comprising two nitrogen atoms and one oxygen atom as heteroatoms.

[0313] In some embodiments, Ring G is selected from

[0314] In some embodiments, Ring G is

[0315] In some embodiments, Ring G is

[0316] In some embodiments, Ring G is

[0320] In some embodiments, Ring G is selected from

[0321] In some embodiments, Ring G is

[0322] In some embodiments, Ring

[0323] In some embodiments, Ring G is

[0324] In some embodiments, Ring

[0325] In some embodiments, Ring G is

[0326] In some embodiments, Ring

[0327] In some embodiments, Ring G is

[0328] In some embodiments, Ring

[0329] In some embodiments, Ring G is

[0330] In some embodiments, Ring

[0331] In some embodiments, Ring G is

[0332] In some embodiments, Ring

[0333] In some embodiments, Ring G is 6 membered monocyclic heteroaryl comprising1-3 heteroatom independently selected from N, O, S.

[0334] In some embodiments, Ring G is 6 membered monocyclic heteroaryl comprising one nitrogen atom as a heteroatom.

[0336] In some embodiments, Ring G is selected from

[0337] In some embodiments, Ring G is selected from

[0338] In some embodiments, Ring G is

[0339] In some embodiments, Ring G is

[0340] In some embodiments, Ring G is 6 membered monocyclic heteroaryl comprising two nitrogen atoms as heteroatoms.

[0342] In some embodiments, Ring G is selected from,

[0346] In some embodiments, Ring

[0347] In some embodiments, Ring G is 8-10 membered bicyclic heteroaryl comprising 1- 3 heteroatom independently selected from N, O, S.

[0348] In some embodiments, Ring G is 8 membered bicyclic heteroaryl comprising 1-3 heteroatom independently selected from N, O, S.

[0349] In some embodiments, Ring G is 9 membered bicyclic heteroaryl comprising 1-3 heteroatom independently selected from N, O, S.

[0350] In some embodiments, Ring G is 9 membered bicyclic heteroaryl comprising 1 heteroatom selected from N, O, S.

[0351] In some embodiments, Ring G is 9 membered bicyclic heteroaryl comprising 2 heteroatoms independently selected from N, O, S.

[0352] In some embodiments, Ring G is 9 membered bicyclic heteroaryl comprising one oxygen atom and one nitrogen atom as heteroatoms.

[0353] In some embodiments, Ring G is

[0354] In some embodiments, Ring G is

[0355] In some embodiments, Ring

[0356] In some embodiments, Ring G is

[0357] In some embodiments, Ring G is

[0358] In some embodiments, Ring

[0359] In some embodiments, Ring G is 9 membered bicyclic heteroaryl comprising 3 heteroatoms independently selected from N, O, S.

[0360] In some embodiments, Ring G is 10 membered bicyclic heteroaryl comprising 1-3 heteroatom independently selected from N, O, S.

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

[0362] Table 2

[0363] In some embodiments, each R1is independently selected from halogen, C1-C6 alkyl, Ci-C6alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R8)2, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0364] In some embodiments, R1is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0365] In some embodiments, R1is C1-C6 alkyl.

[0366] In some embodiments, each R1is independently selected from methyl, ethyl, i- propyl, / / -propyl, z-butyl, / / -butyl, sec-butyl, tert-butyl.

[0367] In some embodiments, R1is methyl.

[0368] In some embodiments, R1is ethyl.

[0369] In some embodiments, R1is propyl.

[0370] In some embodiments, R1is / / -propyl.

[0371] In some embodiments, R1is / -propyl.

[0372] In some embodiments, R1is butyl.

[0373] In some embodiments, R1is / / -butyl.

[0374] In some embodiments, R1is / -butyl.

[0375] In some embodiments, R1is sec-butyl.

[0376] In some embodiments, R1is tert-butyl.

[0377] In some embodiments, R1is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0378] In some embodiments, R1is C1-C6 alkoxy.

[0379] In some embodiments, R1is -OCH3.

[0380] In some embodiments, R1is aryl optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0381] In some embodiments,

[0382] In some embodiments, each R2is independently selected from hydrogen, C1-C6 alkyl.

[0383] In some embodiments, R2is hydrogen.

[0384] In some embodiments, R2is C1-C6 alkyl.

[0385] In some embodiments, R2is 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 0.57.

[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, R3is selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl.

[0393] In some embodiments, R3is H.

[0394] In some embodiments, R3is C1-C6 alkyl.

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

[0396] In some embodiments, R3is selected from methyl, ethyl, zz-propyl, z-propyl, n- butyl, z-butyl, sec-butyl, tert-butyl, zz-pentyl, zz-hexyl.

[0397] In some embodiments, R3is methyl.

[0398] In some embodiments, R4is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkyl-N(R8)2, C1-C6 alkyl-OR8, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -N(R8)2, -OR8.

[0399] In some embodiments, R4is hydrogen.

[0400] In some embodiments, R4is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R8)2, -OR8.

[0401] In some embodiments, R4is C1-C6 alkyl.

[0402] In some embodiments, R4is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl .

[0403] In some embodiments, R4is selected from methyl, ethyl, zz-propyl, z-propyl, n- butyl, z-butyl, sec-butyl, tert-butyl, zz-pentyl, zz-hexyl.

[0404] In some embodiments, R4is methyl.

[0405] In some embodiments, R4is C1-C6 alkyl-N(R8)2

[0406] In some embodiments, R4is -CH2N(Rs)2.

[0407] In some embodiments, R4is -CH2CH2N(Rs)2.

[0408] In some embodiments, R4is -CH2CH2CH2N(R8)2.

[0409] In some embodiments, R4is -CH2CH2CH2CH2N(R8)2.

[0410] In some embodiments, R4is -CH2CH2CH2CH2CH2N(R8)2.

[0411] In some embodiments, R4is -CH2CH2CH2CH2CH2CH2N(R8)2.

[0412] In some embodiments, R4is selected from -C1-C6 alkyl-NH2, -C1-C6 alkyl- N(H)CH3, -CI-C6alkyl-N(CH3)2.

[0413] In some embodiments, R4is C1-C6 alkyl-NH2.

[0414] In some embodiments, R4is -CH2NH2.

[0415] In some embodiments, R4is -CH2CH2NH2.

[0416] In some embodiments, R4is -CH2CH2CH2NH2.

[0417] In some embodiments, R4is -CH2CH2CH2CH2NH2.

[0418] In some embodiments, R4is -CH2CH2CH2CH2CH2NH2.

[0419] In some embodiments, R4is -CH2CH2CH2CH2CH2CH2NH2.

[0420] In some embodiments, R4is -C1-C6 alkyl-N(H)CH3.

[0427] In some embodiments, R4is -Ci-Cs alkyl-N(CH3)2.

[0428] In some embodiments, R4is -CH2N(CH3)2.

[0429] In some embodiments, R4is -CH2CH2N(CH3)2.

[0430] In some embodiments, R4is -CH2CH2CH2N(CH3)2.

[0431] In some embodiments, R4is -CH2CH2CH2CH2N(CH3)2.

[0432] In some embodiments, R4is -CH2CH2CH2CH2CH2N(CH3)2.

[0433] In some embodiments, R4is -CH2CH2CH2CH2CH2CH2N(CH3)2.

[0434] In some embodiments, R4is C1-C6 alkyl-OR8.

[0435] In some embodiments, R4is -CH2-OR8.

[0436] In some embodiments, R4is -CH2-CH2-OR8.

[0437] In some embodiments, R4is -CH2-CH2-CH2-OR8.

[0438] In some embodiments, R4is -CH2-CH2-CH2-CH2-OR8.

[0439] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-OR8.

[0440] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-CH2-OR8.

[0441] In some embodiments, R4is C1-C6 alkyl-OH.

[0442] In some embodiments, R4is -CH2-OH.

[0443] In some embodiments, R4is -CH2-CH2-OH.

[0444] In some embodiments, R4is -CH2-CH2-CH2-OH.

[0445] In some embodiments, R4is -CH2-CH2-CH2-CH2-OH.

[0446] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-OH.

[0447] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-CH2-OH.

[0448] In some embodiments, R4is C1-C6 alkyl-OCHa.

[0449] In some embodiments, R4is -CH2-OCH3.

[0450] In some embodiments, R4is -CH2-CH2-OCH3.

[0451] In some embodiments, R4is -CH2-CH2-CH2-OCH3.

[0452] In some embodiments, R4is -CH2-CH2-CH2-CH2-OCH3.

[0453] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-OCH3.

[0454] In some embodiments, R4is -CH2-CH2-CH2-CH2-CH2-CH2-OCH3.

[0455] In some embodiments, R4is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, - N(R8)2, -OR8.

[0456] In some embodiments, R4is C3-C10 cycloalkyl.

[0457] In some embodiments, R4is cyclopropyl.

[0458] In some embodiments, R5is selected from H, C1-C6 alkyl.

[0459] In some embodiments, R5is hydrogen.

[0460] In some embodiments, R5is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0461] In some embodiments, R5is C1-C6 alkyl.

[0462] In some embodiments, R5is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0463] In some embodiments, R5is selected from methyl, ethyl, zz-propyl, z-propyl, n- butyl, z-butyl, sec-butyl, / ez7-butyl, zz-pentyl, zz-hexyl.

[0464] In some embodiments, R5is methyl.

[0465] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0466] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 3 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0467] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 4 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8..

[0468] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0469] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 6 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, Ci-Cs alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0470] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 7 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8.

[0471] In some embodiments, R6is selected from -OR8and C1-C6 halogenalkyl.

[0472] In some embodiments, R6is -OR8.

[0473] In some embodiments, R6is -OH.

[0474] In some embodiments, R6is -OC1-C6 alkyl.

[0475] In some embodiments, R6is selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.

[0476] In some embodiments, R6is -OCH3.

[0477] In some embodiments, R6is C1-C6 halogenalkyl.

[0478] In some embodiments, R6is monofluoro-C1-C6 alkyl.

[0479] In some embodiments, R6is difluoro-C1-C6 alkyl.

[0480] In some embodiments, R6is trifluoro-C1-C6 alkyl.

[0481] In some embodiments, R6is -CH2F.

[0482] In some embodiments, R6is -CHF2.

[0483] In some embodiments, R6is -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, R7is selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C10 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, R7is 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, R7is C1-C6 alkyl.

[0492] In some embodiments, R7is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0493] In some embodiments, R7is selected from methyl, ethyl, z?-propyl, / -propyl, n- butyl, / -butyl, sec-butyl, / c / 7-butyl, / / -pentyl, / / -hexyl.

[0494] In some embodiments, R7is methyl.

[0495] In some embodiments, R7is / -propyl.

[0496] In some embodiments, R7is / -butyl.

[0497] In some embodiments, R7is oxo.

[0498] In some embodiments, R7is 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, R7is C1-C6 alkoxy.

[0500] In some embodiments, R7is methoxy.

[0501] In some embodiments, R7is -OCH2CH3.

[0502] In some embodiments,

[0503] In some embodiments,

[0504] In some embodiments,

[0505] In some embodiments,

[0506] In some embodiments,

[0507] In some embodiments,

[0508] In some embodiments,

[0509] In some embodiments, R7is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl.

[0510] In some embodiments, R7is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0511] In some embodiments, R7is cyclohexyl.

[0512] In some embodiments, R7is selected from methyl, / -propyl, / -butyl, oxo, methoxy,, cyclohexyl.

[0513] In some embodiments, R6and R7together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle.

[0514] In some embodiments, R6and R7together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle.

[0515] In some embodiments, R6and R7together with the atoms to which they are attached and any intervening atoms, form a 6 membered heterocycle.

[0516] In some embodiments, R6and R7together with the atoms to which they are attached and any intervening atoms, form a 7 membered heterocycle.

[0517] In some embodiments, R6and R7together with the atoms to which they are attached and any intervening atoms, form an 8 membered heterocycle.

[0518] In some embodiments, each R8is independently selected from H, Ci-C& alkyl, C3- C10 cycloalkyl.

[0519] In some embodiments, R8is H.

[0520] In some embodiments, each R8is H.

[0521] In some embodiments, R8is C1-C6 alkyl.

[0522] In some embodiments, each R8is C1-C6 alkyl.

[0523] In some embodiments, each R8is independently selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0524] In some embodiments, R8is methyl.

[0525] In some embodiments, R8is ethyl.

[0526] In some embodiments, R8is propyl.

[0527] In some embodiments, R8is butyl.

[0528] In some embodiments, R8is pentyl.

[0529] In some embodiments, R8is hexyl.

[0530] In some embodiments, each R8is independently selected from H, methyl, ethyl, n- propyl, z-propyl, zz-butyl, sec-butyl, z-butyl, tert-butyl, zz-pentyl, zz-hexyl.

[0531] In some embodiments, R8zz-propyl.

[0532] In some embodiments, R8z-propyl.

[0533] In some embodiments, R8zz-butyl.

[0534] In some embodiments, R8sec-butyl.

[0535] In some embodiments, R8z-butyl.

[0536] In some embodiments, R8tert-butyl.

[0537] In some embodiments, R8zz-pentyl.

[0538] In some embodiments, R8zz-hexyl.

[0539] In some embodiments, R8is C3-C10 cycloalkyl.

[0540] In some embodiments, R8is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0541] In some embodiments, R8is cyclopropyl.

[0542] In some embodiments, R8is cyclobutyl.

[0543] In some embodiments, R8is cyclopentyl.

[0544] In some embodiments, R8is cyclohexyl.

[0545] In some embodiments, R8is cycloheptyl.

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

[0547] In some embodiments, the compound is of Formula (Cl):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N and from 1 to 3 X is N and all other variables are as defined herein.

[0551] In some embodiments, the compound is of Formula (I-AE-0):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N and 1-3 X is N and all other variables are as defined herein.

[0552] In some embodiments, the compound is of Formula (I-AE-O-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each X is independently selected from CH and N and 1-3 X is N and all other variables are as defined herein.

[0553] In some embodiments, the compound is of Formula (I-A):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 (I-A-0):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 (I-A-O-H):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 (I-A-O-H-M):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 (I-A-0-H-M-1):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 (I-A-O-H-M- 1 -a):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 (I-A-O-H-M-l-b):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 (I-A-O-H-M-l-c):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 (I-A-0-H-C1):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 (I-A-0-H-C1-1):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 (I-A-O-H-Cl-l-a):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 (I-A-0-H-C2):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 (I-A-0-H-C2-1):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 (I-A-0-H-C2-l-a):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 Formula (I-A-0-H-C3):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 (I-A-0-H-C3-1):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 (I-A-0-H-C3-l-a):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 (I-A-O-H-M-2):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 (I-A-0-H-M-2-a):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 (1-A-0-H-M-3):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 (I-A-O-H-M-4):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 (I-A-0-H-M-4-a):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 (I-A-0-H-M-5):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 (I-A-0-H-M-5-a):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 (I-A-O-H-M-6):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 (I-A-0-H-M-6-a):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 (I-A-O-H-M-7):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 (I-A-0-H-M-7-a):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 (I-A-0-H-M-8):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 (I-A-0-H-M-8-a):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 (I-A-O-H-M-9):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 (I-A-0-H-M-9-a):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 Formula (I-A-O-H-H):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 (I-A-O-H-H- 1):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 (I-A-0-H-H-l-a):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 (I-A-O-H-H-2):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 (I-A-0-H-H-3):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 (1-A-0-H-H-4):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 (I-A-0-H-H-5):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 (I-A-O-H-H-6):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 (I-A-O-H-H-7):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 (I-A-0-H-H-8):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 (I-A-O-H-H-9):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 Formula (I-A-O-H-F):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 (I-A-O-H-F- 1):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 (I-A-O-H-F-2):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 (I-A-0-H-F-3):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 (I-A-O-H-H-4):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 (I-A-O-H-H-5):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 (I-A-O-H-H-6):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 (I-A-O-H-H-7):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 (I-A-0-H-H-8):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 (I-A-O-H-H-9):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 (I-B):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 (I-B-0):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 (I-B-O-H):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 Formula (I-B-O-H-M):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 (I-B-0-H-M-1):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 (I-B-O-H-M-l-a):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 (I-B-O-H-M-l-b):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 (I-B-O-H-M-2):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 (I-B-0-H-M-3):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 (I-B-O-H-M-4):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 (I-B-0-H-M-5):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 (I-B-O-H-M-6):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 (I-B-O-H-M-7):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 (I-B-0-H-M-8):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 (I-B-O-H-M-9):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 Formula (I-B-O-H-H):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 (I-B-0-H-H-1):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 (I-B-O-H-H-2):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 (I-B-0-H-H-3):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 (I-B-O-H-H-4):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 (I-B-0-H-H-5):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 (I-B-O-H-H-6):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 (I-B-O-H-H-7):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 (I-B-0-H-H-8):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 (I-B-O-H-H-9):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 Formula (I-B-O-H-F):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 (I-B-0-H-F-1):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 (I-B-O-H-F-2):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 Formula (I-B-0-H-F-3):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 (I-B-O-H-F-4):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 (I-B-0-H-F-5):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 (I-B-O-H-F-6):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 (I-B-O-H-F-7):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 (I-B-0-H-F-8):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 (I-B-O-H-F-9):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 (I-C):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 (I-C-0):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 (I-C-O-H):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 Formula (I-C-O-H-M):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 (I-C-0-H-M-1):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 (I-C-O-H-M-l-a):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 (I-C-O-H-M-2):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 (1-C-0-H-M-3):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 (I-C-O-H-M-4):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 (I-C-0-H-M-5):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 (I-C-O-H-M-6):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 (I-C-O-H-M-7):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 (I-C-0-H-M-8):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 (I-C-O-H-M-9):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 Formula (I-C-O-H-H):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 (I-C-0-H-H-1):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 (I-C-O-H-H-2):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 (I-C-0-H-H-3):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 (I-C-O-H-H-4):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 (I-C-0-H-H-5):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 (I-C-O-H-H-6):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 (I-C-O-H-H-7):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 (I-C-0-H-H-8):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 (I-C-O-H-H-9):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 Formula (I-C-O-H-F):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 (I-C-O-H-F-l):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 (I-C-O-H-F-2):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 (I-C-0-H-F-3):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 (I-C-O-H-F-4):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 (I-C-0-H-F-5):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 (I-C-O-H-F-6):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 (I-C-O-H-F-7):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 (I-C-0-H-F-8):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 (I-C-O-H-F-9):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 (I-D):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 (I-D-0):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 (I-D-O-H):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 Formula (I-D-O-H-M):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 (I-D-0-H-M-1):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 (I-D-O-H-M-l-a):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 (I-E):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 (I-E-0):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 (I-E-O-H):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 Formula (I-E-O-H-M):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 (I-E-O-H-M- 1):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 (I-E-O-H-M-l-a):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 (I-E-O-H-M-l-b):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 (I-E-O-H-M-l-c):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):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):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 (1-FH-0-H):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 Formula (I-FH-O-H-M):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 (1-FH-0-H-M-1):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-O-H-M-l-a):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 (I-F):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 (I-F-0):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 (I-F-O-H):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 Formula (I-F-O-H-M):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 (I-F-0-H-M-1):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 (I-F-O-H-M-l-a):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 (I-F-0-H-M-l-b):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 (I-G):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 (I-G-0):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 (I-G-O-H):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 Formula (I-G-O-H-M):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 Formula (I-G-0-H-M-1):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 (I-G-O-H-M-l-a):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 (I-G-O-H-M-l-b):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 (I-G-0-H-M-l-c):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 (I-H):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 (I-H-0):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 (I-H-O-H):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 Formula (I-H-0-H-M):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 (I-H-0-H-M-1):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 (I-H-O-H-M-l-a):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):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 (1-1K-0):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-O-H):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 (1-1K-0-H-M):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-H-M-1):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-O-H-M-l-a):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-O-H-M-l-b):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-O-H-M-l-c):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-O-H-M-l-d):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH, NCI F and all other variables are as defined herein.

[0725] In some embodiments, the compound is of Formula (I-I):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 (1-1-0):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 (I-I-O-H):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 (I-I-0-H-M):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 (I-I-0-H-M-1):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 (I-I-O-H-M-l-a):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 (I-I-0-H-M-l-b):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 (I-J):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 (I-J-0):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 (I-J-O-H):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 (I-J-O-H-M):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 (I-J-O-H-M- 1):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 (I-J-0-H-M-l-a):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 (I-J-O-H-M-l-b):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 (I-K):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 (I-K-0):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 (I-K-O-H):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 Formula (I-K-O-H-M):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 (I-K-O-H-M-l):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 (I-K-O-H-M-l-a):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 (I-K-O-H-M-l-b):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 (I-K-O-H-M-l-c):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 (I-L):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 Formula (I-L-0):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 Formula (I-L-O-H):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 Formula (I-L-O-H-M):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 Formula (I-L-O-H-M- 1):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 Formula (I-L-O-H-M-l -a):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 Formula (LL-1):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 Formula (I-L-1H):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 Formula (I-L-1H-H):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 Formula (I-L-1H-H-M):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 Formula (I-L-l-H-M-1):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 Formula (I-L-l-H-M-l-a):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 Formula (I-L-lH-H-M-l-b):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 Formula (I-L-lH-H-M-l-c):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 Formula (I-L-1H-H-M-2):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 Formula (I-L-lH-H-M-2-a):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 Formula (I-L-1M):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 Formula (I-L-1M-H):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 Formula (I-L-1M-H-M):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 Formula (I-L-1M-H-M-1):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 Formula (I-L-lM-H-M-l-a):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 Formula (I-L-lM-H-M-l-b):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 Formula (I-L-lM-H-M-l-c):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 Formula (I-L-1H-M):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 Formula (I-L-1H-M-M):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 Formula (I-L-1H-M-M-1):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 Formula (I-L-lH-M-M-l-a):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 Formula (I-L-lH-M-M-l-b):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 (I-M):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 (I-M-2):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 Formula (I-M-2HM):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 Formula (I-M-2HM-H):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 Formula (I-M-2HM-H-M):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 (I-M-2HM-H-M-1):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 (I-M-2HM-H-M-l-a)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 (I-M-2HM-H-M-l-b)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 (I-M-3):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 (I-M-3H):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 (I-M-3H-H):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 Formula (I-M-3H-H-M):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 (I-M-3H-H-M-1):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 (I-M-3H-H-M-l-a)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 (I-K):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 (I-N-0):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 Formula (I-N-O-H):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 Formula (I-N-O-H-M):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 Formula (I-N-0-H-M-1):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 (I-N-O-H-M-l-a):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 (I-N-O-H-M-l-b):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):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-A-M):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-A-M-1):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-A-M-l-H):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-A-M-l-M):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-A-M-l-H-a):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-A-M-l-M-a):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-A-M-2):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 (11-A-M-2-H):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-A-M-2-M):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-A-M-2-H-a):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-A-M-2-M-a):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-A-M-3):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-A-M-3 -H):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-A-M-3-M):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-A-M-3-H-a):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-A-M-3-M-a):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-A-M-4):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-A-M-4 -H):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-A-M-4-M):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-A-M-4-H-a):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-A-M-4-M-a):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-A-M-5):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-A-M-5-H):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-A-M-5-M):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-A-M-5-H-a):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-A-M-5-M-a):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-A-M-6):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-A-M-6-H):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-A-M-6-M):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-A-M-6-H-a):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-A-M-6-M-a):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-A-M-7):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-A-M-7-H):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-A-M-7-M):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-A-M-7-H-a):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-A-M-7-M-a):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-A-M-8):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-A-M-8 -H):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-A-M-8-M):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-A-M-8-H-a):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-A-M-8-M-a):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R7is selected from C1-C6 alkyl, or two R7together with the atoms 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):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-B-M):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-B-M-1):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-B-M-l-H):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-B-M-l-M):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-B-M-l-H-a):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-B-M-l-M-a):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-B-M-2):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-B-M-2-H):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-B-M-2-M):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-B-M-2-H-a):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-B-M-2-M-a):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-B-M-3):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-B-M-3-H):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-B-M-3-M):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-B-M-3-H-a):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-B-M-3-M-a):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-B-M-4):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-B-M-4-H):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-B-M-4-M):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-B-M-4-H-a):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-B-M-4-M-a):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-B-M-5):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-B-M-5-H):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-B-M-5-M):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-B-M-5-H-a):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-B-M-5-M-a):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-B-H):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-B-H-1):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-B-H-l-H):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-B-H-l-M):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-B-H-l-H-a):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-B-H-l-M-a):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-B-H-2):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-B-H-2-H):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-B-H-2-M):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-B-H-2-H-a):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-B-H-2-M-a):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-B-H-3):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-B-H-3-H):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-B-H-3-M):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-B-H-3-H-a):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-B-H-3-M-a):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-B-H-4):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-B-H-4-H):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-B-H-4-M):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-B-H-4-H-a):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-B-H-4-M-a):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-B-H-5):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-B-H-5 -H):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-B-H-5-M):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-B-H-5-H-a):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-B-H-5-M-a):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):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-C-M):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-B-M-1):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-C-M-l-H):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-C-M-l-H-a):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):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-D-M):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-D-M-1):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-D-M-l-H):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-D-M-l-H-a):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-D-M-l-H-b):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-D-M-2):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-D-M-2 -H):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-D-M-2 -H-a):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-D-M-2-H-b):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):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-E-M):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-E-M-1):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-E-M-l-H):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-E-M-l-H-a):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):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-F-M):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-F-M-1):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-F-M-l-H):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-F-M-l-H-a):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):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-G-F):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-G-F-1):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-G-F-l-H):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 Formula (II-G-F-l-H-a):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):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-H-M):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-H-M-1):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-H-M-l-H):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-H-M-l-H-a):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):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-I-M):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-I-M-1):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-I-M-l-H):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-I-M-l-H-a):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-I-M-l-H-b):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-I-M- l-H-c):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):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-J-M):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-J-M-1):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-J-M-l-H):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-J-M-l-H-a):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-J-M-l-H-b):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-J-M-l-H-c):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0942] In some embodiments, the compound is of Formula (II-K-M):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0943] In some embodiments, the compound is of Formula (II-K-M-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0944] In some embodiments, the compound is of Formula (II-K-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0945] In some embodiments, the compound is of Formula (II-K-M-l-H-a):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-K-M-l-H-b):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):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-L-M):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 (ILL-M-1):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-L-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0951] In some embodiments, the compound is of Formula (II-L-M-l-H-a):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):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-M-M):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-M-M-1):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-M-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0956] In some embodiments, the compound is of Formula (II-M-M-1 -H-a):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):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-N-M):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-N-M-1):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-N-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0961] In some embodiments, the compound is of Formula (II-N-M-l-H-a):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-N-M-l-H-b):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):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0967] In some embodiments, the compound is of Formula (II-OP-M-l-H-a):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, 2 and all other variables are as defined herein.

[0969] In some embodiments, the compound is of Formula (II-OP-C1):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0972] In some embodiments, the compound is of Formula (II-OP-Cl-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0976] In some embodiments, the compound is of Formula (II-OP-C2- l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0980] In some embodiments, the compound is of Formula (II-OP-C3-l-H-a):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):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-O-M):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-O-M-1):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-0-M-1-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0985] In some embodiments, the compound is of Formula (II-O-M-l-H-a):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-O-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, 2 and all other variables are as defined herein.

[0987] In some embodiments, the compound is of Formula (II-O-C1):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0990] In some embodiments, the compound is of Formula (II-O-Cl-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0994] In some embodiments, the compound is of Formula (II-O-C2-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[0998] In some embodiments, the compound is of Formula (II-O-C3-l-H-a):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):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 (11-P-M):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-P-M-1):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-P-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1003] In some embodiments, the compound is of Formula (II-P-M-l-H-a):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 (11-P-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, 2 and all other variables are as defined herein.

[1005] In some embodiments, the compound is of Formula (II-P-C 1):ci), 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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1008] In some embodiments, the compound is of Formula (II-P-Cl-l-H-a):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein.[ion] In some embodiments, the compound is of Formula (II-P-C2-1-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1012] In some embodiments, the compound is of Formula (II-P-C2-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1016] In some embodiments, the compound is of Formula (II-P-C3-l-H-a):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):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-Q-M):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-Q-M-1):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-Q-M-l-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1021] In some embodiments, the compound is of Formula (II-Q-M-l-H-a):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-Q-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein c is an integer selected from 0, 1, 2 and all other variables are as defined herein.

[1023] In some embodiments, the compound is of Formula (II-Q-C 1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[1024] In some embodiments, the compound is of Formula (II-Q-C 1-1):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-C 1-1-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1026] In some embodiments, the compound is of Formula (II-Q-Cl-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1030] In some embodiments, the compound is of Formula (II-Q-C2-l-H-a):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):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):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):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and all variables are as defined herein.

[1034] In some embodiments, the compound is of Formula (II-Q-C3-l-H-a):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 described 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 described in Table 3 and prodrugs and pharmaceutically acceptable salts thereof.

[1037] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[1038] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[1039] In some embodiments, the compound is selected from the compounds described inTable 3Table 3. Certain examples of the compound of Formula I

[1040] In some embodiments, the compound is a neutral form (i.e., not a salt) of any one of the compounds described in Table 3.

[1041] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 3.

[1042] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 3.

[1043] In some embodiments, the compound is a sodium salt or potassium salt of any one of the compounds described in Table 3.

[1044] In some embodiments, the compound is a sodium salt of any one of the compounds described in Table 3.

[1045] In some embodiments, the compound is a potassium salt of any one of the compounds described in Table 3.

[1046] In some embodiments, the compound is a salt of any acid presented in the Table 4 and any one of the compounds described in Table 3.Table 4. Pharmaceutical acceptable acid forming salts with the Compound of Formula (I).

[1047] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 3.

[1048] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 3.

[1049] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 3.

[1050] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 3.

[1051] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 3.

[1052] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 3.

[1053] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 3.

[1054] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 3.

[1055] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 3.

[1056] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 3.

[1057] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) 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 described in Table 3 and prodrugs and pharmaceutically acceptable salts thereof.

[1059] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[1060] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[1061] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[1062] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally beprepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[1063] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[1064] In some embodiments, the 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 labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[1066] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described 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 described 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 described 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 described in Table 3.

[1070] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is 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 at 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% deuteriumincorporation), 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” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[1072] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a nondeuterium labeled reagent.

[1073] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[1074] In some embodiments, the compound is a18F labeled compound.

[1075] In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof.

[1076] In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[1077] It is understood that the18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,123I,129I,131I,1351,3S,34S,3’S, and / or36S labeled reagent for a non-isotope labeled reagent.

[1078] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,1251,129I,1311,1351,3S,34S,35S, and36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e g.,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certaintherapeutic advantages resulting from greater metabolic stability, e g., increased in vivo half-life or reduced dosage requirements.

[1079] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[1080] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be 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 and, for example, is 550 Daltons or less.

[1081] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[1082] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, 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 in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. Amixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[1084] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[1085] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (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” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[1087] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may 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 is also to be understood that not all atropic isomers may have the same level of activity.

[1089] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existenceto a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[1090] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[1091] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[1092] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I) or (II). Examples of tautomeric forms include keto- , enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci -nitro.keto enol enolate

[1093] As a non-limiting example of tautomerism of the compound of Formula (I) may be presented by compound 23:

[1094] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[1095] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoi somers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[1096] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[1097] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. 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. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[1099] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1100] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thusforming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.[HOI] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to 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 “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[1104] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a monohydrate, a di-hydrate, or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[1105] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, 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 may be determined by Karl Fischer analysis.

[1106] Compounds of any one of the Formulae disclosed herein containing an amine function may also form .V'-oxides. A reference herein to a compound of Formula (I) or (II) that contains an amine function also includes the A-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an A-oxide. Particular examples of A -ox ides are the / V-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. A-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, A-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[1107] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[1108] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.

[1109] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, 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 Pro-drugs”, by H. Bundgaard p. 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”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1110] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, V,V-(Ci-C6 al kyl)2 carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.[Uli] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N- ethyl-A-methylamine or di ethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2 -methoxy ethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.[1H2] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-l-ylmethyl and 4-(CI-C4 alkyl)piperazin- 1 -ylmethyl .

[1113] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).Method of Synthesizing the Compounds

[1114] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[1115] The compounds of Formula (1) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. 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 that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).[1H6] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.Preparation of Compounds[1H7] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures A, B, C or D which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.GENERAL PROCEDURE[1H8] In general, the compound of Formula (I) can be prepared using procedures A, B, C and D described herein.

[1119] According to the first possible option (A), the compound of the Formula (I) can be prepared using the sequence of the reaction presented below:Compound I

[1120] Other option (B) to prepare of the compound of the Formula (I) presented below:

[1121] Other option (C) to prepare of the compound of the Formula (I) presented below:

[1123] It is understood that any of substitutients R'-R7could be modified at any step of the synthetic route.

[1124] All reagents may be commercially available compounds itself or products of synthesis from commercially available reagents. For all intermediates preparation may be used one step or multi step synthetic procedures, including but not limited procedures described herein in preparative part.

[1125] It must be understood that any compound of Formula (I) prepared according to anyone of procedures A-D can be object for further modification led to obtain other compound of Formula (I).Biological Assays

[1126] Compounds designed, selected and / or optimized by methods described above, once produced, 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, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[1127] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, 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 techniques including, but not limited to, those described below.

[1128] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions

[1129] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae 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 a pharmaceutical composition comprising at least one compound selected from Table 3.

[1130] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product whichresults, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[1131] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), 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 comprising 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 a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[1133] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P- cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P- cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P- cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y- cyclodextrin, and trimethyl-y-cyclodextrin, and mixtures thereof.

[1134] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenedi aminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[1135] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethoniumchloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury 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, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury 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 include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture 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, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[1139] In order to adjust the formulation to an acceptable pH (typically a pH range of 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 modifying agent. The pH modifying agent istypically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[1140] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.[H41] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.[H42] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients 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, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[1143] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[1144] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.[H45] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[1146] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[1147] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a TYK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[1148] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a TYK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[1149] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine.Methods of Use

[1150] In some aspects, the present disclosure provides a method of inhibiting of 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.[H51] 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.[H52] 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.[H54] The compounds of the invention are inhibitors of TYK2. In some embodiments, the present invention is directed to a method of inhibiting of TYK2 by contacting TYK2 with a compound of the invention. The contacting can be carried out in vitro or in vivo. In some embodiments, the compounds of the invention can bind to JH2 domain of TYK2. In some embodiments, the present invention provides a method of inhibiting the activity of TYK2. In further embodiments, the present invention provides a method of inhibiting of TYK2, comprising contacting TYK2 with a compound of the invention.

[1155] The compounds of the invention are also useful in treating diseases associated with TYK2. For example, diseases and conditions treatable according to the methods of the 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 35 (IMD35); Cancer; Lymphoma; Primary Cutaneous Anaplastic Large Cell Lymphoma; Lymphoproliferative Syndrome X-Linked, 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 35 (IMD35); Cancer; Lymphoma; Primary Cutaneous Anaplastic Large Cell Lymphoma; Lymphoproliferative Syndrome X-Linked, 1 (XLP1); Polycythemia Vera (PV); Pneumonia.[H57] In some embodiments, the disease or disorder is an autoimmune decease.

[1158] In some embodiments, the autoimmune diseases, including: SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, atopic dermatitis.[H59] In some aspects, the present disclosure provides a method of treating or preventing an autoimmune decease 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 decease 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.[H61] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of TYK2 (e.g., 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 treating or preventing 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 a an autoimmune decease 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 decease in a subject in need thereof.

[1166] 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 inhibiting of TYK2 (e.g., in vitro or in vivo).[H67] 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 meliorating a disease or disorder disclosed herein.

[1168] 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 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 meliorating an autoimmune decease in a subject in need thereof.

[1170] 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 an autoimmune decease in a subject in need thereof.[H71] The present disclosure provides compounds that function as inhibitors of TYK2 (e g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of TYK2 in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[1172] In some embodiments, the TYK2 inhibitor is a compound of the present disclosure.

[1173] Effectiveness of compounds of the disclosure can be determined by industry- accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[1174] The present disclosure also provides a method of 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. In some embodiments, the subject is a human.Routes of Administration

[1176] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[1177] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[1178] Abbreviations used in the following examples and elsewhere herein are:ACN acetonitrile anh. anhydrous aq. aqueous br. broadBSA bovine serum albumin d dupletDCM dichloromethaneDIPEA / V,A-di isopropyl ethyl amineDMF / VA'-dimethyl formamideDMSO dimethyl sulfoxideDTT dithiothreitol h hour(s)HATH (l-[bis(dimethylamino)methylene]-17 / -l,2,3-triazolo[4,5- / >]pyridinium 3- oxide hexafluorophosphateHPLC high pressure (or performance) liquid chromatographyLCMS liquid chromatography mass spectrometry m multiplet M molar MHz megahertz min minutes NBS A-bromosuccinimide NMR nuclear magnetic resonance Pd(dppf)C12 [l ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) q quadruplet rt room temperature s singlet sat. saturated t temperature, triplet TBTU 2-( 1 H-Benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethylaminium tetrafluoroborate TFA trifluoroacetic acid THF tetrahydrofuran TRIS 2-amino-2-(hydroximethyl)propane-l,3-diol TsOH toluenesulfonic acid (e.g., / ?-TsOH) Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneEXAMPLESGeneral synthetical procedures and examples of the compound’s preparation.Synthesis of Building BlocksSynthesis of 4-((2-methoxy-3-(l-methyl-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-2- (pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P5)

[1179] Preparation 1. Ethyl 2-chloro-4-((2-methoxy-3-(l-methyl-lZ7-l,2,4-triazol-3- yl)phenyl)amino)pyrimidine-5-carboxylate (Pl)P1To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (490 mg, 2.22 mmol) in MeCN (5 mL) 2-methoxy-3-(l-methyl-17f-l,2,4-triazol-3-yl)aniline (450 mg, 2.20 mmol) and DIPEA (1.0 mL) were added at rt. The reaction was stirred for 3 h and then solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc : DCM = 3 : 2) to give Pl (785 mg, 92% yield) as a white solid.1H NMR (400 MHz, CDCh), 5: 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-(l-methyl-177-l,2,4-triazol-3- yl)phenyl)amino)-2- (pyri din-2 -ylamino)pyrimidine-5 -carboxylate (P2)To a solution of Pl (780 mg, 2.00 mmol) in dioxane (10 mb, degassed) 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) were added at rt under argon atmosphere. The solution was stirred at 100°C overnight, the mixture wascooled 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. 'H NMR (400 MHz, CDCh), 8: 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-(l-methyl-l / / -l,2,4-triazol-3-yl)phenyl)amino)-2- (pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P3)To a solution of P2 (165 mg, 0.37 mmol) in THF (8.5 mL) water (8.5 mL) and lithium hydroxide (18 mg, 0.75 mmol) were added at rt. The mixture was stirred for 12 h, concentrated and then purified by Cl 8 reverse phase column chromatography (5-100% MeOH in water containing 1% TFA) to give P3 (160 mg, quantitative yield) as a yellow solid. 'H NMR (400 MHz, MeOD-t / 4), 5: 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,lH), 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)

[1182] Preparation 4. 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (P4)l-Bromo-2-m ethoxy-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), Pd(dppf)2C12 (995 mg, 0.86 mmol) were stirred at reflux in 50 mb of dioxane for 18 h. The reaction mixture was diluted by ethyl acetate, washed with water, dried over Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 4) to give P4 (2.08 g, 41%). 'HNMR (400 MHz, CDCh), 5: 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-l,3,2-dioxaborolan-2-yl)aniline(P5)P4 P5Compound P4 (3.3 g. 11.8 mmol) was placed in two-neck round bottom flask before 100 mb of ethanol was added and system was purged with argon. Pd / C (10%, 1.25 g, 1.18 mmol) was added and stream of hydrogen was gurgled through solution for 24 h. Thesolution 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)2-Methoxy-3-(4,4,5,5-tetramethyl-l,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), Pd(PPh3)4 (649 mg, 0.56 mmol) were stirred at reflux in 50 mL of dioxane for 18 h under argon atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc 100%) to give P6 (769 mg, 34%).1HNMR (400 MHz, DMSO-d6), 5: 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)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 rt. The reaction mixture was stirred for 20 h and concentrated in vacuum. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 1) to give P7 (866 mg, 59% yield) as a white solid.XH NMR (400 MHz, DMSO-d6), 5: 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, .7 = 7.2 Hz, 3H).

[1186] Preparation 8. Ethyl 4-(2-methoxy-3-(pyrimidin-2-yl)phenylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylate (P8)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 solution of P7 (866 mg, 2.24 mmol) in dioxane (40 mL, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C overnight, the mixture was cooled and fdtered through a pad of celite. The fdtrate 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.XH NMR (400 MHz, DMSO-t76), 8: 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)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 rt. The reaction mixture was stirred overnight, was concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate wascentrifugated and dried to give P9 (103 mg, 63%) as a yellow solid. LCMS (Cl 8 column 20 x 2 mm, 2.5 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for lOmin, retention time 4.19 min). MS (ESI) m / z 416.35 [MH]+.Synthesis of 4-(2-methoxy-3 '-(octyloxy )biphenyl-3-ylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylic acid (P15)

[1188] Preparation 10. 2-Ethynyl-4-methyl-l-[2-(2-oxoimidazolidin-l-yl)ethyl]-l / 7- indole-5-carbaldehyde (PIO)l-Bromo-2-m ethoxy-3 -nitrobenzene (1.0 g, 4.32 mmol), 3-hydroxyphenylboronic acid (0.711 g, 5.19 mmol), 2N solution ofK2CO3(1.21 g, 8.64 mmol), Pd(PPh3)4(200 mg, 0.17 mmol) were stirred at reflux in 50 mL of toluene / ethanol mixture (50:50) for 18 h. The reaction mixture was filtered and concentrated. The product P10 was used in the next step without purification. flT NMR (400 MHz, DM SO- Jr.), 5: 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 (P11A solution of compound P10 (1 g, 4 mmol) and octyl bromide (0.866 g, 4.4 mmol) in acetonitrile was stirred at reflux with 1.14 g of K2CO3 (8 mmol) for 24 h. Inorganic compounds were filtered off after cooling to rt, the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 4) to give Pll (1410 mg, 97% yield). 'H NMR (400 MHz, DMSO-t / 6), 8: 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= 6.9 Hz, 3H).

[1190] Preparation 12. 2-Methoxy-3 '-(octyloxy )biphenyl-3 -amine (P12)Compound Pll (1.4 g. 4 mmol) was placed in two-neck round bottom flask before 100 mL of ethanol was added and system was purged with argon. Pd / C (10%, 400 mg, 0.4 mmol) was added and stream of hydrogen was gurgled through solution for 24 h. The solution was fdtered through a pad of celite. The fdtrate was then concentrated under reduced pressure. The product P12 (1.3 g, 99%) was used in the next step without purification.1H NMR (400 MHz, DMSO-t / r,), 8: 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- y 1 ami no)py ri mi dine-5 -carb oxy 1 ate (P 13)Ethyl 2,4-dichloropyrimidine-5-carboxylate (793 mg, 3.6 mmol) in ACN (10 mb) was mixed with 2-methoxy-3 '-(octyloxy )biphenyl-3 -amine (P12, 830 mg, 3.6 mmol) and DIPEA (2.0 mb) at rt. The reaction mixture was stirred for 20 h and concentrated in vacuum. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 2) to give P13 (1120 mg, 73% yield) as a white solid. 'H NMR (400 MHz, CDCh), 5: 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-(pyri din-2-ylamino)pyrimidine-5-carboxylate (P14)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 solution of P13 (500 mg, 0.97 mmol) in dioxane (10 mb, degassed) at rt under argon atmosphere After the solution was stirred at 85°C overnight, the mixture was cooled and filtered through a padof 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. 'H NMR (400 MHz, DMSO-d6), 5: 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)A solution of P14 (380 mg, 0.66 mmol) in THF (8.5 mb) was mixed with water (8.5 mb) and lithium hydroxide (84 mg, 2.0 mmol) at rt. The reaction mixture was stirred overnight, concentrated and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P15 (360 mg, quantitative yield) as a yellow solid. LCMS (Cl 8 column 20 x 2 mm, 2.5 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for lOmin, retention time 7.25 min). MS (ESI) m / z 542.3 [MH]+.Synthesis of 4-(2-methoxy-3 -(6-methoxypyri din-3 -yl)phenylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylic acid (P20)P20

[1194] Preparation 16. 2-Methoxy-5-(2-methoxy-3-nitrophenyl)pyridine (P16)P16 l-Bromo-2-m ethoxy-3 -nitrobenzene (1.0 g, 4.32 mmol), 6-m ethoxypyri din-3 -ylboronic acid (0.86 g, 5.63mmol), 2N solution of K2CO3 (1.21 g, 8.64 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) were stirred at reflux in 50 mb of toluene / ethanol mixture (50:50) for 18 h. The reaction mixture was filtered and concentrated. The product P16 was used without purification. ‘HNMR (400 MHz, DMSO-<76), 8: 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-methoxypyri din-3 -yl)aniline (P17)Compound P16 (1.01 g. 3.88 mmol) was placed in two-neck round bottom flask before 100 mb of ethanol was added and system was purged with argon. Pd / C (10%, 400 mg, 0.38 mmol) was added and stream of hydrogen was gurgled through solution for 24 h. Thesolution 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 purification. 'H NMR (400 MHz, DMSO-de), 8: 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-methoxypyri din-3 - yl)phenylamino)pyrimidine-5-carboxylate (P18)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 rt. The reaction mixture was stirred for 20 h and concentrated in vacuum. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 2) to give P18 (1101 mg, 73% yield) as a white solid. 'H NMR (400 MHz, DMSO- d6), 8: 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- (pyri din-2-y 1 ami no)py ri mi dine- 5 -carb oxy 1 ate (P 19)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 solution of P18 (400 mg, 0.97 mmol) in dioxane (40 mL, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C for 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. 'H NMR (400 MHz, DMSO-dis), 8: 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)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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P20 (73 mg, 72%) as a yellow solid. LCMS (Cl 8 column 20 x 2 mm, 2.5 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 5.01 min). MS (ESI) m / z 445.3 [MH]+.Synthesis of 4-(3'-(cyclohexylmethoxy)-2-methoxybiphenyl-3-ylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylic acid (P25)

[1199] Preparation 21. 3'-(Cyclohexylmethoxy)-2-methoxy-3-nitrobiphenyl (P21)A solution of compound PIO (1 g, 4 mmol) and (bromomethyl)cyclohexane (0.78 g, 4.4 mmol) in acetonitrile was stirred at reflux with 1.14 g of K2CO3 (8 mmol) for 24 h. Inorganic compounds were filtered off after cooling to rt, 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).LH NMR (400 MHz, DMSO-t / 6), 8: 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)Compound P21 (1.3 g, 3.8 mmol) was placed in two-neck round bottom flask before 100 mL of ethanol was added and system was purged with argon. Pd / C (10%, 500 mg, 0.4 mmol) was added and stream of hydrogen was gurgled through solution for 24 h. 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. ‘H NMR (400 MHz, DMSO-d6), 5: 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)Ethyl 2,4-dichloropyrimidine-5-carboxylate (565 mg, 2.6 mmol) in ACN (10 mL) was mixed with 2-3 '-(cy cl ohexylmethoxy)-2-methoxybiphenyl-3 -amine (P22, 830 mg, 2.6 mmol)) and DIPEA (2.0 mL) at rt. The reaction mixture was stirred for 20 h and concentrated in vacuum. The residue was purified by silica gel column chromatography (EtOAc : hexane = 1 : 3) to give P23 (1101 mg, 73% yield) as a white solid. 'H NMR (400MHz, CDCh), 8: 11.24 (s, 1H), 8.87 (s, 1H), 8.59 (dd, .7 = 8.0, 1.6 Hz, 1H), 7.34 (t, , / = 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)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 solution of P23 (400 mg, 0.81 mmol) in dioxane (10 mb, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C for 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. 'H NMR (400 MHz, CDCh), 8: 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)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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting solid was centrifugated and dried to give P25 (214 mg, quantitative yield) as a yellow solid. LCMS (Cl 8 column 20 x 2 mm, particle size 2.5 pm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3min, retention time 1.77 min). MS (ESI) m / z 526.5 [MH]+.Synthesis of l-(2,7-diazaspiro[3.5]non-2-yl)-7-(2,2,2-trifluoroethyl)phthalazine (P27)

[1204] Preparation 26. Ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenylamino)-2-((l-methyl-lH-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylate(P26)( I -methyl- l H-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 solution of Pl (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C overnight, the mixture was cooled and fdtered 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 P26 (275 mg, 24 % yield) as a white solid.1H NMR (400 MHz, DMSO- d6): 8 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-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)- 2-((l-methyl-lH-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylic acid (P27)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 rt. The reaction mixture was stirred overnight,concentrated and acidified with IM HC1 to pH = 6. The resulting solid was centrifugated and dried to give P27 (230 mg, 92% yield) as a yellow solid. LCMS (ESI) (Cl 8 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z calcd for C20H21N9O3 435.44; found, 436.2 [M + H]+, ty? = 4.15 min.Synthesis of 4-(2-methoxy-3-(l -methyl- 1H- 1,2, 4-triazol-3-yl)phenylamino)-2-(l -(1,3,5- trimethyl-lH-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylic acid (P29)

[1206] Preparation 28. Ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenylamino)-2-(l-(l,3,5-trimethyl-lH-pyrazol-4-yl)ethylamino)pyrimidine-5- carboxylate (P28)l-(l,3,5-trimethyl-lH-pyrazol-4-yl)ethanamine (118 mg, 0.77 mmol), cesium carbonate (292 g, 0.89mmol), Xantphos (22 mg, 0.04 mmol) and palladium acetate (8 mg, 0.04 mmol) were added to solution of Pl (150 mg, 0.38 mmol) in dioxane (20 mb, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C overnight, the mixture was cooled and filtered through a pad of celite. The filtrate was then concentrated under reducedpressure. The residue was purified by silica gel column chromatography (ethyl acetate : THF 50:50) to give P28 (88 mg, 45 % yield) as a white solid.XHNMR (400 MHz, DMSO- d6): 8 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-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)-2-(l-(l,3,5-trimethyl-lH-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylic acid (P29)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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P29 (100 mg, 55% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for lOmin) m / z 479.8 [M + H]+, fa = 4.17 min.Synthesis of 2-((l-Ethyl-3,5-dimethyl-lH-pyrazol-4-yl)methylamino)-4-(2-methoxy-3- (1 -methyl- 1H-1, 2, 4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P31)

[1208] Preparation 30. Ethyl 2-((l-ethyl-3,5-dimethyl-lH-pyrazol-4-yl)methylamino)-4-(2-methoxy-3-(l -methyl-lH-l,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate(P30)(l-ethyl-3,5-dimethyl-lH-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 solution of Pl (150 mg, 0.38 mmol) in dioxane (20 mL, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C overnight, the mixture was cooled and fdtered through a pad of celite. The fdtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : THF 50:50) to give P30 (88 mg, 45 % yield) as a white solid.XH NMR (400 MHz, DMSO-t / 6), 5: 10.94 (s, 1H), 8.93 (d, J = 8.9 Hz, 1H), 8.72 (d, J = 5.0 Hz, 1H), 8.62 (s,lH), 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, .7= 7.2 Hz, 3H), 1.226-1.20 (m, 5H).

[1209] Preparation 31. 2-((l-Ethyl-3,5-dimethyl-lH-pyrazol-4-yl)methylamino)-4-(2- methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid(P31)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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P31 (130 mg, 98% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 478.3 [M + H]+, fe = 4.18 min.Synthesis of 2-( 1 -(3,5-Dimethyl- 1 H-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)P33

[1210] Preparation 32. Ethyl 2-(l-(3,5-dimethyl-lH-pyrazol-l-yl)propan-2-ylamino)-4-(2-methoxy-3 -( 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)phenylamino)pyrimidine-5-carboxylate(P32)(l-Ethyl-3,5-dimethyl-lH-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 solution of Pl (150 mg, 0.38 mmol) in dioxane (20 mb, degassed) at rt under argon atmosphere. After the solution was stirred 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.XH NMR (400 MHz, DMSO-t76), 8: 10.90 (s, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.61 (s,lH), 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-(l-(3,5-Dimethyl-lH-pyrazol-l-yl)propan-2-ylamino)-4-(2- methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acidA 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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P33 (100 mg, 98% yield) as a yellow solid. LCMS (ESI) (Cl 8 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile + 0.1% TFA, gradient 5 to 87% for 10 min) m / z 478.5 [M + H]+, fa = 4.21 min.Synthesis of 2-{[l-(l,3-Dimethyl-l / / -pyrazol-4-yl)ethyl]amino}-4-{[2-methoxy-3-(5- methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P36)

[1212] Preparation 34. Ethyl 2-chloro-4-{[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl]amino} pyrimidine-5-carboxylate (P34)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-l,3,4-oxadiazol-2-yl)aniline (P59, 450 mg, 2.20 mmol) and DIPEA (1.0 mL) at rt. After the reaction was stirred for 3 h, 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.LH NMR (400 MHz, DMSO-t / e), 8: 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-{[l-(l,3-dimethyl-l / 7-pyrazol-4-yl)ethyl]amino}-4-{[2- methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P35)To a solution of P34 (500 mg, 1.28 mmol) in dioxane (10 mL, degassed) was added 1 -(1 ,3- dimethyl-l / / -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 rt under argon atmosphere. After the solution was stirred at 100°C for 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 (CHCh : MeOH = 95 : 5) to give P35 (568 mg, 89 % yield) as a white solid. LCMS (ESI) 493.5 [M + H]+, / R = 1.25 min.

[1214] Preparation 36. 2-{[l-(l,3-Dimethyl-177-pyrazol-4-yl)ethyl]amino}-4-{[2- methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P36)To a solution of P35 (568 mg, 1.15 mmol) in THF (8.5 mb) was added water (8.5 mb) and lithium hydroxide (240 mg, 5.72 mmol) at rt. After it was stirred for overnight, the mixture was concentrated and then acidified with diluted HC1. Precipitated solid was filtered and dried on air to give a yellow solid of P36 (0.52 g, 98%). LCMS (ESI) 465.5 [M + H]+, / R = 1.13 min.Synthesis of ethyl 2-{[2-(3,5-dimethyl-17 / -pyrazol-l-yl)-l-methylethyl]amino}-4-{[2- methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylate (P38)

[1215] Preparation 37. Ethyl 2-{[2-(3,5-dimethyl-17 / -pyrazol-l-yl)-l- methylethyl]amino}-4-{[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl]amino}pyrimidine-5-carboxylate (P37)To a solution of P34 (500 mg, 1.28 mmol) in dioxane (10 mL, degassed) was added 1 -(3,5- dimethyl-17 / -pyrazol-l-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 rt under argon atmosphere. After the solution was stirred at 100°C for 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 (CHC13: MeOH = 95 : 5) to give P37 (420 mg, 64 % yield) as a white solid. LCMS (ESI) 507.4 [M + H]+, fe = 1.28 min.

[1216] Preparation 38. 2-{[2-(3,5-Dimethyl-l / 7-pyrazol-l-yl)-l-methylethyl]amino}-4- {[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}pyrimidine-5-carboxylic acid (P38)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 rt. After it was stirred for overnight, the mixture was concentrated and then acidified with diluted HC1. Precipitated solid was filtered anddried on air to give a yellow solid of P38 (0.38 g, 95%). LCMS (ESI) 479.3 [M + H]+, fa = 1.06 min.Synthesis of 4-{[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}-2-{[(l- methyl-l / 7-pyrazol-4-yl)methyl]amino}pyrimidine-5-carboxylic acid (P40)

[1217] Preparation 39. Ethyl 4-{[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl]amino}-2- {[(1 -methyl- 17 / -pyrazol-4-yl)methyl]amino}pyrimidine-5- carboxylate (P39)To a solution of P34 (200 mg, 0.51 mmol) in dioxane (10 mL, degassed) was added [(1- methyl-l / / -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 rt under argon atmosphere. After the solution was stirred at 100°C for 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 (CHCh : MeOH = 95 : 5) to give P39 (230 mg, 96 % yield) as a white solid. LCMS (ESI) 465.4 [M + H]+, fe = 1.18 min.

[1218] Preparation 40 4-{[2-Methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}- 2-{ [( l -mcthyl- l / / -pyrazol-4-yl)mcthyl]amino}pyrimidinc-5-carboxylic acid (P40)To a solution of P39 (230 mg, 0.49 mmol) in THF (8.5 mb) was added water (8.5 mb) and lithium hydroxide (100 mg, 2.38 mmol) at rt. After it was stirred for overnight, the mixture was concentrated and then acidified with diluted HC1. Precipitated solid was filtered and dried on air to give a yellow solid of P40 (0.11 g, 51%). LCMS (ESI) 437.4 [M + H]+, / R = 1.15 min.Synthesis of 4-(2-m ethoxy-3 -( 1 -methyl- 1H- 1 ,2,4-triazol-3-yl)phenylamino)-2-( 1 -methyl- lH-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P42)

[1219] Preparation 41. Ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenylamino)-2-(l-methyl-lH-pyrazol-3-ylamino)pyrimidine-5-carboxylate (P41)l-methyl-lH-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 solution of Pl (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at rt under argon atmosphere. After the solution was stirred 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. 'H NMR (400 MHz, DMSO- d6), 5: 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-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)-2-(l -methyl- lH-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P42)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 rt. The reaction mixture was stirred overnight, concentrated, and acidified with IM HC1 to pH = 6. The resulting precipitate wascentrifugated and dried to give P42 (115 mg, 68% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 gm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 422.0 [M + H]+, ZR = 4.27 min.Synthesis of 4-(2-Methoxy-3 -(piperidin- 1 -yl)phenylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylic acid (P47)

[1221] Preparation 43. l-(2-Methoxy-3-nitrophenyl)piperidine (P43)l-Bromo-2-m ethoxy-3 -nitrobenzene (0.5 g, 2.16 mmol), piperidine (0.368 g, 4.32 mmol), CS2CO3 (1.40 g, 4.32 mmol), Pd3(dba)2 (99 mg, 0.108 mmol), XantPhos (62 mg, 0.108 mmol) were stirred at reflux in 50 mb of dioxane 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%).JHNMR (400 MHz, DMSO-t / r,), 5: 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- l-yl)aniline (P44)Compound P43 (210 mg. 0.88 mmol) was placed in two-neck round bottom flask before 100 mL of ethanol was added and system was purged with argon. Pd / C (10%, 200 mg, 0.20 mmol) was added and stream of hydrogen was gurgled through solution for 24 h. The solution was filtered through a pad of celite. The filtrate was then concentrated under reduced pressure. Product P44 (145 mg, 79%) was used in the next step without purification. ‘HNMR (400 MHz, DMSO-t / 6), 5: 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-chl oro-4-(2 -methoxy -3 -(piperi din- 1- yl)phenylamino)pyrimidine-5-carboxylate (P45)Ethyl 2,4-dichloropyrimidine-5-carboxylate (242mg, 1.1 mmol) in ACN (10 mL) was mixed with 2-methoxy-3-(piperidin-l-yl)aniline (P44, 280 mg, 1.35 mmol) and DIPEA (2.0 mL) at rt. After the reaction was stirred for 20 h, 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. 'H NMR (400 MHz, DMSO-tZs), 5: 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-l-yl)phenylamino)-2-(pyridin-2- ylamino)pyrimidine-5-carboxylate (P46)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 solution of P45 (200 mg, 0.51 mmol) in dioxane (40 mL, degassed) at rt under argon atmosphere. After the solution was stirred 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. 'H NMR (400 MHz, DMSO-t / 6), 8: 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, . / = 7.2 Hz, 1H), 7.21 (t, .7 = 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 -(piperi din- l-yl)phenylamino)-2-(pyri din-2- ylamino)pyrimidine-5-carboxylic acid (P47)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 rt. After it was stirred for overnight, the mixture was concentrated, acidified. Resulting solid was centrifugated and dried to give P47 (60 mg, 72%) as a yellow solid. LCMS (C18 column 20 x 2 mm, 2.5 pm, pore size 100 A,water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 4.91 min). MS (ESI) m / z 421.1 [MH]+.Synthesis of 4-((2-methoxy-3-(l-methyl-l / / -l,2,4-triazol-3-yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P49)

[1226] Preparation 48. Ethyl 4-((2-methoxy-3 -(1 -methyl- \H- 1,2, 4-triazol-3- yl)phenyl)amino)-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P48)A solution of Pl (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 reaction mixture was stirred at 100°C overnight, 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 P48 (213 mg, 24 % yield) as a white solid, 'l l NMR (400 MHz, CDCh), 8: 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).

[1227] Preparation 49. 4-((2-Methoxy-3-(l-methyl-17 / -l,2,4-triazol-3-yl)phenyl)amino)-2- (pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P49)A solution of P48 (165 mg, 0.37 mmol) in THF (8.5 mL) was mixed with water (8.5 mL) and lithium hydroxide (18 mg, 0.75 mmol) at rt. The reaction mixture was stirred overnight, concentrated and then purified by C18 reverse phase column chromatography (5-100% MeOH in water containing 1% TFA) to give P49 (160 mg, quantitative yield) as a yellow solid. 'H NMR (400 MHz, MeOD-J4), 8: 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,lH), 7.38-7.36 (m, 2H), 4.04 (s, 3H), 3.79 (s, 3H).Synthesis of 2-(3-tert-Butyl- 1 -methyl- lH-pyrazol-5-ylamino)-4-(2-methoxy-3-(l- methyl- 1H-1, 2, 4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P51)

[1228] Preparation 50. Ethyl 2-(3-te / 7-butyl-l-methyl-lH-pyrazol-5-ylamino)-4-(2- methoxy-3-(l -methyl- 1H-1, 2, 4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylate (P50)A solution of Pl (200 mg, 0.51 mmol), 3-tert-butyl-l-methyl-lH-pyrazol-5-amine (780 mg, 5.1 mmol), cesium carbonate (650 mg, 2.0 mmol), Xantphos (29 mg, 0.05 mmol) and palladium acetate (12 mg, 0.05 mmol) in dioxane (40 mL, degassed) was purged with argon. The reaction mixture was stirred at 85°C overnight, 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 P50 (140 mg, 54 % yield) as a white solid. 'H NMR (400 MHz, CDCU), 5: 11.19 (br. s, 1H), 8.74 (s, 1H), 8.29-8.27 (m, 1H), 8.11 (s, 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.06 (t, J= 8.0 Hz, 1H), 6.16 (s, 1H), 5.60 (dd, J = 6.2, 2.1 Hz, 1H), 4.39 (q, J= 7.2 Hz, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H).

[1229] Preparation 51. 2-(3- / er / -Butyl-l-methyl-lH-pyrazol-5-ylamino)-4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)pyrimidine-5-carboxylic acid (P51)A solution of P50 (140 mg, 0.28 mmol) in THF (8.5 mL) was mixed with water (8.5 mL) and lithium hydroxide (117 mg, 0.75 mmol) at rt. The reaction mixture was stirred overnight, concentrated and then purified by C18 reverse phase column chromatography(5-100% MeOH in water containing 1% TFA) to give P51 (70 mg, 53% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water- acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 478.3 [M + H]+, / R = 5.16 min.Synthesis of 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)-2-(6- methylpyridin-2-ylamino)pyrimidine-5-carboxylic acid (P53)

[1230] Preparation 52. Ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenylamino)-2-(6-methylpyridin-2-ylamino)pyrimidine-5-carboxylate (P52)A solution of Pl (250 mg, 0.64 mmol), 6-methylpyridin-2-amine (696 mg, 6.4 mmol), cesium carbonate (832 mg, 2.56 mmol), Xantphos (64 mg, 0.06 mmol) and palladium acetate (15 mg, 0.06 mmol) in dioxane (40 mb, degassed) was purged with argon. The reaction mixture was stirred at 85°C for overnight, 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 P52 (206 mg, 70 % yield) as a white solid. ’H NMR (400 MHz, CDCh), 5: 10.93 ( s, 1H), 8.93 (s, 1H), 8.69 (br. s, 1H), 8.56 (d, J= 7.4 Hz, 1H), 8.18-8.13(m, 3H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H),7.55 (t, J = 8.1 Hz, 1H), 7.21 (t, J= 8.0 Hz, 1H), 6.85 (d, J= 7.4 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 2.50 (s, 3H), 1.41 (t, J= 7.2 Hz, 3H).

[1231] Preparation 53. 4-(2-Methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)- 2-(6-methylpyridin-2-ylamino)pyrimidine-5-carboxylic acid (P53)To a solution of P52 (206 mg, 0.447 mmol) in THF (8.5 mL) water (8.5 mL) and lithium hydroxide (188 mg, 4.47 mmol) were added at rt. The reaction mixture was stirred overnight, concentrated and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P53 (150 mg, 77%) as a yellow solid. LCMS (ESI) (Cl 8 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 433.5 [M + H]+, / R = 4.39 min.Synthesis of ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)-2-(l- methyl-3-phenyl-lH-pyrazol-5-ylamino)pyrimidine-5-carboxylate (P55)

[1232] Preparation 54 Ethyl 4-(2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenylamino)-2-(l-methyl-3-phenyl-lH-pyrazol-5-ylamino)pyrimidine-5-carboxylate (P54)A solution of Pl (250 mg, 0.641 mmol), l-methyl-3-phenyl-lH-pyrazol-5-amine (1114 mg, 6.44 mmol), cesium carbonate (1105 mg, 3.4 mmol), Xantphos (35 mg, 0.06 mmol) and palladium acetate (13 mg, 0.06 mmol) in dioxane (40 mL, degassed) was purged with argon. The reaction mixture was stirred at 85°C overnight, 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 P54 (170 mg, 50 % yield) as a white solid.1HNMR (400 MHz, DMSO-t / 6), 5: 11.95 (br. s, 1H), 10.94 (s, 1H), 9.94 (br. s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 7.81-7.78 (m, 2H), 7.47-7.28 (m, 5H), 6.73 (s, 1H), 4.36 (q, J= 7.2 Hz, 2H), 3.94 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H), 1.34 (t, J = 12 Hz, 3H).

[1233] Preparation 55. 4-(2-Methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenylamino)-2-(l-methyl-3-phenyl-lH-pyrazol-5-ylamino)pyrimidine-5-carboxylic acid (P55)A solution of P54 (170 mg, 0.33 mmol) in THF (8.5 mL) was mixed with water (8.5 mL) and lithium hydroxide (136 mg, 3.28 mmol) at rt. The reaction mixture was stirred overnight, concentrated and acidified with IM HC1 to pH = 6. The resulting precipitate wascentrifugated and dried to give P55 (360 mg, quantitative yield) as a yellow solid. LCMS (C18 column 20 x 2 mm, 2.5 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 5.31 min). MS (ESI) m / z 498.5 [MH]+.Synthesis of 2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)aniline (P59)

[1234] Preparation 56. tert-Butyl 2-(2-methoxy-3-nitrobenzoyl)hydrazinecarboxylate(P56)A mixture of 2-methoxy-3-nitro-benzoic acid (4.2 g, 21.3 mmol), Zc / 7-butyl hydrazinecarboxylate (2.814 g, 21.3 mmol), TBTU (10.2 g, 32 mmol) and DIPEA (5.7 ml, 32 mmol) in DCM (200 ml) was stirred at rt overnight. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (hexane / Et2O 1 : 1) to provide P56 (5.8 g, 78% yield). 'H NMR (400 MHz, DMSO-t / e), 8: 10.16 (s, 1H), 9.05 (s, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.67 (d, J= 6.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 3.89 (s, 3H), 1.43 (s, 9H).

[1235] Preparation 57. 2-Methoxy-3 -nitrobenzohydrazide (P57)A solution of HC1 in 1,4-dioxane (3M, 20 ml) was added to a solution of P56 (4.4 g, 14.1 mmol) inDCM / MeOH 1 : 1 (100 ml) atrt, the reaction mass was stirred for 48 h. The formed precipitate was filtered, washed with Et2O and dried on air to provide the product P57 (2.5 g, 84% yield). ‘HNMR (400 MHz, DMSO-d6), 8: 11.60 (s, 1H), 8.09 (dd, J= 8.1, 1.7 Hz, 1H), 7.80 (dd, J= 7.7, 1.7 Hz, 1H), 7.44 (t, J= 7.9 Hz, 1H), 3.88 (s, 3H).

[1236] Preparation 58. 2-(2-Methoxy-3-nitrophenyl)-5-methyl-l,3,4-oxadiazole (P58)A mixture of P57 (2 g, 9.48 mmol), 1,1,1 -trimethoxy ethane (50 ml) and ammonium chloride (0.152 g, 2.84 mmol) was stirred at 150°C overnight. Then the reaction mass was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (hexane / EtOAc 2: 1, 1 : 1) to provide P58 (0.943 g, 42% yield). 'H NMR (400 MHz, DMSO-i / e), 8: 8.18 (dd, J= 17.2, 8.0 Hz, 2H), 7.54 (t, J= 8.0 Hz, 1H), 3.89 (s, 3H), 2.62 (s, 3H).

[1237] Preparation 59. 2-Methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)aniline (P59)A mixture of P58 (1.075 g, 4.57 mmol) and 10% Pd / C (0.1 g, 0.1 mass) in EtOH (50 ml) was stirred under flow of H2 at rt for 12 h. Then Pd / C was fdtered, the solvent from mother liquor was removed under reduced pressure to provide the product P59 (0.926 g, 99% yield). 'H NMR (400 MHz, DMSO-t / e), 8: 6.99 - 6.95 (m, 2H), 6.93 - 6.88 (m, 1H), 5.26 (s, 2H), 5.26 (s, 2H), 3.69 (s, 3H), 2.57 (s, 3H).Synthesis of 4- { [2-methoxy-3 -(5 -methyl -1,3 ,4-oxadiazol -2-yl)phenyl]amino } -2- (pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P61)

[1238] Preparation 60. Ethyl 4-{[2-methoxy-3-(5-methyl-l,3,4-oxadiazol-2- yl)phenyl]amino}-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P60)A mixture of P34 (1.365 g, 3.5 mmol), 2-aminopyridine (0.987 g, 10.5 mmol), palladium acetate (0.15 g, 0.66 mmol), Xantphos (0.45 g, 0.78 mmol) and cesium carbonate (1.71 g, 52.5 mmol) in 1,4-dioxane (50 ml) was stirred at 100°C overnight under argon atmosphere. The mixture was cooled and filtered through a pad of celite, the solvent from mother liquor was removed under reduced pressure. The residue was purified by column chromatography on silica gel (2-10% of MeOH in DCM) to provide the product P60 (0.243 g, 31% yield). ‘H NMR (400 MHz, DMSO-r / e), 8: 10.93 (s, 1H), 10.44 (s, 1H), 9.16 - 9.08 (m, 1H), 8.85 (s, 1H), 8.40 - 8.35 (m, 1H), 8.07 - 8.02 (m, 1H), 7.80 - 7.71 (m, 1H), 7.60 (d, J= 6.2 Hz, 1H), 7.32 (t, J= 8.2 Hz, 1H), 7.09 (s, 1H), 4.36 (q, J= 7.1 Hz, 2H), 3.85 (s, 3H), 2.61 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H).

[1239] Preparation 61 4-{[2-Methoxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]amino}- 2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P61)A solution of lithium hydroxide monohydrate (0.068 g, 1.63 mmol) in water (10 ml) was added to a suspension of P60 (0.243 g, 0.543 mmol) in THF (25 mb) at rt, the reaction mixture was stirred overnight. The solvents were removed under reduced pressure, the residue was dissolved in water (10 ml), the obtained solution was acidified to pH 5-6 with10% HC1, the formed precipitate was filtered, washed with water and dried under reduced pressure to provide the product P61 (0.209 g, 92%). LCMS (ESI) (Cl 8 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min) m / z 420.5 [M + H]+, / R = 1.08 min.Synthesis of 4-{[3-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-(pyridin-2- ylamino)pyrimidine-5-carboxylic acid (P65)

[1240] Preparation 62. 3-(l,3-Benzoxazol-2-yl)-2-methoxyaniline (P62)A mixture of P5 (1 g, 4 mmol), 2-chloro-l,3-benzoxazole (0.614 g, 4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) and cesium carbonate (3.25 g, 119 mmol) in 1,4-dioxane (50 ml) and water (20) was stirred at 100°C overnight under argon atmosphere. Then 200 ml of water was added, the product was extracted with DCM (2x100 ml). Combined organic layers were dried over NajSCh and evaporated. The residue was purified by column chromatography on silica gel (hexane / Et2O 2: 1, 1 : 1) to provide P62 (0.594 g, 62% yield). 'H NMR (400 MHz, DMSO-tfc), 5: 7.84 - 7.74 (m, 2H), 7.46 - 7.37 (m, 2H), 7.23 (dd, J= 7.7, 1.4 Hz, 1H), 7.01 (t, J= 7.8 Hz, 1H), 6.94 (dd, J = 7.9, 1.5 Hz, 1H), 5.26 (s, 2H), 3.78 (s, 3H).

[1241] Preparation 63. Ethyl 4-{[3-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2- chloropyrimidine-5-carboxylate (P63)A mixture of P62 (1.248 g, 5.2 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (1.149 g, 5.2 mmol) and DIPEA (1.84 ml, 10.4 mmol) in acetonitrile (5 mL) was stirred at rt overnight. The solvent was removed under reduced pressure, the residue was dissolved in DCM (50 ml), the obtained solution was washed with water, dried over NazSO-u the solvent was removed under reduced pressure. The residue was washed with Et20 and dried to provide the product P63 (1.529 g, 69% yield). ’H NMR (400 MHz, DMSO4), 5: 11.04 (s, 1H), 8.89 (s, 1H), 8.62 (d, J= 8.2 Hz, 1H), 7.93 - 7.78 (m, 3H), 7.46 (dt, J= 13.0, 7.7 Hz, 3H), 4.43 (q, J= 7.1 Hz, 2H), 3.92 (s, 3H), 1.38 (t, J= 7.1 Hz, 3H).

[1242] Preparation 64. Ethyl 4-{[3-(l,3-benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-(pyri din-2 -ylamino)pyrimidine-5-carboxylate (P64)A mixture of P63 (0.366 g, 0.861 mmol), 2-aminopyridine (0.243 g, 2.58 mmol), palladium acetate (0.05 g, 0.22 mmol), Xantphos (0.15 g, 0.26 mmol) and cesium carbonate (0.421 g, 1.29 mmol) in dioxane (25 ml) was stirred at 100°C overnight under argon atmosphere. The mixture was cooled and filtered through a pad of celite, the solvent from mother liquor was removed under reduced pressure. The residue was purified by column chromatography on silica gel (2-10% of MeOH in DCM) to provide the product P64 (0.155 g, 38% yield). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 483.7 [M + H]+, fa = 6.84 min.

[1243] Preparation 65. 4-{[3-(l ,3-Benzoxazol-2-yl)-2-methoxyphenyl]amino}-2-(pyri din-2 -ylamino)pyrimidine-5-carboxylic acid (P65)A solution of lithium hydroxide monohydrate (0.048 g, 1.97 mmol) in water (10 ml) was added to a suspension of P64 (0.095 g, 0.197 mmol) in THF (10 mb) at rt, the reaction mixture was stirred overnight. The solvents were removed under reduced pressure, the residue was dissolved in water (10 ml), the obtained solution was acidified to pH 5-6 with 10% HC1, the formed precipitate was filtered, washed with water and dried under reduced pressure to provide the product P65 (0.087 g, 91%). 'H NMR (400 MHz, DMSO-t / e), 8: 11.45 (s, 1H), 10.92 (s, 1H), 9.13 (s, 1H), 8.84 (s, 1H), 8.40 (s, 1H), 8.00 - 7.78 (m, 4H), 7.50-7.34 (m, 4H), 7.17 (s, 1H), 3.92 (s, 3H).Synthesis of 4-{[3-(5-isopropyl-l,3,4-oxadiazol-2-yl)-2-methoxyphenyl]amino}-2- (pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P71)

[1244] Preparation 66. 7V-Isobutyryl-2-methoxy-3 -nitrobenzohydrazide (P66)2-Methylpropanoyl chloride (1.37 g, 12.9 mmol) was added dropwise to a solution of P57 (2.46 g, 11.7 mmol) and DIPEA (6.2 ml, 35 mmol) in DCM (50 ml) at 10°C, the reaction mixture was stirred at rt for 3 h. The mixture was washed with 10% aq. HC1 (2x20 ml), theorganic layer was dried over Na2SO4, the solvent was removed under reduced pressure to provide the product P66 (2 g, 61% yield). ‘H NMR (400 MHz, DMSO-J6), 5: 10.29 (s, 1H), 9.98 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 3.93 (s, 3H), 3.34-3.23 (m, 1H), 1.08 (d, J= 6.7 Hz, 6H).

[1245] Preparation 67. 2-Isopropyl-5-(2-methoxy-3 -nitrophenyl)-!, 3, 4-oxadiazole (P67)A solution of 4-methylbenzenesulfonyl chloride (1.53 g, 8 mmol) in CH3CN (20 ml) was added dropwise to a solution of P66 (1.5 g, 5,34 mmol) and DIPEA (1.9 ml, 10.68 mmol) in CH3CN (50 ml) at 10°C, the reaction mixture was stirred at rt overnight. Some water was added and the mixture was acidified to pH 3-4 with 3% aq. HC1, the product was extracted with DCM (2x100 ml), the combined organic layers were dried over NazSCU, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane / Et2O 2: 1, 1 : 1) to provide the product P67 (1.2 g, 86% yield). 'l I NMR (400 MHz, DMSO-^e), 5: 8.25 (dd, J= 7.9, 1.6 Hz, 1H), 8.17 (dd, J = 8.1, 1.7 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 3.91 - 3.89 (m, 3H), 3.34-3.23 (m, 1H), 1.44 - 1.35 (m, 6H).

[1246] Preparation 68. 3-(5-Isopropyl-l,3,4-oxadiazol-2-yl)-2-methoxyaniline (P68)A mixture of P67 (1.2 g, 4.56 mmol) and 10% Pd / C (0.12 g, 0.1 mass.) in EtOH (50 ml) was stirred under flow of H2 at rt for 12 h. Then Pd / C was filtered, the solvent from mother liquor was removed under reduced pressure to provide P68 (1 g, 99% yield). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min) m / z 234.4 [M + H]+, fa = 1.15 min.

[1247] Preparation 69. Ethyl 2-chloro-4-{[3-(5-isopropyl-l,3,4-oxadiazol-2-yl)-2- methoxyphenyl]amino}pyrimidine-5-carboxylate (P69)A mixture of P68 (1 g, 4.3 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (0.948 g, 4.3 mmol) and DIPEA (1.5 ml, 8.6 mmol) in acetonitrile (50 mL) was stirred at rt overnight. The solvent was removed under reduced pressure, the residue was dissolved in DCM (50 ml), washed with water, dried over NazSCU. The solvent was removed under reduced pressure, the residue was washed with Et2O and dried to provide the product P69 (1.293 g, 72% yield).XH NMR (400 MHz, DMSO-de), 8: 11.00 (s, 1H), 8.88 (s, 1H), 8.60 (d, J= 8.1 Hz, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.42 (t, J= 8.1 Hz, 1H), 4.42 (q, J= 7.0 Hz, 2H), 3.85 (s, 3H), 3.34-3.23 (m, 1H), 1.44-1.34 (m, 9H).

[1248] Preparation 70. Ethyl 4-{[3-(5-isopropyl-l,3,4-oxadiazol-2-yl)-2- methoxyphenyl]amino}-2-(pyridin-2-ylamino)pyrimidine-5-carboxylate (P70)A mixture of P69 (1.293 g, 3.09 mmol), 2-aminopyridine (0.871 g, 9.27 mmol), palladium acetate (0.2 g, 0.89 mmol), Xantphos (0.6 g, 1.04 mmol) and cesium carbonate (1.51 g, 4.63 mmol) in 1,4-dioxane (50 ml) was stirred at 100°C overnight under argon atmosphere. The mixture was cooled and filtered through a pad of Celite, the solvent from mother liquor was removed under reduced pressure. The residue was purified by column chromatography on silica gel (2%, 5%, 10% of MeOH in DCM) to provide the product P70 (0.484 g, 33% yield). LCMS (ESI) (Cl 8 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water- acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min) m / z 476.4 [M + H]+, fa = 1.31 min.

[1249] Preparation 71. 4-{[3-(5-Isopropyl-l,3,4-oxadiazol-2-yl)-2- methoxyphenyl]amino}-2-(pyridin-2-ylamino)pyrimidine-5-carboxylic acid (P71)A solution of lithium hydroxide monohydrate (0.427 g, 10 mmol) in water (10 ml) was added to a suspension of P70 (0.484 g, 1.02 mmol) in THF (25 mL) at rt, the reaction mass was stirred overnight. The solvents were removed under reduced pressure, the residue was dissolved in water (10 ml), the obtained solution was acidified to pH 5-6 with 10% HC1, the formed precipitate was filtered, washed with water and dried under reduced pressure to provide the product P71 (0.14 g, 32%). LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min) m / z 448.5 [M + H]+, / R = 1.2 min.Synthesis of 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l-methyl-lH- pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P73)

[1250] Preparation 72. Ethyl 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l- methyl-lH-pyrazol-3-ylamino)pyrimidine-5-carboxylate (P72)1 -methyl- lH-pyrazol-3 -amine (679 mg, 7.0 mmol), cesium carbonate (919 mg, 2.82 mmol), Xantphos (44 mg, 0.07 mmol), and palladium acetate (16 mg, 0.07 mmol) were added to solution of P63 (300 mg, 0.77 mmol) in dioxane (50 mL, degassed) at rt under argon atmosphere. After the solution was stirred 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 P72 (230 mg, 71% yield) as a white solid. 'H NMR (400 MHz, DMSO- d6), 5: 11.35 (br. s, 1H), 8.74 (s, 1H), 8.41 (d, J= 6.8 Hz, 1H), 7.70 (d, 1H), 7.66-7.59 (m, 7H), 7.06 (t, J= 8.0 Hz, 1H), 4.35 (q, J= 7.2 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[1251] Preparation 73. 4-(3-(Benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l- methyl-lH-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (P73)A solution of P72 (230 mg, 0.47 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (199 mg, 4.7 mmol) at rt. The reaction mixture was stirred overnight,concentrated and acidified with IM HC1 to pH = 6. The resulting precipitate was centrifugated and dried to give P73 (197 mg, 91% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 458.6 [M + H]+, ZR = 5.56 min.Synthesis of 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l-(3,5-dimethyl- lH-pyrazol-l-yl)propan-2-ylamino)pyrimidine-5-carboxylic acid (P75)

[1252] Preparation 74. Ethyl 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l-(3,5-dimethyl-lH-pyrazol-l-yl)propan-2-ylamino)pyrimidine-5-carboxylate (P74)l-(3,5-dimethyl-lH-pyrazol-l-yl)propan-2-amine (358 mg, 2.34 mmol), cesium carbonate (760 mg, 2.34 mmol), Xantphos (35 mg, 0.06 mmol) and palladium acetate (13 mg, 0.06 mmol) were added to solution of P63 (250 mg, 0.586 mmol) in dioxane (50 mL, degassed) at rt under argon atmosphere. After the solution was stirred at 85°C for 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 P74 (230 mg, 71% yield) as a white solid. 'H NMR (400 MHz, DMSO-dis), 8: 10.98 (br. s, 1H), 8.91 (d, J = 6.8 Hz, 1H), 8.62 (s, 1H), 7.91- 7.77 (m, 4H), 7.49-7.34 (m, 3H), 5.70 (s, 1H), 4.59-4.46 (m, 1H), 4.33 (q, J= 7.2 Hz, 2H), 4.14-4.07 (m, 1H), 3.98-3.90 (m, 4H), 2.22-2.02 (m, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.14- 1.10 (m, 3H).

[1253] Preparation 75. 4-(3-(Benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l-(3,5- dimethyl-lH-pyrazol-l-yl)propan-2-ylamino)pyrimidine-5-carboxylic acid (P75)A solution of P74 (70 mg, 0.13 mmol) in THF (15 mL) was mixed with water (15 mL) and lithium hydroxide (54 mg, 1.3 mmol) at rt. The reaction mixture was stirred overnight, concentrated and acidified with IM HC1 to pH = 6. The resulting solid was centrifugated and dried to give P75 (60 mg, 91% yield) as a yellow solid. LCMS (ESI) (C18 column 100 x 4.6 mm, 5.0 pm, pore size 100 A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min) m / z 514.5 [M + H]+, fa = 5.40 min.Synthesis of 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l-(l,3,5-trimethyl- lH-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylic acid (P77)

[1254] Preparation 76. Ethyl 4-(3-(benzo[d]oxazol-2-yl)-2-methoxyphenylamino)-2-(l -(l,3,5-trimethyl-lH-pyrazol-4-yl)ethylamino)pyrimidine-5-carboxylate (P76)A solution of P63 (200 mg, 0.472 mmol), l-(l,3,5-trimethyl-lH-pyrazol-4-yl)ethanamine (721 mg, 4.72 mmol), cesium carbonate (614 mg, 1.89 mmol), Xantphos (35 mg, 0.06 mmol) and palladium acetate (13 mg, 0.06 mmol) in dioxane (40 mL, degassed) was purged with argon. Mixture was stirred at 85°C overnight, 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 P76 (250 mg, 97 % yield) as a white solid. ’H NMR (400 MHz, DMSO-d6): 8 10.97 (br s, 1H), 8.66 (s, 1H), 8.59 (d, J= 6.8 Hz, 1H), 8.23 (d, J= 7.1 Hz...

Claims

CLAIMSWhat is claimed is:

1. A compound of F ormul a (I) :or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, whereinRing Z is 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-4 heteroatom selected from N, O, S;Ring G is selected from aryl, 5-10 membered heterocyclyl comprising 1-3 heteroatom selected from N, O, S or 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatom selected from N, O, S; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, and N(R8)2, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl; or two R1together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heterocycle or heteroaryl, wherein heterocycle or heteroaryl optionally substituted with one or more substituents independently selected from halogen, Ci-C6alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8each R2is independently selected from hydrogen, C1-C6 alkyl;R3is selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;R4is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkyl-N(R8)2, C1-C6 alkyl-OR8, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R5is selected from H, C1-C6 alkyl; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R8)2, -OR8;R6is selected from -OR8, C1-C6 halogenalkyl;R7is selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C10 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; or R6and R7together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle; each R8is independently selected from H, C1-C6 alkyl, C3-C10 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; wherein, cycloalkyl is a mono or polycyclic saturated carbon rings containing 3-18 carbon atoms; aryl is a cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7- 12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B;heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.

2. The compound of claim 1, wherein the compound is of Formula (I-AE):or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein each X is independently selected from CH and N and 1-3 X is N.

3. The compound of claim 1, wherein the compound is of Formula (I-FH):or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, wherein Y is selected from O, S, NH.

4. The compound of claim 1, wherein the compound is of Formula (I-IK):or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, wherein W is selected from O, S, NH.

5. The compound of claim 1, wherein the compound is of Formula (I-L):or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

6. The compound of claim 1, wherein the compound is of Formula (I-M):or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

7. The compound of claim 1, wherein the compound is of Formula (LN):or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

8. The compound of claim 1, wherein the compound is of Formula (II- A), (II-B), (II- C), (ILD), (ILE), (ILF), (II-G), (II-H), (ILI), (II- J), (ILK), (ILL), (ILM), (ILN), (ILO), (II- P), (H-Q):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. A pharmaceutical composition comprising the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active agents.

12. A method of inhibiting of TYK2 in a cell, comprising contacting the cell with a compound of any one of claims 1-9 or a pharmaceutical composition of claim 10 or 11.

13. The method of claim 12, wherein the contacting is in vitro or in vivo.

14. A method for the treatment or prevention of a disease or disorder associated with TYK2 comprising administering to a subject in need thereof a compound of any one of claims 1-9 or a pharmaceutical composition of claim 10 or 11.

15. The method of claim 14, wherein the disease or disorder is selected from the group consisting of proliferative, metabolic, allergic, autoimmune and inflammatory diseases.

16. The method of claim 14, wherein the disease or disorder is selected from the group consisting of immunodeficiency, cancer, lymphoma, lymphoproliferative syndrome X- linked, 1 (XLP1), polycythemia vera (PV), pneumonia.

17. The method of claim 15, wherein the autoimmune disease is selected from the group consisting of including: SLE, type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, psoriasis, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, atopic dermatitis.

18. The method of any one of claims 12-17, wherein the subject is a mammal.

19. The method of claim 18, wherein the subject is a human.

20. A compound selected from:

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