Fused azoled as tyk2 inhibitors and uses thereof

Abstract

Described herein are compounds that are TYK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of TYK2 activity. Formula (I)

Description

TYK2 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No.63 / 504,718 filed May 26, 2023, and US Provisional Application No.63 / 602,921 filed November 27, 2023, each of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] The present invention relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2). Compounds of the present disclosure may inhibit certain cytokine signaling, for example IL-12, IL-23, and IFNα signaling. Additional aspects of the invention include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes useful in the synthesis of the compounds.

[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT3, STAT4, and STAT6. SUMMARY OF THE INVENTION

[0004] Compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the present disclosure are inhibitors of TYK2. In some embodiments, compounds are selective for TYK2 over other JAKs. For example, compounds may bind specifically to the pseudokinase domain (JH2) of TYK2 thereby enhancing selectivity over JAK family members. In some embodiments, a compound of the present disclosure may be an allosteric modulator or noncompetitive inhibitor of TYK2. In additional embodiments, a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders. In some embodiments, the compounds of the present disclosure penetrate the blood-brain barrier and interact with the central nervous system.

[0005] In one aspect, the present disclosure provides compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; V1is -NR5-, -O-, -S-, -S(=O)-, or -SO2-; R5is hydrogen, deuterium, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -S(=O)R17, -SO2R17, or - SO2N(R16)2; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, - C(=O)R6, -CO2R6, -C(=O)N(R6)2, -S(=O)R7, -SO2R7, or -SO2N(R6)2; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; R4is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8; each R8is independently halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstitutedor substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, - C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or - SO2N(R6)2; or two R8groups on adjacent atoms of Ring B are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; t is 1, 2, 3, or 4; or R4is -C(=O)R9, -C(=O)NR9R10, or -C(=O)OR9; R9is hydrogen, unsubstituted or substituted C1-C6alkyl, C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R10is hydrogen, C1-C6alkyl, or C1-C6fluoroalkyl; Z is -NR11-, -O-, -S-, -S(=O)-, or -SO2-; R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, - SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; B1is N or CR13a; B2is N or CR13b; R13aand R13bare each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, - SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2;R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; each R6is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R6on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; and each R7is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0006] In some embodiments, the compound is further defined as a compound of Formula (I-A):Formula (I-A) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, or 4; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; n is 0, 1, or 2; p is 0 or 1; V1is -NR5-, -O-, or -S-; R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, - CN, -OR6, -N(R6)2, or -SR6, wherein: each R6is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle,-CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0007] In some embodiments, the compound is further defined as a compound of Formula (I-B):Formula (I-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; andR14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0008] In another aspect, the present disclosure provides compounds of Formula (II):Formula (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 1 or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl;each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, and substituted deuteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -CH2CN, -OR15, -CH2OR15, -N(R15)2, -CH2N(R15)2, -SR15, and - CH2SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl.

[0009] In still another aspect, the present disclosure provides compounds of Formula (III):Formula (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: t is 1, 2, 3, or 4; Het is monocyclic heteroaryl; each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1- C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl;R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OR15, -N(R15)2, or -SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl.

[0010] In some embodiments of a compound of Formula (III), t is 1 or 2. In some embodiments, Het is pyrazolyl, imidazolyl, or pyridyl. In some embodiments, each R8is independently unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently methyl, 2-(dimethylamino)ethyl, 2-hydroxypropan-2-yl, 1- methylazetidin-3-yl, or morpholinopyridin-2-yl.

[0011] In yet another aspect, the present disclosure provides compounds of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1;Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, - N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0012] In another aspect, the present disclosure provides compounds of Formula (V):Formula (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl;or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl;R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0013] In some embodiments, the compound is further defined as:Formula (V-A) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0014] In some embodiments, the compound is further defined as:Formula (V-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0015] In some embodiments, the compound is further defined as:Formula (V-C) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0016] In some embodiments, the compound is further defined as:Formula (V-D) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0017] In some embodiments, the compound is further defined as:Formula (V-E) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0018] In some embodiments, the compound is further defined as:Formula (V-F) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; andR14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0019] In some embodiments of a compound disclosed herein, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments of a compound disclosed herein, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl. In some embodiments, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, or unsubstituted or substituted cycloalkyl. In some embodiments, R18is unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted cycloalkyl. In some embodiments, R18is hydrogen, methyl, or cyclopropyl. In some embodiments, R18is methyl or cyclopropyl.

[0020] In some embodiments of a compound disclosed herein, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, each R17is fluoro. In some embodiments, two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl. In some embodiments, two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0021] In some embodiments of a compound disclosed herein, Y1is hydrogen, methyl, or (methoxy)methyl. In some embodiments of a compound disclosed herein, Y1is hydrogen or methyl. In some embodiments of a compound disclosed herein, Y2is hydrogen, methyl, or (methoxy)methyl. In some embodiments, Y2is hydrogen or methyl. In some embodiments, Y1is methyl or (methoxy)methyl and Y2is hydrogen. In some embodiments, Y1is methyl and Y2is hydrogen. In some embodiments, Y1and Y2are both hydrogen. In some embodiments, Y1and Y2are taken together with the carbon atom to which they are attached to form a 3- to 6-membered monocyclic heterocycloalkane. In some embodiments, Y1and Y2are taken together with the carbon atom to which they are attached to form 3-oxetane.

[0022] In some embodiments of a compound disclosed herein, R1is unsubstituted or substituted C2-C6alkyl. In some embodiments, R1is ethyl, 2-methoxyethyl, 2-fluoroethyl, or 2,2-difluoroethyl. In some embodiments, R1is C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl. In some embodiments, R1is methyl, difluoromethyl, or trideuteromethyl. In some embodiments, R1is unsubstituted or substituted C1-C6alkyl. In some embodiments, R1is methyl or difluoromethyl. In some embodiments, R1is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is cyclopropyl or oxetan-3-yl. In some embodiments,R3is C1-C6deuteroalkyl. In some embodiments, R3is trideuteromethyl. In some embodiments, R11is C1-C6alkyl or C1-C6deuteroalkyl. In some embodiments, R11is methyl or trideuteromethyl.

[0023] In some embodiments of a compound disclosed herein, X1is N. In some embodiments, X1is CR12. In some embodiments, X2is CR12. In some embodiments, X3is CR12. In some embodiments, X3is N. In some embodiments, each R12is independently hydrogen or halogen. In some embodiments, each R12is independently hydrogen or fluoro. In some embodiments, R12is hydrogen. In some embodiments, R12is fluoro.

[0024] In some embodiments of a compound disclosed herein, B1is N. In some embodiments, R14is hydrogen or C1-C6alkyl. In some embodiments, R14is hydrogen.

[0025] In still another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

[0026] In yet another aspect, the present disclosure provides methods of treating a TYK2- mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0027] In another aspect, the present disclosure provides methods of treating an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0028] In some embodiments, the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

[0029] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0030] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated foradministration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule. In some embodiments, the pharmaceutical composition in the form of an ointment, a lotion, a cream, an oil, a gel, a transdermal patch, or other topical formulation. In additional embodiments, the pharmaceutical composition is in the form of a liquid solution, suspension, gel, depot, or other preparation that can be administered to the eye or surrounding tissue (e.g., eye drops).

[0031] Described herein are compounds of Formulae (I)–(V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof useful in the treatment of TYK2-mediated disorders. Described herein are compounds of Formulae (I)–(V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of an inflammatory or autoimmune disease. In some embodiments, the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the disease is selected from psoriasis, psoriatic arthritis, vitiligo, atopic dermatitis, alopecia, and hidradenitis suppurativa. In some embodiments, the disease is selected from interferonopathies such as, by way of example, Alcardi-Goutieres syndrome.

[0032] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formulae (I)–(V), or a pharmaceutically acceptable salt, or solvate thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation; and / or (e) administered by nasal administration; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[0033] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0034] In any of the embodiments disclosed herein, the mammal is a human.

[0035] In some embodiments, compounds provided herein are orally administered to a human.

[0036] Articles of manufacture, which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating TYK2, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating TYK2, are provided.

[0037] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0038] TYK2 activation has been linked to many diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.

[0039] In particular, IL-23 activation of TYK2 is associated with inflammatory diseases such as inflammatory bowel disease (IBD), Crohn's disease, celiac disease, and ulcerative colitis. As the downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behcet’s disease. TYK2 has also been associated with diseases and conditions of the skin, such as psoriasis, vitiligo, atopic dermatitis, hidradenitis suppurativa, scleroderma; or diseases and conditions of the eye, such as Sjögren’s syndrome, uveitis, and dry eye.

[0040] TYK2 is associated with respiratory diseases and conditions such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of the TYK2 / STAT6 pathway.

[0041] TYK2 is also associated with autoimmune diseases and conditions, such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinationdisorders. Various type I IFN signaling pathways dependent on TYK2 signaling have implicated TYK2 in SLE and other autoimmune diseases and conditions.

[0042] TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis.

[0043] TYK2 has also been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. These effects are largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects. However, studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 / STAT1 signaling to maintain cancer cell survival through upregulation of anti- apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases.

[0044] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Αβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Αβ administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients.

[0045] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

[0046] There is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased mobility across blood-brain barrier or with increased activity or increased selectivity over other JAK kinases (especially JAK2). In some embodiments, the present disclosure provides inhibitors of TYK2 that show increased mobility across the blood-brain barrier. In some embodiments, the TYK2 inhibitors show selectivity over JAK1, JAK2, and / or JAK3. In some embodiments, compounds with this selectivity (particularly over JAK2) deliver a pharmacological response that favorably treats one or more of the diseases or conditions described herein without the side-effects associated with the inhibition of JAK2. For example, compounds with increased activity or increased selectivity over other JAK kinases (especially JAK2). The present disclosure relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase2 (TYK2) and inhibit certain cytokine signaling, in particular IL-23 and IFNα signaling, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat certain autoimmune diseases, multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE), and other CNS demyelination disorders, and to intermediates and processes useful in the synthesis of the compounds.

[0047] In some embodiments, the TYK2 inhibitors described herein are used in the treatment of a disease or condition in a mammal. Compounds of the Present Disclosure

[0048] Compounds described herein, including pharmaceutically acceptable salts, tautomers, and solvates thereof, are inhibitors of TYK2. In some embodiments, compounds described herein are selective for TYK2 over other JAKs. In some embodiments, compounds described herein bind selectively / specifically to the pseudokinase domain (JH2) of TYK2. In some embodiments, a compound described herein binds to an allosteric site of TYK2. In additional embodiments, a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders. In some embodiments, the compounds described herein exhibit improved pharmacokinetic properties or blood-brain penetration compared to other TYK2 inhibitors. In some embodiments, the compounds described herein exhibit improved bioavailability, CNS exposure, potency, selectivity, stability, permeability, Breast Cancer Resistance Protein (BCRP) efflux profile, clearance rate, or partition coefficient compared to other TYK2 inhibitors, such as (S)-6- (cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide.

[0049] In some aspects, the present disclosure provides compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2;V1is -NR5-, -O-, -S-, -S(=O)-, or -SO2-; R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, - C(=O)R6, -CO2R6, -C(=O)N(R6)2, -S(=O)R7, -SO2R7, or -SO2N(R6)2; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; R4is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8; each R8is independently halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, - C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or - SO2N(R6)2; or two R8groups on adjacent atoms of Ring B are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; t is 1, 2, 3, or 4; or R4is -C(=O)R9, -C(=O)NR9R10, or -C(=O)OR9; R9is hydrogen, unsubstituted or substituted C1-C6alkyl, C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R10is hydrogen, C1-C6alkyl, or C1-C6fluoroalkyl; Z is -NR11-, -O-, -S-, -S(=O)-, or -SO2-;R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, - SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; B1is N or CR13a; B2is N or CR13b; R13aand R13bare each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, - SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; each R6is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R6on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; and each R7is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle,-CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0050] In some embodiments of a compound of Formula (I), Z is -NR11-, -O-, -S-, -S(=O)-, or - SO2-. In some embodiments, Z is -NR11-, -O-, -S-, or -SO2-. In some embodiments, Z is -NR11-, -O- , or -S-. In some embodiments, Z is -NR11- or -O-. In some embodiments, Z is -NR11- or -S-. In some embodiments, Z is -O- or -S-. In some embodiments, Z is -O-. In some embodiments, Z is -S- . In some embodiments, Z is -NR11-.

[0051] In some embodiments of a compound of Formula (I), B2is N or CR13b. In some embodiments, B2is CR13b. In some embodiments, B2is N.

[0052] In some embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8; or R4is -C(=O)R9, - C(=O)NR9R10, or -C(=O)OR9.

[0053] In some embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, unsubstituted or substituted bicyclic heterocycle, unsubstituted or substituted spirocyclic carbocycle, unsubstituted or substituted spirocyclic heterocycle, unsubstituted or substituted bridged carbocycle, or unsubstituted or substituted bridged heterocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8.

[0054] In some embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substitutedbicyclic heterocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8.

[0055] In some embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5- membered heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8.

[0056] In some embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted monocyclic 6-membered heteroaryl or an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 5- membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted phenyl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In some embodiments, R4is a Ring B that is an unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8.

[0057] In further embodiments of a compound of Formula (I), R4is a Ring B that is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In still further embodiments, R4is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8. In yet further embodiments, R4is a Ring B that is an unsubstituted orsubstituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with t instances of R8.

[0058] In some embodiments of a compound of Formula (I), t is 1, 2, 3, or 4. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1 or 3. In some embodiments, t is 2 or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0059] In some embodiments of a compound of Formula (I), or R4is -C(=O)R9, -C(=O)NR9R10, or -C(=O)OR9. In some embodiments, R4is -C(=O)R9or -C(=O)NR9R10. In some embodiments, or R4is -C(=O)R9or -C(=O)OR9. In some embodiments, or R4is -C(=O)NR9R10or -C(=O)OR9. In some embodiments, or R4is -C(=O)R9. In some embodiments, or R4is -C(=O)NR9R10. In some embodiments, or R4is -C(=O)OR9.

[0060] In some embodiments of a compound of Formula (I), R9is hydrogen, unsubstituted or substituted C1-C6alkyl, C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R9is unsubstituted or substituted monocyclic carbocycle. In some embodiments, R9is unsubstituted or substituted C3-C8 cycloalkyl. In some embodiments, R9is unsubstituted C3-C8 cycloalkyl. In some embodiments, R9is cyclopropyl.

[0061] In some embodiments of a compound of Formula (I), R9is substituted C3-C8cycloalkyl. In some embodiments, R9is substituted C3-C4cycloalkyl. In some embodiments, R9is substituted with n instances of R17. In some embodiments, each R17is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or - SO2N(R6)2. In some embodiments, each R17is independently deuterium, halogen, C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, - C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, or -NR6C(=O)R7. In some embodiments, each R17is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, or -N(R6)2. In some embodiments, each R17is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OH, - OR7, or -N(R6)2. In some embodiments, each R17is independently deuterium, halogen, -CN, -OH, - OR7, or -N(R6)2. In some embodiments, each R17is independently halogen. In some embodiments, each R17is fluoro.

[0062] In some embodiments of a compound of Formula (I), R10is hydrogen, C1-C6alkyl, or C1- C6fluoroalkyl. In some embodiments, R10is hydrogen or C1-C6fluoroalkyl. In some embodiments, R10is C1-C6alkyl or C1-C6fluoroalkyl. In some embodiments, R10is hydrogen or C1-C6alkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is C1-C6alkyl. In some embodiments, R10is C1-C6fluoroalkyl.

[0063] In some embodiments of a compound of Formula (I), the compound is further defined as a compound of Formula (I-A):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, or 4; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; n is 0, 1, or 2; p is 0 or 1; V1is -NR5-, -O-, or -S-; R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, - CN, -OR6, -N(R6)2, or -SR6, wherein: each R6is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein:each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0064] In some embodiments of a compound of Formula (I), the compound is further defined as a compound of Formula (I-A):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, or 4; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; n is 0, 1, or 2; p is 0 or 1; V1is -NR5-, -O-, or -S-;R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, - CN, -OR6, -N(R6)2, or -SR6, wherein: each R6is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0065] In some embodiments of a compound of Formula (I) or (I-A), q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0 or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0or 2. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, q and r are both 1.

[0066] In some embodiments of a compound of Formula (I) or (I-A), m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0067] In some embodiments of a compound of Formula (I) or (I-A), each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, - NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2. In some embodiments, each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, - NR6C(=O)R7. In some embodiments, each R2is independently deuterium, halogen, C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, - NR6C(=O)R7. In some embodiments, each R2is independently deuterium, halogen, C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, -OH, -OR7, or -N(R6)2.

[0068] In some embodiments of a compound of Formula (I) or (I-A), the compound is further defined as a compound of Formula (I-B): Formula (I-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1;R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0069] In some embodiments of a compound of Formula (I) or (I-A), the compound is further defined as a compound of Formula (I-B):Formula (I-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, -C(=O)N(R15)2, -CH2C(=O)N(R15)2, - N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, -CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, - SR15, -CH2SR15, -S(=O)R16, -CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or - CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N- containing heterocycle;each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0070] In another aspect, the present disclosure provides compounds of Formula (II):Formula (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 1 or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, and substituted deuteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -CH2CN, -OR15, -CH2OR15, -N(R15)2, -CH2N(R15)2, -SR15, and - CH2SR15;each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl.

[0071] In some embodiments, the compound of Formula (II) is further defined as:Formula (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 1 or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; each R17is fluoro; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, and substituted deuteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -CH2CN, -OR15, -CH2OR15, -N(R15)2, -CH2N(R15)2, -SR15, and - CH2SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl.

[0072] In still another aspect, the present disclosure provides compounds of Formula (III):Formula (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: t is 1, 2, 3, or 4; Het is monocyclic heteroaryl; each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1- C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OR15, -N(R15)2, or -SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl.

[0073] In some embodiments, the compound of Formula (III) is further defined as:Formula (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: t is 1, 2, 3, or 4; Het is monocyclic heteroaryl; each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1- C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OR15, -N(R15)2, or -SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl.

[0074] In some embodiments of a compound of Formula (III), t is 1, 2, 3, or 4. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1 or 3. Insome embodiments, t is 2 or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0075] In some embodiments of a compound of Formula (III), Het is Het is monocyclic heteroaryl. In some embodiments, Het is monocyclic 5-membered heteroaryl or monocyclic 6- membered heteroaryl. In some embodiments, Het is monocyclic 5-membered heteroaryl. In some embodiments, Het is pyrazolyl or imidazolyl. In some embodiments, Het is monocyclic 6- membered heteroaryl. In some embodiments, Het is pyridyl.

[0076] In some embodiments of a compound of Formula (III), each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted cycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted C1-C6alkyl. In some embodiments, each R8is independently methyl, 2-(dimethylamino)ethyl, or 2-hydroxypropan-2-yl. In some embodiments, each R8is independently unsubstituted or substituted cycloalkyl. In some embodiments, each R8is independently unsubstituted or substituted heterocycloalkyl. In some embodiments, each R8is independently1-methylazetidin-3-yl, or morpholinopyridin-2-yl.

[0077] In another aspect, the present disclosure provides compounds of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1;Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, - N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0078] In some embodiments, the compound of Formula (IV) is further defined as:Formula (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1;Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, - N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; each R17is fluoro; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0079] In still another aspect, the present disclosure provides compounds of Formula (V):Formula (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl;R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0080] In some embodiments, the compound of Formula (IV) is further defined as: Formula (V)or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl;wherein: R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1- C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0081] In some embodiments of a compound of Formula (V), the compound is further defined as:Formula (V-A) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0082] In some embodiments of a compound of Formula (V-A), the compound is further defined as:Formula (V-A) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0083] In some embodiments of a compound of Formula (V), the compound is further defined as:Formula (V-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0084] In some embodiments of a compound of Formula (V-B), the compound is further defined as:Formula (V-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0085] In some embodiments of a compound of Formula (V), the compound is further defined as:Formula (V-C) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0086] In some embodiments of a compound of Formula (V-C), the compound is further defined as:Formula (V-C) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0087] In some embodiments of a compound of Formula (V), the compound is further defined as:( ) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0088] In some embodiments of a compound of Formula (V-D), the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0089] In some embodiments of a compound of Formula (V), the compound is further defined as:Formula (V-E) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0090] In some embodiments of a compound of Formula (V), the compound is further defined as:Formula (V-F) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3- C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; andR14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

[0091] In some embodiments of a compound disclosed herein, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted cycloalkyl. In some embodiments, R18is hydrogen, unsubstituted or substituted C1-C6alkyl, or unsubstituted or substituted cycloalkyl. In some embodiments, R18is unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted cycloalkyl. In some embodiments, R18is unsubstituted or substituted C1-C6alkyl. In some embodiments, R18is unsubstituted C1-C6alkyl. In some embodiments, R18is methyl. In some embodiments, R18is unsubstituted or substituted cycloalkyl. In some embodiments, R18is cyclopropyl. In some embodiments, R18is hydrogen, methyl, or cyclopropyl. In some embodiments, R18is hydrogen.

[0092] In some embodiments of a compound disclosed herein, R9is . In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0 or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl. In some embodiments, each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted C3-C6cycloalkyl. In some embodiments, each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R17is fluoro. In some embodiments, two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0093] In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form 3- to 6-membered monocyclic heterocycloalkyl. In some embodiments, Y1and Y2are each independently hydrogen or C1-C6alkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form 3- to 6-membered monocyclic heterocycloalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, or C1-C6heteroalkyl. In some embodiments, Y1and Y2are each independently hydrogen or C1-C6alkyl. In some embodiments, Y1and Y2are each hydrogen. In some embodiments, Y1and Y2are each independently C1-C6alkyl. In some embodiments, Y1and Y2are each independently C1-C6heteroalkyl. In some embodiments, Y1and Y2are each independently hydrogen, methyl, or (methoxy)methyl. In some embodiments, Y1and Y2are each independently hydrogen or methyl. In some embodiments, Y1and Y2are each methyl. In some embodiments, Y1and Y2are taken together with the carbon atom to which they are attached to form 3- to 6- membered monocyclic heterocycloalkyl. In some embodiments, Y1and Y2are taken together with the carbon atom to which they are attached to form 3-oxetane.

[0094] In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl or C1-C6heteroalkyl. In some embodiments, Y1and Y2are each independently hydrogen or C1-C6alkyl, wherein at least one of Y1and Y2is C1-C6alkyl. In some embodiments, Y1and Y2are each independently hydrogen, methyl, or (methoxy)methyl, wherein at least one of Y1and Y2is methyl or (methoxy)methyl. In some embodiments, Y1and Y2are each independently hydrogen or methyl, wherein at least one of Y1and Y2is methyl.

[0095] In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1and Y2are each independently hydrogen, C1-C6alkyl, or C1-C6heteroalkyl. Insome embodiments, Y1and Y2are each independently hydrogen or C1-C6alkyl. In some embodiments, Y1and Y2are each independently hydrogen, methyl, or (methoxy)methyl. In some embodiments, Y1and Y2are each independently hydrogen or methyl. In some embodiments, Y1is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; and Y2is hydrogen. In some embodiments, Y1is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and Y2is hydrogen. In some embodiments, Y1is C1-C6alkyl, C1-C6deuteroalkyl, C1- C6fluoroalkyl, or C1-C6heteroalkyl; and Y2is hydrogen. In some embodiments, Y1is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and Y2is hydrogen. In some embodiments, Y1is C1-C6alkyl or C1-C6heteroalkyl and Y2is hydrogen. In some embodiments, Y1is C1-C6alkyl and Y2is hydrogen. In some embodiments, Y1is methyl or (methoxy)methyl and Y2is hydrogen. In some embodiments, Y1is methyl and Y2is hydrogen. In some embodiments, Y1is hydrogen; and Y2is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1is hydrogen; and Y2is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1is hydrogen; and Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1- C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1is hydrogen; and Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1is hydrogen and Y2is C1-C6alkyl or C1-C6heteroalkyl. In some embodiments, Y1is hydrogen and Y2is C1-C6alkyl. In some embodiments, Y1is hydrogen and Y2is methyl or (methoxy)methyl. In some embodiments, Y1is hydrogen and Y2is methyl. In some embodiments, Y1and Y2are both hydrogen.

[0096] In some embodiments, Y1is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y1is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y1is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl. In some embodiments, Y1is hydrogen or C1-C6alkyl. In some embodiments, Y1is hydrogen, methyl, or (methoxy)methyl. In some embodiments, Y1is hydrogen or methyl. In some embodiments, Y1is hydrogen. In some embodiments, Y1is methyl. In some embodiments, Y1is (methoxy)methyl.

[0097] In some embodiments, Y2is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y2is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y2is C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl. In some embodiments, Y2is C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, Y2is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl. In some embodiments, Y2is hydrogen or C1-C6alkyl. In some embodiments, Y2ishydrogen, methyl, or (methoxy)methyl. In some embodiments, Y2is hydrogen or methyl. In some embodiments, Y2is hydrogen. In some embodiments, Y2is methyl. In some embodiments, Y2is (methoxy)methyl.

[0098] In some embodiments, R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -S(=O)R7, -SO2R7, or - SO2N(R6)2. In some embodiments, R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle. In some embodiments, R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle. In some embodiments, R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl. In some embodiments, R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle. In some embodiments, R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl.

[0099] In some embodiments, R1is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted C1-C6deuteroalkyl. In some embodiments, R1is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is unsubstituted or substituted C1-C6alkyl. In some embodiments, R1is methyl, difluoromethyl, ethyl, 2-methoxyethyl, 2-fluoroethyl, or 2,2-difluoroethyl. In some embodiments, R1is C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl. In some embodiments, R1is methyl, or difluoromethyl, or trideuteromethyl. In some embodiments, R1is methyl or difluoromethyl. In some embodiments, R1is unsubstituted or substituted C1-C6deuteroalkyl. In some embodiments, R1is trideuteromethyl. In some embodiments, R1is unsubstituted or substituted cycloalkyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is oxetan-3-yl.

[0100] In some embodiments, R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is unsubstituted or substituted C2-C6alkyl or unsubstituted or substituted C2-C6deuteroalkyl. In some embodiments, R1is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl. In some embodiments, R1is unsubstituted or substituted C2-C6alkyl. In some embodiments, R1is ethyl, 2-methoxyethyl, 2- fluoroethyl, or 2,2-difluoroethyl. In some embodiments, R1is unsubstituted or substituted C2-C6deuteroalkyl.

[0101] In some embodiments, R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle. In some embodiments, R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, R11is hydrogen, C1- C6alkyl, or C1-C6deuteroalkyl. In some embodiments, R11is hydrogen or C1-C6alkyl. In some embodiments, R11is hydrogen or C1-C6deuteroalkyl. In some embodiments, R11is C1-C6alkyl or C1-C6deuteroalkyl. In some embodiments, R11is methyl or trideuteromethyl. In some embodiments, R11is hydrogen. In some embodiments, R11is C1-C6alkyl. In some embodiments, R11is methyl. In some embodiments, R11is C1-C6deuteroalkyl. In some embodiments, R11is trideuteromethyl.

[0102] In some embodiments, X1, X2, and X3are each independently CR12or N. In some embodiments, X1, X2, and X3are each CR12. In some embodiments, X1is N; and X2and X3are each independently CR12or N. In some embodiments, X1is N; and X2and X3are each CR12. In some embodiments, X1and X2are each independently CR12or N; and X3is N. In some embodiments, X1and X2are each CR12; and X3is N. In some embodiments, X1is CR12or N. In some embodiments, X1is CR12. In some embodiments, X1is N. In some embodiments, X2is CR12or N. In some embodiments, X2is CR12. In some embodiments, X2is N. In some embodiments, X3is CR12or N. In some embodiments, X3is CR12. In some embodiments, X3is N.

[0103] In some embodiments, each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2- C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, - OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2. In some embodiments, each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, - SO2R7, or -SO2N(R6)2. In some embodiments, each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted heterocycle. In some embodiments, each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl. In some embodiments, each R12is independently hydrogen, halogen, or unsubstituted or substituted C1-C6alkyl. In some embodiments, each R12is independently hydrogen or halogen. In some embodiments, each R12is independently hydrogen or fluoro. In some embodiments, at least one R12is hydrogen. In some embodiments, R12is hydrogen. In some embodiments, at least one R12is independently halogen. In some embodiments, R12is fluoro.

[0104] In some embodiments, B1is N or CR13a. In some embodiments, B1is N or CH. In some embodiments, B1is N. In some embodiments, B1is CR13a. In some embodiments, B1is CH. In some embodiments, B2is N or CR13b. In some embodiments, B2is N or CH. In some embodiments, B2is N. In some embodiments, B2is CR13b. In some embodiments, B2is CH.

[0105] In some embodiments, R13aand R13bare each independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, - S(=O)R7, -SO2R7, or -SO2N(R6)2. In some embodiments, R13aand R13bare each independently hydrogen, halogen, or unsubstituted or substituted C1-C6alkyl. In some embodiments, R13aand R13bare each independently hydrogen or halogen. In some embodiments, R13aand R13bare each hydrogen. In some embodiments, R13aand R13bare each independently halogen.

[0106] In some embodiments, R13ais hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, - CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2. In some embodiments, R13ais hydrogen, halogen, or unsubstituted or substituted C1-C6alkyl. In someembodiments, R13ais hydrogen or halogen. In some embodiments, R13ais hydrogen. In some embodiments, R13ais halogen. In some embodiments, R13bis hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2- C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, - OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or - SO2N(R6)2. In some embodiments, R13bis hydrogen, halogen, or unsubstituted or substituted C1-C6alkyl. In some embodiments, R13bis hydrogen or halogen. In some embodiments, R13bis hydrogen. In some embodiments, R13bis halogen.

[0107] In some embodiments, R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle. In some embodiments, R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl. In some embodiments, R14is hydrogen or C1-C6alkyl. In some embodiments, R14is hydrogen.

[0108] In some embodiments, the compound is further defined as:,or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0109] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0110] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0111] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0112] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0113] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0114] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0115] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0116] In some embodiments, the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0117] In some embodiments, the compound is further defined as: , , or ; or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0118] In some embodiments, the compound is further defined as: or ; or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0119] In yet another aspect, the present disclosure provides compounds of the formula:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0120] In still another aspect, the present disclosure provides compounds of the formula:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0121] The “or1” designation in the structures throughout this application refers to stereocenters which are arbitrarily assigned. Compounds are prepared as single stereoisomers (including relative stereochemistry to other stereocenters labeled with the “or1”) but absolute stereochemistry is notknown. For example, compounds with a single “or1” in the structure or either pure (R) or pure (S), not a racemic mixture.

[0122] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

[0123] In still another aspect, the present disclosure provides methods of treating a TYK2- mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0124] In yet another aspect, the present disclosure provides methods of treating an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

[0125] In some embodiments, compounds described herein have the following structure:.

[0126] In some embodiments, B1, B2, R1, R2, R3, R4, R14, V1, X1, X2, X3, Z, m, q, and r are as described herein.

[0127] In some embodiments, compounds described herein have the following structure:.

[0128] In some embodiments, V1and X3are as described herein. In some embodiments, V1and X3are as described in Table 1.

[0129] In some embodiments, compounds described herein have the following structure: .

[0130] In some embodiments, X3is as described herein. In some embodiments, X3is as described in Table 1.

[0131] In some embodiments, compounds described herein have the following structure: .

[0132] In some embodiments, , B1, R3, R11, R14, R17, X1, X2, X3, Y1, Y2, n, and p are as described herein.

[0133] In some embodiments, compounds described herein have the following structure: .

[0134] In some embodiments, , R17, X3, Y1, Y2, n, and p are as described herein. In some embodiments, , R17, X3, Y1, Y2, n, and p are as described in Table 2.

[0135] In some embodiments, compounds described herein have the following structure: .

[0136] In some embodiments, n, R2, R4, R6, R7, R10, X1, X2, X3, A1, A2, Ring A, R8, and p are as described herein.

[0137] In some embodiments, compounds described herein have the following structure:

[0138] In some embodiments, Het, t, and R8are as described herein. In some embodiments, Het, t, and R8are as described in Table 3.

[0139] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0140] Exemplary compounds described herein include the compounds described in the following Tables. All compounds disclosed herein containing a stereocenter were isolated as a single isomer obtained by chiral separation of the corresponding racemic mixture. Unless noted, absolute stereochemistry was not determined. Table 1:

[0141] Compounds in Table 1 are named: 97: 6-(cyclopropanecarboxamido)-4-((2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; and 98: 6-(cyclopropanecarboxamido)-4-((2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'- [1,2,3]triazolo[4,5-c]quinolin]-6'-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0142] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 1. Table 2:

[0143] Compounds in Table 2 are named: 8: rel-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((S)-2,4,5-trimethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 9: rel-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R)-2,4,5-trimethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 10: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R*)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 11: rel-6-((R)-2,2-difluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R)-2,4,5-trimethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide;12: rel-6-((R)-2,2-difluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((S)-2,4,5-trimethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 18: rel-(R)-6-(3,3-difluorocyclobutane-1-carboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 22: rel-6-((1s,3R)-3-fluorocyclobutane-1-carboxamido)-N-(methyl-d3)-4-(((S)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 23: rel-6-((1r,3R)-3-fluorocyclobutane-1-carboxamido)-N-(methyl-d3)-4-(((R)-2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 35: rel-4-(((R)-8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin- 6-yl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 36: rel-4-(((R)-8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin- 6-yl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 37: rel-4-(((R)-8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin- 6-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 38: rel-4-(((R)-8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin- 6-yl)amino)-6-((1S,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 41: 4-(((R*)-2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 42: 4-(((R*)-2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3- carboxamide; 53: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 54: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 63: rel-4-(((R)-8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)- 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)nicotinamide; 64: rel-4-(((R)-8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)- 6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)nicotinamide;65: rel-4-(((R)-8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)- 6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide; 66: rel-4-(((R)-8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)- 6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide; 77: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-ethyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 78: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-ethyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 79: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-ethyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 80: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-ethyl-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 81: rel-(R)-6-(cyclopropanecarboxamido)-4-((4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 82: rel-(R)-6-(cyclopropanecarboxamido)-4-((4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 83: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 84: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 89: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 90: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 100: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 101: rel-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R)-3,4,5-trimethyl- 4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 102: rel-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((S)-3,4,5-trimethyl- 4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 103: rel-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R)-3,4,5-trimethyl- 4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 104: rel-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((S)-3,4,5-trimethyl- 4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide;106: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide; 108: rel-4-((3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-6-((1R,2R)-2- fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide; 109: rel-4-((3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-6-((1R,2S)-2- fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide; 113: rel-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-((5-methyl-4,5- dihydropyrido[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 114: rel-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-((5-methyl-4,5- dihydropyrido[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 120: rel-6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((S)-3,4,5-trimethyl- 4,5-dihydropyrido[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 121: rel-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-(((R)-3,4,5-trimethyl- 4,5-dihydropyrido[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 122: rel-(R)-6-(cyclopropanecarboxamido)-4-((4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 123: rel-(R)-6-(cyclopropanecarboxamido)-4-((4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 130: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5-tetramethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 131: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide; 132: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,4,5-tetramethyl-4,5-dihydro-3H- imidazo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide; 133: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 134: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 135: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,5-trimethyl-3,5- dihydrospiro[imidazo[4,5-c][1,7]naphthyridine-4,3'-oxetan]-6-yl)amino)pyridazine-3-carboxamide; 136: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 137: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide;138: rel-(R)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 139: rel-(R)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 140: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrido[3,4- e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 141: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 142: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,5-trimethyl-3,5- dihydrospiro[imidazo[4,5-c][1,7]naphthyridine-4,3'-oxetan]-6-yl)amino)pyridazine-3-carboxamide; 143: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 144: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 145: rel-(R)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 146: rel-(R)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 147: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrido[3,4- e][1,2,3]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide; 148: 6-(cyclopropanecarboxamido)-4-((3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 149: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide; 150: (R)-6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 151: 6-(cyclopropanecarboxamido)-4-((3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 152: (S)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro-1H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 153: (R)-6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro-1H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 154: 6-(cyclopropanecarboxamido)-4-((1-(difluoromethyl)-5-methyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide;155: (S)-6-(cyclopropanecarboxamido)-4-((4-(methoxymethyl)-2,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 156: (R)-6-(cyclopropanecarboxamido)-4-((4-(methoxymethyl)-2,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 157: N-(methyl-d3)-6-((R)-spiro[2.3]hexane-1-carboxamido)-4-(((S)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 158: N-(methyl-d3)-6-((S)-spiro[2.3]hexane-1-carboxamido)-4-(((S)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide; 159: N-(methyl-d3)-6-((R)-spiro[2.4]heptane-1-carboxamido)-4-(((S)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 160: N-(methyl-d3)-6-((S)-spiro[2.4]heptane-1-carboxamido)-4-(((S)-2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 161: 6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-2,5-dimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 162: (S)-6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 163: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(2-fluoroethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 164: rel-(R)-6-(cyclopropanecarboxamido)-4-((2-(2,2-difluoroethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 165: (S)-6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-2,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 166: rel-(R)-6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 167: 6-(cyclopropanecarboxamido)-4-((3-(difluoromethyl)-2,5-dimethyl-4,5-dihydro-3H- imidazo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 168: (S)-6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,4,5-trimethyl-4,5-dihydro-3H- imidazo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 169: 6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,5-dimethyl-4,5-dihydro-3H-imidazo[4,5- c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 170: 6-(cyclopropanecarboxamido)-4-((2-cyclopropyl-3,5-dimethyl-4,5-dihydro-3H-imidazo[4,5- c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 171: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,3,5-trimethyl-3,5- dihydrospiro[imidazo[4,5-c]quinoline-4,3'-oxetan]-6-yl)amino)pyridazine-3-carboxamide;172: 6-(cyclopropanecarboxamido)-4-((3,5-dimethyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxalin- 6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 173: rel-(R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3,4,5-trimethyl-4,5-dihydro- [1,2,3]triazolo[1,5-a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide; 174: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-[1,2,3]triazolo[1,5- a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide; 175: rel-(R)-6-(cyclopropanecarboxamido)-4-((4,5-dimethyl-4,5-dihydro-[1,2,3]triazolo[1,5- a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0144] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 2. Table 3:

[0145] Compounds in Table 3 are named: 176: rel-(R)-N-(methyl-d3)-6-((1-(1-methylazetidin-3-yl)-1H-pyrazol-3-yl)amino)-4-((2,4,5- trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3- carboxamide; 13: rel-(R)-N-(methyl-d3)-6-((1-methyl-1H-pyrazol-3-yl)amino)-4-((2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 14: rel-(R)-6-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((2,4,5-trimethyl- 4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 15: rel-(R)-6-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamidee; 16: rel-(R)-N-(methyl-d3)-6-((1-methyl-1H-imidazol-4-yl)amino)-4-((2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide; 17: rel-(R)-6-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)amino)-N-(methyl-d3)-4-((2,4,5- trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3- carboxamide; and 19: rel-(R)-N-(methyl-d3)-6-((5-morpholinopyridin-2-yl)amino)-4-((2,4,5-trimethyl-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide.

[0146] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 3.

[0147] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0148] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0149] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley- VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0150] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formulae (I)–(V) with an acid. In some embodiments, the compound of Formulae (I)–(V) (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylicacid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0151] In some embodiments, a compound of Formulae (I)–(V) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0152] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formulae (I)–(V) with a base. In some embodiments, the compound of Formulae (I)– (V) is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formulae (I)–(V) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0153] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0154] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formulae (I)–(V), as well as active metabolites of these compounds having the same type of activity.

[0155] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formulae (I)–(V) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0156] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0157] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl,123I,124I,125I,131I,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0158] In some embodiments, the compounds of Formulae (I)–(V) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formulae (I)–(V) exists in the R configuration. In some embodiments, the compound of Formulae (I)–(V) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0159] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds of Formulae (I)–(V) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed bychromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0160] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0161] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[0162] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formulae (I)–(V) as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.

[0163] In some embodiments, any one of the hydroxyl group(s), amino group(s) and / or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0164] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0165] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0166] In some instances, heterocyclic rings may exist in tautomeric forms. In such situations, it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below. For example, pyridones could exist in the following tautomeric forms: , , and ; all of which are encapsulated within the group, “substituted pyridines.” Similarly, triazolones could exist in the following tautomeric forms, which include zwitterionic forms:, , and ; all of which are encapsulated within the group, “substituted 5-membered heteroaryl.” Similarly, pyrazoles, triazoles, pyrimidines, and the like are known to tautomerize; for the purpose of this disclosure, all tautomeric forms (including charged and zwitterionic tautomers) are considered within the scope of the present disclosure. Synthesis of Compounds

[0167] Compounds of Formulae (I)–(V) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0168] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0169] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0170] In some embodiments, compounds described herein are prepared as described in Scheme A. Scheme A: variables are as defined in Formulae (I)–(V).

[0171] In some embodiments, nucleophilic substitution of one chloro group of intermediate A with the free amino group of B affords intermediate C. In some embodiments, for example when intermediate A is a pyridazine compound (B1= N), this substitution can be carried out with a suitable Lewis acid such as Zn(OAc)2. In other embodiments, for example when intermediate B is a pyridine compound (B1= CH), this substitution is carried out by deprotonation of the amino groupwith a suitable base, such as LDA. In still other embodiments, intermediate C may be accessed by a cross-coupling reaction of intermediates A and B. Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like. Finally, in some embodiments, intermediate C is converted to the final compound D (e.g., compound 1) via a cross-coupling reaction. Cross- coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.

[0172] In some embodiments, compounds are prepared as described in the Examples. Certain Terminology

[0173] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0174] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C6" indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0175] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0176] An “alkylene” group 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. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0177] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0178] The term “alkylamine” refers to the –N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0179] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a C1-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.

[0180] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a C1-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0181] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and –CH2CH=CH2.

[0182] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3-C≡CCH2CH3, - CH2C≡CH.

[0183] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

[0184] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0185] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclicfrom “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0186] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0187] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.

[0188] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0189] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

[0190] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C- attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0191] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1- C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6- C9heteroaryl.

[0192] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0193] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0194] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0195] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, - NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), - C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1- C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0196] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR18, -CO2R18, -C(=O)N(R18)2, -N(R18)2, - NR18C(=O)R19, -SR18, -S(=O)R19, -SO2R19, or -SO2N(R18)2; each R18is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R18groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R19is independently selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

[0197] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0198] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0199] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

[0200] The term “degrader” as used herein, refers to a bifunctional compound that binds to and / or inhibits both a TYK2 kinase and an E3 ubiquitin ligase resulting in the ubiquitination and subsequent degradation of the TYK2 kinase. In particular, in some instances, degraders are bifunctional or proteolysis-targeting chimeric (PROTAC®) protein degrader compounds, which find utility as modulators of targeted ubiquitination of TYK2 proteins, which are then degraded and / or inhibited by the bifunctional compounds. In some instances, such bifunctional molecules function by recruiting the TYK2 kinase to the E3 ubiquitin ligase for ubiquitination and subsequent degradation of the TYK2 kinase. The degrader comprises a TYK2 binding moiety (e.g., a group comprising a compound described herein) bound to an E3 ubiquitin ligase moiety, optionally through a linker.

[0201] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to thedesired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0202] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0203] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0204] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0205] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formulae (I)–(V), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formulae (I)–(V), or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0206] The terms “article of manufacture” and “kit” are used as synonyms.

[0207] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0208] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. Pharmaceutical Compositions

[0209] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0210] A compound or a pharmaceutical composition of the present disclosure is, in some embodiments, useful for the treatment of a TYK2 mediated disease or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder wherein TYK2 is overexpressed or hyperactive. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder which would benefit from a reduction in TYK2 activity or expression.

[0211] In some embodiments, the pharmaceutical composition is useful in the treatment of disease or disorder associated with high levels of cytokines driven by TYK2, such as interferons(e.g. IFN-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF. In some embodiments, the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratory disease or disorder, type 1 diabetes, and interferonopathies such as Alcardi-Goutieres syndrome, or combinations thereof.

[0212] In some embodiments, the pharmaceutical composition is useful in the treatment of an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is an auto-inflammatory disease or disorder, a host-mediated inflammatory disease or disorder, an injury- related inflammatory disease or disorder, an infection-related inflammatory disease or disorder, a hyperproliferative (e.g., cancer, fibrosis) mediated inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder or infection-related inflammatory disease or disorder is a respiratory disease or disorder. In some embodiments, the respiratory disease or disorder is associated with a viral in microbial infection. In some embodiments, the respiratory disease or disorder is a problematic immune response to a viral or microbial infection. In some embodiments, the respiratory disease or disorder is associated with a coronavirus such as MERS- CoV, SARS-CoV-1, or SARS-CoV-2. In some embodiments, the pharmaceutical composition is effective in decreasing symptoms associated with COVID-19, or an immune response associated therewith.

[0213] In some embodiments, the pharmaceutical composition is useful in the treatment of an autoimmune disease or disorders. In some embodiments, an autoimmune disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, an autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, an autoimmune disease or disorder is psoriasis. In some embodiments, an autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, an autoimmune disease or disorder is dry eye or uveitis. In some embodiments, an autoimmune disease or disorder is Crohn’s disease. In some embodiments, an autoimmune disease or disorder is atopic dermatitis.

[0214] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effectedby any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, topical application such as creams or ointments. Additional examples of local administration of the present compounds include eye drops, ocular creams, gels or hydrogels, implants, transdermal patches, or drug depots. In some embodiments, a pharmaceutical composition is administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, dry powder spray).

[0215] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0216] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee coresare provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0217] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0218] Pharmaceutical compositions may also be formulated as a depot preparation. Such long- acting formulations may be administered by implantation (for example subcutaneously). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0219] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0220] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0221] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0222] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. TYK2 and Central Nervous System (CNS) Disorders

[0223] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin), and interleukins (e.g. IL-6, IL-10, IL-12, IL-23, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF).

[0224] Mice containing the rs3456443 loss of function (LoF) mutation in the pseudokinase domain of TYK2 show a decreased risk of disease in EAE, with evidence showing that this is due to impaired IL-12, IL-23, and Type 1 IFN signaling (See, Dendrou et al, Sci Transl Med (2016)). Cytokine induced pSTAT phosphorylation by the rs3456443 genotype in primary human immune cells confirm a dose response for wild type – heterozygous – homozygous for IFN-α / β, IL-23, and IL-12, confirming that this is a TYK2 LoF mutation. This LoF mutation in TYK2 leads to decreased demyelination and increased remyelination of neurons, which supports the role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

[0225] Additionally, increased levels of IL-12 and IL-23 have been found in MS lesions, and IFN-γ and IL-17 are upregulated in active MS plaques (See, Windhagen et al, J Exp Med (1996); Li et al, Brain (2007); Tzartos et al, Am J Path (2008)). IL-12 and IL-23 are widely implicated in the pathogenesis of EAE: IL-12 p40 neutralizing mAb prevents clinical EAE; mice genetically deficient in IL-12 p40 or IL-23 p19 are resistant to EAE; and systemic injection of recombinant IL- 12 or intracerebral injection of an IL-23 encoding adenoviral vector induces clinical relapses ofEAE. Accordingly, use of a TYK2 inhibitor can interrupt this important pathology in MS and other CNS disorders.

[0226] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide, which demonstrates its role in potential treatment of Alzheimer’s Disease (AD). Decreased TYK2 phosphorylation of STAT3 following Aβ administration leads to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. (See, Wan et al., J. Neurosci. (2010) 30(20):6873-6881).

[0227] In some embodiments, certain TYK2 inhibitors described herein penetrate the blood-brain barrier. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of more than 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean brain:plasma ratio of about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or more.

[0228] In some embodiments, the compounds of this disclosure are useful in neuroinflammatory diseases and conditions. In some embodiments, neuroinflammatory diseases and conditions include, but are not limited to, multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder. In some embodiments, compounds of the instant disclosure are useful in the treatment of multiple sclerosis (MS). In some embodiments, the MS is relapsing MS or relapsing-remitting MS (RRMS). In some embodiments, compounds of the instant disclosure are useful in the treatment of a neuromyelitis optica spectrum disorder, such as neuromyelitis optica. In some embodiments, compounds of the instant disclosure are useful in the treatment of encephalomyelitis, including acute disseminated encephalomyelitis. In some embodiments, compounds of the instant disclosure are useful in the treatment of polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy. In some embodiments, compounds of the instant disclosure are useful in the treatment of encephalitis, including autoimmune encephalitis. Methods of Dosing and Treatment Regimens

[0229] In one embodiment, the compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of TYK2 activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of suchtreatment, involves administration of pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0230] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0231] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0232] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0233] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0234] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according tothe particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0235] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0236] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0237] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0238] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[0239] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[0240] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Treatments

[0241] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0242] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0243] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0244] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0245] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0246] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0247] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. EXAMPLES

[0248] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: Abbreviations: ACN acetonitrile CAN ceric ammonium nitrate DCM dichloromethane DIBAL diisobutylaluminum hydride DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acidES electrospray FBS fetal bovine serum GST glutathione S-transferase HEK human embryonic kidney HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HMDS bis(trimethylsilyl)amide HPLC high pressure liquid chromatography HTRF homogenous time resolved fluorescence IC50 half maximal inhibitory concentration IFN interferon IL interleukin IPA isopropyl alcohol JAK Janus kinase LCMS liquid chromatography-mass spectrometry MDI metered drug inhalant MW microwave NMR nuclear magnetic resonance SEAP secreted embryonic alkaline phosphatase STAT signal transducer and activator of transcription T3P propanephosphonic acid anhydride TBAF tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layer chromatography TYK non-receptor tyrosine-protein kinase

[0249] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Example 1: 4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-1):

[0250] Step-1: 1-(5-bromo-2-(methyl-d3)-2H-1,2,3-triazol-4-yl)ethan-1-one (I-1a): I-1a (4.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I- 21b (8.0 g, 32.8 mmol) and dimethylacetamide (14.3 g, 164.0 mmol) as the starting materials. LCMS (ES) m / z; 207.0 [M+H]+.

[0251] Step-2-3: tert-butyl (1-(5-bromo-2-(methyl-d3)-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-1c): I-1c (12.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-1a (10.0 g, 48.3 mmol) and methylamine hydrochloride (6.52 g, 96.6 mmol) as the starting materials. LCMS (ES) m / z;. [M+H]+.

[0252] Step-4: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-(methyl-d3)-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-1d): I-1d (4.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-1c (6.0 g, 18.6 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (8.16 g, 46.6 mmol) as the starting materials. LCMS (ES) m / z; 373.0 [M+H]+.

[0253] Step-5: 6-chloro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-1e): I-1e (2.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-1d (4.0 g, 10.75 mmol) as the starting material. LCMS (ES) m / z; 253.1 [M+H]+.

[0254] Step-6: N-(4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-1f): I-1f (5.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-1e (5.0 g, 19.78 mmol) and cyclopropanecarboxamide (3.4 g, 39.57 mmol) as the starting materials. LCMS (ES) m / z; 302.2 [M+H]+.

[0255] Step-7: 4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-1): I-1 (3.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-1f (5 g, 16.6 mmol) as the starting material. LCMS (ES) m / z; 234.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.2 Hz, 1H); 6.82 (d, J = 5.2 Hz, 1H); 5.82 (s, 2H); 4.35 (q, J = 7.2 Hz, 1H); 2.42 (s, 3H); 1.11 (d, J = 7.2 Hz, 3H).

[0256] Note: Racemate I-1 (2.4 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 21 mm x 5 μm); Mobile phase: n-Hexane:IPA (90:10); Flow rate: 40 mL / min)] to afford two enantiomers {I-1A (0.55 g): peak-1; Rt; 12.04 min and I-1B (0.55 g): peak- 2; Rt; 15.20 min}, which were used further without their absolute configuration determination. Example 2: 2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2):

[0257] Step-1-2: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl- d3)carbamate (I-2b): I-2b (15.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-24a (13.5 g, 66.2 mmol) and methylamine-d3hydrochloride (9.33 g, 132.0 mmol) as the starting materials. LCMS (ES) m / z; 322.1 [M+H]+.

[0258] Step-3: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl)(methyl-d3)carbamate (I-2c): I-2c (6.3 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-2b (14.0 g, 38.8 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (17.0 g, 96.9 mmol) as the starting materials. LCMS (ES) m / z; 373.0 [M+H]+.

[0259] Step-4: 6-chloro-2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-2d): I-2d (2.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-2c (7.0 g, 18.8 mmol) as the starting material. LCMS (ES) m / z; 253.1 [M+H]+.

[0260] Step-5: N-(2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-2e): I-2e (2.3 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-2d (2.6 g, 10.3 mmol) and cyclopropanecarboxamide (1.31 g, 15.4 mmol) as the starting materials. LCMS (ES) m / z; 302.3 [M+H]+.

[0261] Step-6: 2,4-dimethyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-2): I-2 (1.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-2e (2.4 g, 7.96 mmol) as the starting material. LCMS (ES) m / z; 234.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.2 Hz, 1H); 6.82 (d, J = 5.2 Hz, 1H); 5.82 (s, 2H); 4.35 (q, J = 7.2 Hz, 1H); 4.32 (s, 3H); 1.12 (d, J = 7.2 Hz, 3H).

[0262] Note: Racemate I-2 (1.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK OJ-H (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA (60:40); Flow rate: 40 mL / min)] to afford two enantiomers {I-2A (0.45 g): peak-1; Rt; 5.6 min and I-2B (0.45 g): peak-2; Rt; 6.82 min}, which were used further without their absolute configuration determination.Example 3: 2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3):

[0263] Step-1: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-2,2,2-d3-1-ol (I-3a): To a stirred solution of I-16b (5.0 g, 26.3 mmol) in anhydrous THF (50.0 mL) was added 1M solution of CD3MgI in Et2O (39.3 mL, 39.3 mmol) at -10 °C and the reaction mixture was allowed to warm to room temperature over 20 min. After complete consumption of starting material, it was quenched with addition of saturated NH4Cl solution (40 mL), and extraction was carried out using EtOAc (70 mL x 2). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution of 0-25% EtOAc in heptane) to afford desired compound 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-2,2,2-d3-1-ol I-3a (4.7 g) as a colourless liquid.1H NMR (400 MHz, DMSO-d6) δ 5.28 (d, J = 4.8 Hz, 1H); 4.77 (d, J = 4.8 Hz, 1H); 4.11 (s, 3H).

[0264] Step-2: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one-2,2,2-d3 (I-3b): To a stirred solution of I-3a (5.0 g, 23.9 mmol) in DCM (50.0 mL) was added DMP (13.2 g, 31.1 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction progress was monitored by LCMS. After completion, it was filtered through Celite bed and washed with DCM (100 mL x 2). The resulting filtrate was washed with saturated NaHCO3solution (50 mL), water (100 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% EtOAc in heptane) to afford desired compound 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one-2,2,2-d3 I-3b (4.3 g) as an off-white solid. LCMS (ES) m / z; 207.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 4.25 (s, 3H).

[0265] Step-3: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethan-2,2,2-d3-1-amine (I-3c): To a stirred solution of I-3b (6.5 g, 31.4 mmol) in THF (30 mL) was added titanium(IV) isopropoxide (18.6 mL, 63.0 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2in THF (78.5 mL, 157.0 mmol) and the reaction mixture was stirred at room temperature for 16 h. To this was then added NaBH4(2.37 g, 63.0 mmol) at 0 °C and the reaction mixture was then allowed to warm to room temperature over 2 h. After completion, saturated NaHCO3solution (50 mL) was added to it and washed with EtOAc (50 mL x 2). The aqueous NaHCO3solution containing 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethan-2,2,2-d3-1-amine I-3c was used in the next step without further purification. LCMS (ES) m / z; 222.0 [M+1H]+.

[0266] Step-4: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethyl-2,2,2- d3)(methyl)carbamate (I-3d): I-3d (5.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-3c (5.5 g, 24.75 mmol) as the starting material. LCMS (ES) m / z; 322.0 [M+H]+.

[0267] Step-5: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl-2,2,2-d3)(methyl)carbamate (I-3e): I-3e (3.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-3d (5.5 g, 17.05 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (7.5 g, 42.65 mmol) as the starting materials. LCMS (ES) m / z; 373.1 [M+H]+.

[0268] Step-6: 6-chloro-2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-3f): I-3f (4.4 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-3e (7.0 g, 18.8 mmol) as the starting material. LCMS (ES) m / z; 253.0 [M+H]+.

[0269] Step-7: N-(2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-3g): I-3g (1.75 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-3f (2.2 g, 8.7 mmol) and cyclopropanecarboxamide (1.48 g, 17.4 mmol) as the starting materials. LCMS (ES) m / z; 302.1 [M+H]+.

[0270] Step-8: 2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-3): I-3 (2.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-3g (3.0 g, 9.95 mmol) as the starting material. LCMS (ES) m / z; 234.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 5.2 Hz, 1H); 6.83 (d, J = 5.2 Hz, 1H); 5.84 (s, 2H); 4.34 (s, 1H); 4.20 (s, 3H); 2.42 (s, 3H).

[0271] Note: Racemate I-3 (2.8 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA (85:15); Flow rate: 40 mL / min)] to afford two enantiomers {I-3A (1.0 g): peak-1; Rt; 10.04 min and I-3B (1.0 g): peak-2; Rt; 12.26 min}, which were used further without their absolute configuration determination. Example 4: 2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I- 4):

[0272] Step-1: 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (I-4a): Argon gas was purged through a stirred suspension of I-21a (20.0 g, 88.2 mmol), cyclopropyl boronic acid (13.6 g, 159.0 mmol) and Na2CO3(18.7 g, 176.0 mmol) in DCE (200 mL) and 2-Me THF (200 mL) for 15 min. To this was then added Cu(OAc)2(12.8 g, 70.5 mmol) and 2,2′-bipyridine (11.0 g, 70.5 mmol). The reaction mixture was then stirred at 70 °C for 16 h in a sealed tube. It was then cooled to room temperature, filtered through celite bed and washed with EtOAc (50 mL x 3). The combined filtrate was washed with 200 mL of 1N HCl, brine (50 mL), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-5% EtOAc in hexane) to afford desired compound 4,5-dibromo-2-cyclopropyl-2H- 1,2,3-triazole I-4a (8.0 g) as a yellow liquid.1H NMR (400 MHz, DMSO) δ 4.13-4.16 (m, 1H); 1.05-1.12 (m, 2H); 0.74-0.77 (m, 2H).

[0273] Step-2: 5-bromo-2-cyclopropyl-2H-1,2,3-triazole-4-carbaldehyde (I-4b): I-4b (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-4a(5.0 g, 18.75 mmol) as the starting material.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H); 4.15- 4.09 (m, 1H); 1.47-1.43 (m, 2H); 1.23-1.17 (m, 2H).

[0274] Step-3-4: tert-butyl ((5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-4d): I-4d (2.2 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2 and 3) using I-4b (2.5 g, 11.6 mmol) and methyl amine hydrochloride (1.56 g, 23.1 mmol) as the starting materials. LCMS (ES) m / z; 331.1 [M+H]+.

[0275] Step-5: tert-butyl ((2-cyclopropyl-5-(2-fluoro-3-nitrophenyl)-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-4e): I-4e (1.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-4d (1.8 g, 5.44 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.21g, 8.16 mmol) as the starting materials. LCMS (ES) m / z; 392.1 [M+H]+.

[0276] Step-6: 1-(2-cyclopropyl-5-(2-fluoro-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)-N- methylmethanamine (HCl salt) (I-4f): To a stirred solution of I-4e (1.7 g, 4.34 mmol) in DCM (5.0 mL) was added a 4M solution of HCl in 1,4-dioxane (10.0 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature over 4 h (reaction progress was monitored by TLC). After completion, volatiles were removed under reduced pressure and saturated NaHCO3solution (20 mL) was added to the residue. Extraction was carried out using EtOAc (30 mL x 3); the combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-(2-cyclopropyl-5-(2-fluoro-3- nitrophenyl)-2H-1,2,3-triazol-4-yl)-N-methylmethanamine I-4f (1.5 g) as a yellow solid. LCMS (ES) m / z; 292.0 [M+H]+.

[0277] Step-7: 2-cyclopropyl-5-methyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinoline (I-4g): To a stirred solution of I-4e (1.5 g, 4.58 mmol) in 1,4-dioxane (10.0 mL) was added DIPEA (4.23 mL, 22.9 mmol) and the reaction mixture was allowed to stir at 85 °C for 3 h. After completion, it was cooled to room temperature and saturated NaHCO3solution (10 mL) was added to it. Extraction was carried out using DCM (2 x 50 mL); the combined organic extracts were washed with water (50 mL), brine (30 mL), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-15% EtOAc in heptane) to afford the desired compound 2-cyclopropyl-5-methyl-6-nitro-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c]quinoline I-4g (1.0 g) as an orange solid. LCMS (ES) m / z; 272.0 [M+H]+.

[0278] Step-8: 2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6- amine (I-4): To a stirred solution of I-4g (1.0 g, 3.69 mmol) and NH4Cl (1.97 g, 36.9 mmol) in EtOH (10.0 mL) and water (10.0 mL) was added Zn (2.41 g, 36.9 mmol) portion-wise at 0 °C. It was then allowed to stir at room temperature for 1 h. After completion, the reaction mixture wasfiltered off through celite bed and washed with EtOH (30 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-20% EtOAc in heptane) to afford desired compound 2-cyclopropyl-5-methyl-4,5- dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine I-4 (0.75 g) as an off-white solid. LCMS (ES) m / z; 242.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.92-6.85 (m, 2H); 6.65 (dd, J1 = 2.4 Hz, J2 = 7.6 Hz, 1H); 5.01 (s, 2H); 4.10 (s, 2H); 4.09-4.07 (m, 1H); 2.37 (s, 3H); 1.21-1.18 (m, 2H); 1.09- 1.06 (m, 2H). Example 5: Preparation of 2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-5):

[0279] Step-1: tert-butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-cyclopropyl-2H-1,2,3-triazol- 4-yl)methyl)(methyl)carbamate (I-5a): I-5a (3.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-4d (5.3 g, 16.0 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (7.01 g, 40.0 mmol) as the starting materials. LCMS (ES) m / z; 382.0 [M+H]+.

[0280] Step-2: 6-chloro-2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-5b): To a solution of I-5a (3.0 g, 7.86 mmol) in DCM (30.0 mL) was added TFA (3.0 mL) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. After completion, volatiles were removed under reduced pressure and dried (co-evaporation with 1,4- dioxane). To this was added 1,4-dioxane (20.0 mL) and DIPEA (7.92 mL, 39.1mmol) at room temperature. The reaction mixture was then stirred at 85 °C for 3 h. After completion, volatileswere removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-15% EtOAc in hexane) to afford the desired compound 6-chloro-2-cyclopropyl-5- methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine I-5b (1.0 g) as a yellow solid. LCMS (ES) m / z; 262.0 [M+H]+.

[0281] Step-3: N-(2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-5c): I-5c (0.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-5b (1.0 g, 3.82 mmol) and cyclopropanecarboxamide (0.49 g, 5.73 mmol) as the starting materials. LCMS (ES) m / z; 311.2 [M+H]+.

[0282] Step-4: 2-cyclopropyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-5): I-5 (0.4 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-5c (0.8 g, 2.58 mmol) as the starting material. LCMS (ES) m / z; 243.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 4.8 Hz, 1H); 6.79 (d, J = 4.8 Hz, 1H); 5.86 (s, 2H); 4.18 (s, 2H); 4.15-4.12 (m, 1H); 2.41 (s, 3H); 1.23-1.18 (m, 2H); 1.12-1.07 (m, 2H). Example 6: Preparation of 2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-6):

[0283] Step-1: 1-(5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4-yl)ethan-1-one (I-6a): I-6a (2.4 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-4a(4.0 g, 15.0 mmol) and dimethylacetamide (4.0 mL, 75.0 mmol) as the starting materials. LCMS (ES) m / z; 230.0 [M+H]+.

[0284] Step-2-3: tert-butyl (1-(5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-6c): I-6c (5.0.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-6a (4.5 g, 19.55 mmol) and methylamine hydrochloride (2.64 g, 39.1 mmol) as the starting materials. LCMS (ES) m / z; 344.9 [M+H]+.

[0285] Step-4: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-cyclopropyl-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-6d): I-6d (1.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-6c (5.0 g, 14.5 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (6.35 g, 36.2 mmol) as the starting materials. LCMS (ES) m / z; 340.1 [(M-tBu)+H]+.

[0286] Step-5: 6-chloro-2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-6e): I-6e (0.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-6d (1.2 g, 3.03 mmol) as the starting material. LCMS (ES) m / z; 276.1 [M+H]+.

[0287] Step-6: N-(2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-6f): I-6f (0.4 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-6e (0.6 g, 2.18 mmol) and cyclopropanecarboxamide (0.28 g, 3.26 mmol) as the starting materials. LCMS (ES) m / z; 325.2 [M+H]+.

[0288] Step-7: 2-cyclopropyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-6): I-6 (0.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-6f (0.7 g, 2.16 mmol) as the starting material. LCMS (ES) m / z; 257.2 [M+H]+.Example 7: Preparation of 8-fluoro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-7):

[0289] Step-1: tert-butyl methyl((2-methyl-5-(tributylstannyl)-2H-1,2,3-triazol-4- yl)methyl)carbamate (I-7a): Argon gas was purged through a stirred suspension of I-16d (3.0 g, 9.4 mmol) in hexabutylditin ( 3.43 mL, 10.3 mmol) for 15 min. To this was then added Pd(OAc)2(0.021 g, 0.094 mmol) and tricyclohexylphosphine (0.053 g, 0.188 mmol). The reaction mixture was then stirred at 110 °C for 24 h in a sealed tube. It was then cooled to room temperature, filtered through celite bed and washed with EtOAc (50 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0- 70% EtOAc in heptane) to afford desired compound tert-butyl methyl((2-methyl-5- (tributylstannyl)-2H-1,2,3-triazol-4-yl)methyl)carbamate I-7a (4.0 g) as a pale yellow semi-solid.1H NMR (400 MHz, DMSO) δ 4.40 (s, 2H); 4.12 (s, 3H); 2.68 (s, 3H); 1.48 (m, 6H); 1.40 (s, 9H); 1.30 (m, 6H); 1.09 (t, J = 8.4 Hz, 6H); 0.85 (t, J = 7.2 Hz, 9H).

[0290] Step-2: tert-butyl ((5-(2,5-difluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-7b): Argon gas was purged through a stirred suspension of I-7a (4.0 g, 7.76 mmol), 1-bromo-2,5-difluoro-3-nitrobenzene (1.85 g, 7.76 mmol) and LiCl (0.76 g, 17.85 mmol) in DMF (40.0 mL) for 15 min. To this was then added Pd(PPh3)4(0.89 g, 0.77 mmol) and CuI (0.74 g, 3.88 mmol). The reaction mixture was then stirred at 90 °C for 1 h in a sealed tube. It was then cooled to room temperature, ice cold water (50 mL) was added to it and extracted with EtOAc (70 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% EtOAc in hexane) to afford tert-butyl ((5-(2,5- difluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate I-7b (2.3 g) as a colourless semi-solid. LCMS (ES) m / z; 384.1 [M+H]+.

[0291] Step-3: 8-fluoro-2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-7c): I-7c (1.2 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-7b (2.3 g, 6.00 mmol) as the starting material. LCMS (ES) m / z; 264.2 [M+H]+.

[0292] Step-4: 8-fluoro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-7): To a stirred solution of I-7c (0.98 g, 3.72 mmol) and NH4Cl (1.99 g, 37.23 mmol) in EtOH (30.0 mL) and water (10.0 mL) was added Zn (2.43 g, 37.23 mmol) portion-wise at 0 °C. It was then allowed to stir at 40 °C for 2 h. After completion, the reaction mixture was filtered off through celite bed and washed with EtOH (30 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-55% EtOAc in heptane) to afford desired compound 8-fluoro-2,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-amine I-7 (0.77 g) as an off-white solid. LCMS (ES) m / z; 234.0 [M+H]+. Example 8: Preparation of 8-fluoro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-4,4-d2-6-amine (I-8):

[0293] Step-1: tert-butyl ((5-(2,5-difluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)methyl-d2)(methyl)carbamate (I-8a): I-8a (2.9 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-19c (4.6 g, 15.0 mmol) and 2-(2,5-difluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.96 g, 31.4 mmol) as the starting materials. LCMS (ES) m / z; 386.1 [M+H]+.

[0294] Step-2: 8-fluoro-2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline- 4,4-d2 (I-8b): I-8b (1.85 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-8a (2.9 g, 7.53 mmol) as the starting material. LCMS (ES) m / z; 266.0 [M+H]+.

[0295] Step-3: 8-fluoro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-4,4-d2-6- amine (I-8): I-8 (1.1 g) was synthesized by following procedure as described for the synthesis of I- 7 (step-4) using I-8b (1.75 g, 6.6 mmol) as the starting material. LCMS (ES) m / z; 236.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J1= 2.8 Hz, J2= 8.8 Hz, 1H); 6.43 (dd, J1= 2.8 Hz, J2=10.4 Hz, 1H); 4.33 (br s, 2H); 4.25 (s, 3H); 2.30 (s, 3H). Example 9: Preparation of 8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-9):

[0296] Step-1: tert-butyl (1-(5-(2,5-difluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-9a): I-9a (4.3 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-24c (4.5 g, 14.1 mmol) and 2-(2,5-difluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.43 g, 22.6 mmol) as the starting materials. LCMS (ES) m / z; 398.0 [M+H]+.

[0297] Step-2: 8-fluoro-2,4,5-trimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinoline (I-9b): I-9b (2.9 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-9a (4.25 g, 10.8 mmol) as the starting material. LCMS (ES) m / z; 278.0 [M+H]+.

[0298] Step-3: 8-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6- amine (I-9): I-9 (2.15 g) was synthesized by following procedure as described for the synthesis of I-7 (step-4) using I-9b (2.9 g, 10.45 mmol) as the starting material. LCMS (ES) m / z; 248.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.55 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H); 6.43 (dd, J1 = 2.8 Hz, J2 =10.4 Hz, 1H); 5.33 (br s, 2H); 4.24 (q, J = 7.2 Hz, 1H); 4.14 (s, 3H); 2.31 (s, 3H); 1.07 (d, J = 6.8 Hz, 3H).Example 10: Preparation of 8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-amine (I-10):

[0299] Step-1: tert-butyl (1-(5-(2,5-difluoro-3-nitrophenyl)-2-(methyl-d3)-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-10a): I-10a (4.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-1c (5.05 g, 15.7 mmol) and 2-(2,5-difluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.47 g, 15.7 mmol) as the starting materials. LCMS (ES) m / z; 401.0 [M+H]+.

[0300] Step-2: 8-fluoro-4,5-dimethyl-2-(methyl-d3)-6-nitro-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinoline (I-10b): I-10b (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-10a (5.0 g, 12.5 mmol) as the starting material. LCMS (ES) m / z; 281.0 [M+H]+.

[0301] Step-3: 8-fluoro-4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-10): I-10 (2.2 g) was synthesized by following procedure as described for the synthesis of I-7 (step-4) using I-10b (3.5 g, 12.5 mmol) as the starting material. LCMS (ES) m / z; 251.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.55 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H); 6.43 (dd, J1 = 2.8 Hz, J2 =10.4 Hz, 1H); 5.35 (br s, 2H); 4.25 (q, J = 7.2 Hz, 1H); 2.32 (s, 3H); 1.08 (d, J = 6.8 Hz, 3H). Example 11: Preparation of 8-fluoro-2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-amine (I-11):

[0302] Step-1: tert-butyl (1-(5-(2,5-difluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl-2,2,2-d3)(methyl)carbamate (I-11a): I-11a (4.3 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-3d (4.3 g, 13.4 mmol) and 2-(2,5- difluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.07 g, 28.2 mmol) as the starting materials. LCMS (ES) m / z; 345.0 [(M-tBu)+H]+.

[0303] Step-2: 8-fluoro-2,5-dimethyl-4-(methyl-d3)-6-nitro-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinoline (I-11b): I-11b (6.4 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-11a (13.0 g, 32.5 mmol) as the starting material. LCMS (ES) m / z; 281.0 [M+H]+.

[0304] Step-3: 8-fluoro-2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-11): I-11 (5.0 g) was synthesized by following procedure as described for the synthesis of I-7 (step-4) using I-11b (6.4 g, 22.8 mmol) as the starting material. LCMS (ES) m / z; 251.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 6.85 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H); 6.42 (dd, J1= 2.8 Hz, J2=10.4 Hz, 1H); 4.26 (br s, 2H); 4.20 (s, 3H); 4.11 (s, 1H); 2.45 (s, 3H). Example 12: Preparation of 2-cyclopropyl-8-fluoro-5-methyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c]quinolin-6-amine (I-12):

[0305] Step-1: tert-butyl ((2-cyclopropyl-5-(2,5-difluoro-3-nitrophenyl)-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-12a): I-12a (0.4 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-4d (0.5 g, 1.51 mmol) and 2-(2,5-difluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 g, 2.72 mmol) as the starting materials. LCMS (ES) m / z; 354.1 [(M-tBu)+H]+.

[0306] Step-2: 1-(2-cyclopropyl-5-(2,5-difluoro-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)-N- methylmethanamine (HCl salt) (I-12b): I-12b (1.8 g) was synthesized by following procedure as described for the synthesis of I-2 (step-7) using I-12a (1.8 g, 4.4 mmol) as the starting material. LCMS (ES) m / z; 310.0 [M+H]+.

[0307] Step-3: 2-cyclopropyl-8-fluoro-5-methyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolone (1-12c): I-12c (1.1 g) was synthesized by following procedure as described for the synthesis of I-5 (step-5) using I-12b (1.8 g, 5.21 mmol) as the starting material. LCMS (ES) m / z; 290.0 [M+H]+.

[0308] Step-4: 2-cyclopropyl-8-fluoro-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-12): I-12 (0.35 g) was synthesized by following procedure as described for the synthesis of I-7 (step-4) using I-12c (0.5 g, 1.73 mmol) as the starting material. LCMS (ES) m / z; 260.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.53 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H); 6.41 (dd, J1 = 2.8 Hz, J2 =10.4 Hz, 1H); 5.37 (br s, 2H); 4.10 (s, 2H); 4.09-4.07 (m, 1H); 2.32 (s, 3H); 1.21-1.17 (m, 2H); 1.09-1.04 (m, 2H). Example 13: 5-ethyl-2-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-13):

[0309] Step-1-2: tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)methyl)(ethyl)carbamate (I-13b): I-13b (4.1 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2 and 3) using I-16b (5.0 g, 26.3 mmol) and MeNH2(2M solution in THF) (16.0 mL, 31.6 mmol) as the starting materials. LCMS (ES) m / z; 319.1 [M+H]+.

[0310] Step-3: tert-butyl ethyl((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)methyl)carbamate (I-13c): I-13c (4.1 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-13b (4.0 g, 12.5 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.68 g, 13.8 mmol) as the starting materials. LCMS (ES) m / z; 380.0 [M+H]+.

[0311] Step-4: N-((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)methyl)ethanamine (TFA salt) (I-13d): I-13d (4.0 g) was synthesized by following procedure as described for the synthesis of I-19 (step-5) using I-13c (4.1 g, 10.8 mmol) as the starting material. LCMS (ES) m / z; 280.0 [M+H]+.

[0312] Step-5: 5-ethyl-2-methyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I- 13e): I-13e (1.6 g) was synthesized by following procedure as described for the synthesis of I-19 (step-6) using I-13d (4.0 g, 10.6 mmol) as the starting material. LCMS (ES) m / z; 260.1 [M+H]+.

[0313] Step-6: 5-ethyl-2-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I- 13): I-13 (1.4 g) was synthesized by following procedure as described for the synthesis of I-16 (step-6) using I-13e (1.6 g, 6.17 mmol) as the starting material. LCMS (ES) m / z; 230.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H); 7.02 (t, J = 8.0 Hz, 1H); 6.73 (dd, J1= 1.2 Hz, J2=8.0 Hz, 1H); 4.23 (s, 2H); 4.21 (s, 3H); 4.05 (br s, 2H); 2.76 (q, J = 7.2 Hz, 2H); 1.07 (t, J = 7.2 Hz, 3H). Example 14: 5-ethyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-14):

[0314] Step-1: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-ethylethan-1-amine (I-14a): To a stirred solution of I-24a (10.0 g, 49.0 mmol) in THF (49.0 mL) was added titanium(IV) isopropoxide (29.0 mL, 98.0 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2in THF (49.0 mL, 98.0 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure. It was then diluted with MeOH (50.0 mL) and to this was added NaBH4(3.71 g, 98.0 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, saturated NaHCO3solution (50 mL) was added to it and washed with EtOAc (50 mL x 2). The aqueous NaHCO3solution containing 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-ethylethan-1-amine I-14a was carried forward for the next step.

[0315] Step-2: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(ethyl)carbamate (I-14b): I-14b (6.0 g) was synthesized by following procedure as described for the synthesis of I- 16 (step-3). LCMS (ES) m / z; 333.0 [M+H]+.

[0316] Step-3: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl)(ethyl)carbamate (I-14c): I-14c (2.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-14b (4.5 g, 13.5 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (5.92 g, 33.8 mmol) as the starting materials. LCMS (ES) m / z; 384.1 [M+H]+.

[0317] Step-4: 6-chloro-5-ethyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-14d): I-14d (2.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-14c (6.0 g, 15.6 mmol) as the starting material. LCMS (ES) m / z; 264.0 [M+H]+.

[0318] Step-5: N-(5-ethyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-14e): I-14e (2.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-14d (2.0 g, 7.58 mmol) and cyclopropanecarboxamide (1.29 g, 15.2 mmol) as the starting materials. LCMS (ES) m / z; 313.4 [M+H]+.

[0319] Step-6: 5-ethyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin- 6-amine (I-14): I-14 (1.1 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-14e (2.0 g, 6.4 mmol) as the starting material. LCMS (ES) m / z; 245.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 4.8 Hz, 1H); 6.83 (d, J = 5.2 Hz, 1H); 5.70 (s, 2H); 4.51 (q, J = 7.2 Hz, 1H); 4.18 (s, 3H); 2.82-2.72 (m, 2H); 1.08 (d, J = 7.2 Hz, 3H); 0.90 (t, J = 7.2 Hz, 3H).

[0320] Note: Racemate I-14 (1.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA with 0.1% DEA (85:15); Flow rate: 40 mL / min)] to afford two enantiomers {I-14A (0.4 g): peak-1; Rt; 8.05 min and I-14B (0.4 g): peak-2; Rt; 10.56 min}, which were used further without their absolute configuration determination.Example 15: 4-ethyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-15):

[0321] Step-1: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-1-ol (I-15a): I-15a (1.2 g) was synthesized by following procedure as described for the synthesis of I-3 (step-1) using I-16b (5.0 g, 26.3mmol) and EtMgBr (3M solution in Et2O) (13.0 mL, 39.5 mmol) as the starting materials.1H NMR (400 MHz, CDCl3) δ 4.74 (q, J = 6.8 Hz, 1H); 4.15 (s, 3H); 2.09 (d, J = 6.4 Hz, 1H); 1.96-1.88 (m, 2H); 0.96 (t, J = 7.6 Hz, 3H).

[0322] Step-2: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-1-one (I-15b): I-15b (2.0 g) was synthesized by following procedure as described for the synthesis of I-3 (step-2) using I-15a (4.0 g, 18.2 mmol) as the starting material. LCMS (ES) m / z; 217.8 [M+H]+.

[0323] Step-3-4: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)propyl)(methyl)carbamate (I-15d): I-15d (12.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-15b (10.0 g, 45.9 mmol) and methylamine hydrochloride (6.19 g, 91.7 mmol) as the starting materials. LCMS (ES) m / z; 333.0 [M+H]+.

[0324] Step-5: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)propyl)(methyl)carbamate (I-15e): I-15e (1.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-15d (3.0 g, 9.0 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (3.95 g, 22.5 mmol) as the starting materials. LCMS (ES) m / z; 384.1 [M+H]+.

[0325] Step-6: 6-chloro-4-ethyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-15f): I-15f (3.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-15e (7.0 g, 18.2 mmol) as the starting material. LCMS (ES) m / z; 264.0 [M+H]+.

[0326] Step-7: N-(4-ethyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-15g): I-15g (4.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-15f (4.0 g, 15.2 mmol) and cyclopropanecarboxamide (2.58 g, 30.3 mmol) as the starting materials. LCMS (ES) m / z; 313.1 [M+H]+.

[0327] Step-8: 4-ethyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin- 6-amine (I-15): I-15 (3.0 g) was synthesized by following procedure as described for the synthesis of I-10 (step-4) using I-15g (5.0 g, 16.0 mmol) as the starting material. LCMS (ES) m / z; 245.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 4.8 Hz, 1H); 6.79 (d, J = 4.8 Hz, 1H); 5.83 (s, 2H); 4.05 (s, 3H); 4.01 (t, J = 7.6 Hz, 1H); 2.44 (s, 3H); 1.35-1.13 (m, 2H); 0.84 (t, J = 7.2 Hz, 3H).

[0328] Note: Racemate I-15 (3.0 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IG (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA with 0.1% DEA (80:20); Flow rate: 40 mL / min)] to afford two enantiomers {I-15A (1.0 g): peak-1; Rt; 9.70 min and I-15B (1.0 g): peak-2; Rt; 12.05 min}, which were used further without their absolute configuration determination. Example 16: 5-cyclopropyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-16):

[0329] Step-1: 1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethan-1- one (I-16a): I-16a (8.2 g) was synthesized by following procedure as described for the synthesis ofI-18 (step-1) using I-24a (10.0 g, 49.0 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (12.9 g, 73.5 mmol) as the starting materials. LCMS (ES) m / z; 255.1 [M+H]+.

[0330] Step-2: N-(1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)ethyl)cyclopropanamine (I-16b): To a stirred solution of I-16a (4.1 g, 16.1 mmol) and cyclopropanamine (2.23 mL, 32.2 mmol) in MeOH (10.0 mL) was added acetic acid (1.84 mL, 32.2 mmol) at 0 °C. It was then stirred at room temperature for 16 h. Volatiles were then removed under reduced pressure and the residue was dissolved in MeOH (15.0 mL). To this was added NaBH3CN (2.0 g, 32.2 mmol) at 0 °C and the reaction mixture was then allowed to warm to room temperature over 2 h. After completion (as indicated by LCMS), saturated NaHCO3solution (50 mL) was added to it and extraction was carried out using EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution of 0-80% EtOAc in heptane) to afford desired compound N-(1-(5-(2-chloro- 3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)cyclopropanamine I-16b (3.5 g) as a yellow semi-sold. LCMS (ES) m / z; 296.1 [M+H]+.

[0331] Step-3: 6-chloro-5-cyclopropyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-16c): To a stirred solution of I-16b (2.0 g, 6.76 mmol) in NMP (2.0 mL) was added DIPEA (9.42 mL, 54.1 mmol) at room temperature. It was then irradiated at 130 °C for 2 h in a microwave oven. After completion, the reaction mixture was cooled to room temperature and water (10 mL) was added to it. Extraction was carried out using EtOAc (25 mL x 2); the combined extracts were washed with water (15 mL), brine (15 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution of 0-25% EtOAc in heptane) to afford desired compound 6-chloro-5- cyclopropyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine I-16c (1.2 g) as a yellow sold. LCMS (ES) m / z; 276.0 [M+H]+.

[0332] Step-4: N-(5-cyclopropyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-16d): I-16d (1.25 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-16c (2.5 g, 9.05 mmol) and cyclopropanecarboxamide (1.16 g, 13.6 mmol) as the starting materials. LCMS (ES) m / z; 325.0 [M+H]+.

[0333] Step-5: 5-cyclopropyl-2,4-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-16): I-16 (0.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-16d (1.25 g, 3.86 mmol) as the starting material. LCMS (ES) m / z; 257.2 [M+H]+.Example 17: 2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-17):

[0334] Step-1: 1-(5-bromo-2-ethyl-2H-1,2,3-triazol-4-yl)ethan-1-one (I-17a): I-71a (8.1 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-23a (29.0 g, 114.0 mmol) and dimethylacetamide (49.6 g, 569.0 mmol) as the starting materials. LCMS (ES) m / z; 218.0 [M+H]+.

[0335] Step-2-3: tert-butyl (1-(5-bromo-2-ethyl-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-17c): I-17c (10.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-17a (10.0 g, 45.9 mmol) as the starting material. LCMS (ES) m / z; 277.1 [(M-tBu)+H]+.

[0336] Step-4: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-ethyl-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-17d): I-17d (4.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-17c (5.0 g, 15.0 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (5.99 g, 22.5 mmol) as the starting materials. LCMS (ES) m / z; 384.2 [M+H]+.

[0337] Step-5: 6-chloro-2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-17e): I-17e (2.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-17d (4.1 g, 11.1 mmol) as the starting material. LCMS (ES) m / z; 264.0 [M+H]+.

[0338] Step-6: N-(2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-17f): I-17f (2.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-17e (2.1 g, 7.96 mmol) and cyclopropanecarboxamide (1.36 g, 15.9 mmol) as the starting materials. LCMS (ES) m / z; 313.2 [M+H]+.

[0339] Step-7: 2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin- 6-amine (I-17): I-17 (1.1 g) was synthesized by following procedure as described for the synthesisof I-18 (step-4) using I-17f (2.0 g, 6.4 mmol) as the starting material. LCMS (ES) m / z; 245.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 5.2 Hz, 1H); 6.81 (d, J = 5.2 Hz, 1H); 5.82 (s, 2H); 4.47 (q, J = 7.2 Hz, 2H); 4.33 (q, J = 6.8 Hz, 1H); 2.47 (s, 3H); 1.47 (t, J = 7.2 Hz, 3H); 1.08 (d, J = 7.2 Hz, 3H).

[0340] Note: Racemate I-17 (1.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA in 0.1% DEA (80:20); Flow rate: 40 mL / min)] to afford two enantiomers {I-17A (0.3 g): peak-1; Rt; 12.20 min and I-17B (0.35 g): peak-2; Rt; 14.80 min}, which were used further without their absolute configuration determination. Example 18: Preparation of 2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-18):

[0341] Step-1: tert-butyl (1-(2-ethyl-5-(2-fluoro-3-nitrophenyl)-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-18a): I-18a (4.7 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-17c (5.0 g, 15.0 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.99 g, 22.5 mmol) as the starting materials. LCMS (ES) m / z; 294.0 [(M-Boc)+H]+.

[0342] Step-2: 1-(2-ethyl-5-(2-fluoro-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)-N-methylethan-1- amine (TFA salt) (I-18b): I-18b (3.4 g) was synthesized by following procedure as described for the synthesis of I-19 (step-5) using I-18a (4.7 g, 11.9 mmol) as the starting material. LCMS (ES) m / z; 294.2 [M+H]+.

[0343] Step-3: 2-ethyl-4,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-18c): I-18c (3.0 g) was synthesized by following procedure as described for the synthesis of I-5 (step-5) using I-18b (3.4 g, 11.6 mmol) as the starting material. LCMS (ES) m / z; 274.0 [M+H]+.

[0344] Step-4: 2-ethyl-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-18): I-18 (2.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-6) using I-18c (3.0 g, 11.0 mmol) as the starting material. LCMS (ES) m / z; 244.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J1= 1.2 Hz, J2= 7.6 Hz, 1H); 7.02 (t, J = 8.0 Hz, 1H); 6.72 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H); 4.49 (q, J = 7.6 Hz, 2H); 4.25 (q, J = 6.8 Hz, 1H); 4.13 (br s, 2H); 2.50 (s, 3H); 1.60 (t, J = 6.8 Hz, 3H); 1.24 (d, J = 6.8 Hz, 3H).

[0345] Note: Racemate I-18 (2.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK OJ-H (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane: 0.1% DEA in Ethanol (70:30); Flow rate: 40 mL / min)] to afford two enantiomers {I-18A (1.0 g): peak-1; Rt; 6.16 min and I-18B (1.0 g): peak-2; Rt; 12.01 min}, which were used further without their absolute configuration determination. Example 19: Preparation of 4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-19):

[0346] Step-1: 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole (I-19a): To a stirred solution of I-21a (15.0 g, 66.1 mmol) in DMF (150.0 mL) was added Cs2CO3(43.1 g, 132.0 mmol) and 3- iodooxetane (14.6 g, 79.3 mmol) at room temperature. The reaction mixture was then stirred at 120 °C for 16 h. After complete consumption of starting material (as indicated by TLC), it was cooled to room temperature and ice-cold water (150 mL) was added to it. Extraction was carried out using Et2O (3 x 100 mL); the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-6% EtOAc in n-hexane) to afford 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole I-19a (13.0 g) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 5.76-5.71 (m, 1H); 5.16 (t, J = 6.8 Hz, 2H); 5.06 (t, J = 7.6 Hz, 2H).

[0347] Step-2: 1-(5-bromo-2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl)ethan-1-one (I-19b): I-19b (4.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-19a (6.5 g, 22.95 mmol) and dimethylacetamide (20.0 g, 115.0 mmol) as the starting materials.1H NMR (400 MHz, CDCl3) δ 5.82-5.73 (m, 1H); 5.20 (t, J = 6.8 Hz, 2H); 5.09 (t, J = 7.6 Hz, 2H); 2.57 (s, 3H).

[0348] Step-3-4: tert-butyl ((5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-19d): I-19d (9.3 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2 and 3) using I-19b (7.6 g, 30.9 mmol) and methyl amine hydrochloride (4.17 g, 61.8 mmol) as the starting materials. LCMS (ES) m / z; 361.1 [M+H]+.

[0349] Step-5: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-(oxetan-3-yl)-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-19e): I-19e (2.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-19d (4.6 g, 12.85 mmol) and (2- chloro-3-fluoropyridin-4-yl)boronic acid (6.75 g, 38.6 mmol) as the starting materials. LCMS (ES) m / z; 356.0 [(M-tBu)+H]+.

[0350] Step-6: 6-chloro-4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-19f): I-19f (2.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2, 3) using I-19e (5.4 g, 13.1 mmol) as the starting material. LCMS (ES) m / z; 292.1 [M+H]+.

[0351] Step-7: N-(4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-19g): I-19g (2.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-19f (2.7 g, 9.25 mmol) and cyclopropanecarboxamide (1.58 g, 18.5 mmol) as the starting materials. LCMS (ES) m / z; 341.0 [M+H]+.

[0352] Step-8: 4,5-dimethyl-2-(oxetan-3-yl)-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-19): I-19 (1.75 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-19g (3.01 g, 8.83 mmol) as the starting material. LCMS (ES) m / z; 273.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 5.2 Hz, 1H); 6.88 (d, J = 4.8 Hz, 1H); 5.94-5.89 (m, 1H); 5.86 (s, 2H); 5.04-4.96 (m, 4H); 4.41 (q, J = 6.8 Hz, 1H); 2.41 (s, 3H); 1.14 (d, J = 7.2 Hz, 3H).

[0353] Note: Racemate I-19 (1.75 g) was resolved by chiral HPLC separation [Column: CHIRALPAK OJ-H (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane: 0.1% DEA in IPA (50:50); Flow rate: 40 mL / min)] to afford two enantiomers {I-19A (0.54 g): peak-1; Rt; 8.80 min and I-19B (0.56 g): peak-2; Rt; 13.59 min}, which were used further without their absolute configuration determination. Example 20: Preparation of 2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-20):

[0354] Step-1: 4,5-dibromo-2-(2-methoxyethyl)-2H-1,2,3-triazole (I-20a): To a stirred solution of I-21a (20.0 g, 88.0 mmol) and 1-bromo-2-methoxyethane (8.33 mL, 88 mmol) in DMA (90 mL) was added triethylamine (37.3 mL, 264.3 mmol) at room temperature. It was then allowed to stir at 55 °C for 16 h. It was then cooled to room temperature and water (50 mL) was added to it.Extraction was carried out using EtOAc (100 mL x 3); the combined organic extracts were washed with water (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0- 2% EtOAc in heptane) to afford desired compound 4,5-dibromo-2-(2-methoxyethyl)-2H-1,2,3- triazole I-20a (12.3 g) as a colourless oil. LCMS (ES) m / z; 284.1 [M+H]+.

[0355] Step-2: 1-(5-bromo-2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)ethan-1-one (I-20b): To a stirred solution of I-20a (5.0 g, 17.55 mmol) in anhydrous THF (100 mL) was added a 2.5M solution of n-BuLi in cyclohexane (6.48 mL, 12.97 mmol) at -78 °C and stirred for 30 min. To this was then added DMA (8.2 mL, 87.75 mmol) at -78 °C. The reaction mixture was stirred at the same temperature for another 30 min. After completion, it was quenched with addition of saturated NH4Cl solution (50 mL), and extraction was carried out using EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-30% EtOAc in Hexane) to afford desired compound N-(3-(5-bromo-2- methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide I-20b (1.2 g) as a yellow oil. LCMS (ES) m / z; 248.0 [M+H]+.

[0356] Step-3: 1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-(2-methoxyethyl)-2H-1,2,3-triazol-4- yl)ethan-1-one (I-20c): I-20c (2.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-20b (5.0 g, 20.2 mmol) and (2-chloro-3-fluoropyridin-4- yl)boronic acid (8.84 g, 50.4 mmol) as the starting materials. LCMS (ES) m / z; 299.1 [M+H]+.

[0357] Step-4: 1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-(2-methoxyethyl)-2H-1,2,3-triazol-4- yl)-N-methylethan-1-amine (I-20d): To a stirred solution of I-20c (6.3 g, 21.1 mmol) in THF (45.0 mL) was added titanium(IV) isopropoxide (12.5 mL, 42.2 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2in THF (31.6 mL, 63.3 mmol) and the reaction mixture was stirred at 60 °C for 16 h. It was then cooled to room temperature and volatiles were removed under reduced pressure. It was then diluted with MeOH (45.0 mL) and to this was added NaBH4(2.39 g, 63.3 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, saturated NaHCO3solution (50.0 mL) was added to it and washed with EtOAc (30 mL x 2). The aqueous NaHCO3solution containing 1-(5-(2-chloro-3- fluoropyridin-4-yl)-2-(2-methoxyethyl)-2H-1,2,3-triazol-4-yl)-N-methylethan-1-amine I-20d (6.3 g, crude) was carried forward for the next step. LCMS (ES) m / z; 314.1 [M+H]+.

[0358] Step-5: 6-chloro-2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-20e): I-20e (5.1 g) was synthesized by following procedure as describedfor the synthesis of I-5 (step-5) using I-20d (6.3 g, 20.1 mmol) as the starting material. LCMS (ES) m / z; 294.0 [M+H]+.

[0359] Step-6: N-(2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-20f): I-20f (3.9 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-20e (5.1 g, 17.4 mmol) and cyclopropanecarboxamide (2.22 g, 26.0 mmol) as the starting materials. LCMS (ES) m / z; 343.2 [M+H]+.

[0360] Step-7: 2-(2-methoxyethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-20): I-20 (2.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-20f (4.9 g, 14.3 mmol) as the starting material. LCMS (ES) m / z; 275.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 4.8 Hz, 1H); 6.84 (d, J = 4.8 Hz, 1H); 5.82 (s, 2H); 4.60 (t, J = 5.6 Hz, 2H); 4.36 (q, J = 6.8 Hz, 1H); 3.85 (t, J = 5.6 Hz, 2H); 3.23 (s, 3H); 2.42 (s, 3H); 1.11 (d, J = 7.2 Hz, 3H).

[0361] Note: Racemate I-20 (1.7 g) was resolved by chiral HPLC separation [Column: Chiralcel OJ-H (250 mm x 20 mm x 5 μm); Mobile phase: n-Hexane: Ethanol with 0.1% DEA (70:30); Flow rate: 19 mL / min] to afford two enantiomers {I-20A (0.73 g): peak-1; Rt; 5.54 min and I-20B (0.72 g): peak-2; Rt; 7.48 min}, which were used without confirming their absolute configuration. Example 21: Preparation of 4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-

[0362] Step-1: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(cyclopropyl)methanone (I-21a): I- 21a (9.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-16a (15.0 g, 62.3 mmol) and N-methoxy-N-methylcyclopropanecarboxamide (6.43 g, 49.8 mmol) as the starting material. LCMS (ES) m / z; 230.1 [M+H]+.

[0363] Step-2: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-1-cyclopropyl-N- methylmethanamine (I-21b): I-21b (6.0 g) was synthesized by following procedure as described for the synthesis of I-20 (step-4) using I-21a (7.0 g, 30.4 mmol) and methyl amine (2M solution in THF) (30.4 mL, 60.9 mmol) as the starting materials. LCMS (ES) m / z; 245.1 [M+H]+. Step-3: tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)(cyclopropyl)methyl)(methyl)carbamate (I-21c): I-21c (6.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-3) using I-21b (6.0 g, 24.5 mmol) as the starting material. LCMS (ES) m / z; 345.1 [M+H]+. Step-4: tert-butyl (cyclopropyl(5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)methyl)(methyl)carbamate (I-21d): I-21d (4.7 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-21c (4.0 g, 11.6 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.64 g, 17.4 mmol) as the starting materials. LCMS (ES) m / z; 406.0 [M+H]+. Step-5: 4-cyclopropyl-2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I- 21e): I-21e (1.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-21d (5.0 g, 12.3 mmol) as the starting material. LCMS (ES) m / z; 286.0 [M+H]+. Step-6: 4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I- 21): I-21 (0.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step- 6) using I-21e (1.5 g, 5.26 mmol) as the starting material. LCMS (ES) m / z; 256.2 [M+H]+. Example 22: Preparation of 4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c]quinolin-6-amine (I-22):

[0364] Step-1: tert-butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)(cyclopropyl)methyl)(methyl)carbamate (I-22a): I-22a (7.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-21c (8.5 g, 24.6 mmol) and (2- chloro-3-fluoropyridin-4-yl)boronic acid (10.8 g, 61.6 mmol) as the starting materials. LCMS (ES) m / z; 396.2 [M+H]+.

[0365] Step-2: 6-chloro-4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-22b): I-22b (10.0 g) was synthesized by following procedure as described for the synthesis of I-5 (step-2) using I-22a (14.4 g, 36.4 mmol) as the starting material. LCMS (ES) m / z; 276.1 [M+H]+.

[0366] Step-3: N-(4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-22c): I-22c (1.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-22b (4.0 g, 14.5 mmol) and cyclopropanecarboxamide (2.47 g, 29.0 mmol) as the starting materials. LCMS (ES) m / z; 325.2 [M+H]+.

[0367] Step-4: 4-cyclopropyl-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-22): I-22 (0.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-22c (1.5 g, 4.62 mmol) as the starting material. LCMS (ES) m / z; 257.3 [M+H]+. Example 23: Preparation of 4,5-dimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro- 2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-23):

[0368] Step-1: 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (I-23a): To a solution of I-21a (26.0 g, 115.0 mmol) in anhydrous THF (100.0 mL) was added NaH (60% suspension) (5.96 g, 149.0 mmol) at 0 °C and stirred for 15 min. To this was then added 2- (trimethylsilyl)ethoxymethyl chloride (21.3 mL, 120.0 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of staring material, ice cold water (50 mL) was added to it and extraction was carried out using EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of (0-2% EtOAc in heptane) to afford 4,5-dibromo-2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-1,2,3-triazole I-23a (21.8 g) as a colourless liquid. LCMS (ES) m / z; 355.8 [M+H]+.1H NMR (400 MHz, CDCl3) δ 5.59 (s, 2H); 3.67 (t, J = 8.0 Hz, 2H); 0.93 (t, J = 5.2 Hz, 2H); 0.02 (s, 9H).

[0369] Step-2: 1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)ethan- 1-one (I-23b): I-23b (13.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-23a (22.0 g, 61.6 mmol) and dimethylacetamide (28.5 mL, 80.1 mmol) as the starting materials.1H NMR (400 MHz, DMSO-d6) δ 5.79 (s, 2H); 3.72 (t, J = 8.0 Hz, 2H); 2.59 (s, 3H); 0.90 (t, J = 8.0 Hz, 2H); 0.03 (s, 9H).

[0370] Step-3-4: tert-butyl (1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3- triazol-4-yl)ethyl)(methyl)carbamate (I-23d): I-23d (14.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2-3) using I-23b (13.0 g, 40.6 mmol) and methylamine hydrochloride (5.48 g, 81.2 mmol) as the starting materials. LCMS (ES) m / z; 435.1 [M+H]+.

[0371] Step-5: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-23e): I-23e (11.0 g) was synthesized by following procedure as described for the synthesis of I-10 (step-1) using I-23d (13.0 g, 29.9 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (7.85 g, 44.8 mmol) as the starting materials. LCMS (ES) m / z; 486.1 [M+H]+.

[0372] Step-6: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2H-1,2,3-triazol-4- yl)ethyl)(methyl)carbamate (I-23f): 1M solution of TBAF in THF (198.0 mL, 198.0 mmol) was added to a stirred solution of I-23e (12.0 g, 24.7 mmol) in THF (120.0 mL) at room temperature and the resulting mixture was stirred at 80 °C for 16 h. After complete consumption of starting material, it was cooled to room temperature and water (100 mL) was added to it. Extraction was carried out using EtOAc (3 x 100 mL); the combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-2% MeOH in DCM) to afford tert-butyl(1-(5-(2-chloro-3-fluoropyridin-4-yl)-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate I-23f (7.7 g) as a brown liquid. LCMS (ES) m / z; 354.1 [M-H]+.

[0373] Step-7: 6-chloro-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-23g): I-23g (4.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-23f (7.79 g, 21.9 mmol) as the starting material. LCMS (ES) m / z; 236.1 [M+H]+.

[0374] Step-8: 6-chloro-4,5-dimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-23h): I-23h (3.0 g) was synthesized by following procedure as described for the synthesis of I-23 (step-1) using I-23g (2.5 g, 10.6 mmol) as the starting material. LCMS (ES) m / z; 366.1 [M+H]+.

[0375] Step-9: N-(4,5-dimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-23i): I-23i (2.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-23h (0.9 g, 3.15 mmol) and cyclopropanecarboxamide (3.0 g, 8.2 mmol) as the starting materials. LCMS (ES) m / z; 415.0 [M+H]+.

[0376] Step-10: 4,5-dimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-23): I-23 (1.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-23i (2.7 g, 6.51 mmol) as the starting material. LCMS (ES) m / z; 347.0 [M+H]+. Example 24: Preparation of 2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-24):

[0377] Step-1: 6-chloro-2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-24a): To a solution of I-23g (4.2 g, 17.8 mmol) and sodium chlorodifluoroacetate (2.72 g, 17.8 mmol) in DMF (50.0 mL) was added Cs2CO3(11.6 g, 35.6 mmol) at room temperature and the reaction was stirred at 100 °C for 3 h. After complete consumption of staring material, it was cooled to room temperature and water (50 mL) was added to it. Extraction was carried out using EtOAc (50 mL x 3), the combined organic extracts were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-6% EtOAc in heptane) to afford desire compound 6-chloro-2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine I-24a (1.0 g) as an off-white solid {LCMS (ES) m / z; 286.0 [M+H]+} along with 6-chloro-3-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine I-24b (1.0 g) and 6-chloro-1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridine I-24c (1.0 g).

[0378] Step-2: N-(2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-24d): I-24d (1.1 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-24a (0.9 g, 3.15 mmol) and cyclopropanecarboxamide (0.4 g, 4.73 mmol) as the starting materials. LCMS (ES) m / z; 335.2 [M+H]+.

[0379] Step-3: 2-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-24): I-24 (0.7 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-24d (1.1 g, 2.6 mmol) as the starting material. LCMS (ES) m / z; 267.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.18 (t, J = 57.2 Hz, 1H); 7.87 (d, J = 4.8 Hz, 1H); 6.92 (d, J = 4.8 Hz, 1H); 6.00 (s, 2H); 4.51 (q, J = 7.2 Hz, 1H); 2.45 (s, 3H); 1.19 (d, J = 6.8 Hz, 3H).

[0380] Note: Racemate I-24 (0.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK OJ H (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:Ethanol with 0.1% DEA (70:30); Flow rate: 40 mL / min)] to afford two enantiomers {I-24A (0.26 g): peak-1; Rt; 12.27 min and I-24B (0.25 g): peak-2; Rt; 15.64 min}, which were used further without their absolute configuration determination.Example 25: Preparation of 1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-25):

[0381] Step-1: N-(1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-25a): I-25a (1.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-24c (1.0 g, 3.5 mmol) and cyclopropanecarboxamide (0.45 g, 5.25 mmol) as the starting materials. LCMS (ES) m / z; 335.2 [M+H]+.

[0382] Step-2: 1-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-25): I-25 (0.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-25a (1.0 g, 2.99 mmol) as the starting material. LCMS (ES) m / z; 267.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.54 (t, J = 57.2 Hz, 1H); 7.89 (d, J = 5.2 Hz, 1H); 6.88 (d, J = 5.2 Hz, 1H); 6.07 (s, 2H); 4.51 (q, J = 7.2 Hz, 1H); 2.45 (s, 3H); 1.13 (d, J = 6.8 Hz, 3H).

[0383] Note: Racemate I-25 (0.6 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA with 0.1% DEA (90:10); Flow rate: 40 mL / min)] to afford two enantiomers {I-25A (0.23 g): peak-1; Rt; 14.55 min and I-25B (0.25 g): peak-2; Rt; 16.21 min}, which were used further without their absolute configuration determination. Example 26: Preparation of 3-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-3H- [1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-26):

[0384] Step-1: N-(3-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-26a): I-26a (0.9 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-24b (0.85 g, 2.98 mmol)and cyclopropanecarboxamide (0.38 g, 4.46 mmol) as the starting materials. LCMS (ES) m / z; 335.2 [M+H]+.

[0385] Step-2: 3-(difluoromethyl)-4,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-26): I-26 (0.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-26a (0.9 g, 2.69 mmol) as the starting material. LCMS (ES) m / z; 267.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.41 (t, J = 57.2 Hz, 1H); 7.87 (d, J = 5.2 Hz, 1H); 6.99 (d, J = 5.2 Hz, 1H); 5.91 (s, 2H); 4.74 (q, J = 7.2 Hz, 1H); 2.45 (s, 3H); 1.15 (d, J = 6.8 Hz, 3H).

[0386] Note: Racemate I-26 (0.5 g) was resolved by chiral HPLC separation [Column: CHIRALPAK OJ H (250 mm x 30 mm x 5 μm); Mobile phase: n-Hexane:IPA with 0.1% DEA (80:20); Flow rate: 40 mL / min)] to afford two enantiomers {I-26A (0.16 g): peak-1; Rt; 15.82 min and I-26B (0.16 g): peak-2; Rt; 21.29 min}, which were used further without their absolute configuration determination. Example 27: Preparation of 2,4,4,5-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-27):

[0387] Step-1: 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol (I-27a): To a stirred solution of I-16a (10 g, 41.5 mmol) in THF (100 mL) was added a 2M solution of n-BuLi in cyclohexane (22.8 mL, 45.7 mmol) at -78 °C and stirred for 30 min at -78 °C. To this was then added acetone (15.4 mL, 208.0 mmol) at -78 °C. The reaction mixture was then allowed to warm to room temperature over 1 h. It was then quenched with addition of saturated NH4Cl solution (50mL), and extraction was carried out using EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0- 50% EtOAc in heptane) to afford desired compound 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)propan-2-ol I-27a (8.0 g) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 5.15 (s, 1H); 4.08 (s, 3H); 1.50 (s, 6H).

[0388] Step-2: 4-(2-azidopropan-2-yl)-5-bromo-2-methyl-2H-1,2,3-triazole (I-27b): To a stirred solution of I-27a (10 g, 45.4 mmol) in DCM (100 mL) was added TMSN3 (9.03 mL, 68.2 mmol) and FeCl3 (1.47 g, 9.09 mmol) at 0 °C. The reaction mixture was then allowed to stir at room temperature for 4 h. After complete consumption of staring material, it was quenched with addition of saturated NH4Cl solution (50 mL), and extraction was carried out using DCM (75 mL x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude 4-(2- azidopropan-2-yl)-5-bromo-2-methyl-2H-1,2,3-triazole I-27b (10.0 g) was carried forward to next step without any purification.1H NMR (400 MHz, DMSO-d6) δ 4.13 (s, 3H); 1.66 (s, 6H).

[0389] Step-3: 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-2-amine (I-27c): To a stirred solution of I-27b (20.0 g, 81.6 mmol) in THF (200 mL) was added zinc (21.3 g, 326.0 mmol) and acetic acid (18.7 mL, 326.0 mmol) at 0 °C. The reaction mixture was then allowed to stir at room temperature for 16 h. Zinc dust was then filtered off through celite and washed with MeOH (20 mL x 2). Volatiles were then removed under reduced pressure and dried (co-evaporation with MeOH). The resulting crude 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-2-amine I- 27c (14.0 g) was carried forward to the next step without any purification. LCMS (ES) m / z; 218.9 [M+H]+.

[0390] Step-4: 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)propan-2-amine (I-27d): To a stirred solution of I-27c (7.0 g, 32.0 mmol) in THF (70.0 mL) was added an aqueous solution of NaHCO3(13.4 g, 160.0 mmol in 35 mL water) and (Boc)2O (11,0 mL, 47.9 mmol) at 0 °C. The reaction mixture was then allowed to stir at room temperature for 16 h. Water (50 mL) was added to it and extraction was carried out using EtOAc (2 x 75 mL). The combined organic extracts were washed with water (50 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford the desired compound 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)propan-2-amine I-27d (8.0 g) as an off-white solid. LCMS (ES) m / z; 319.1 [M+H]+.

[0391] Step-5: tert-butyl (2-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)propan-2-yl)carbamate (I-27e): I-27e (4.0 g) was synthesized by following procedure asdescribed for the synthesis of I-18 (step-1) using I-27d (10.0 g, 31.3 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (11.0 g, 62.7 mmol) as the starting materials. LCMS (ES) m / z; 370.2 [M+H]+.

[0392] Step-6: 6-chloro-2,4,4-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-27f): I-27f (2.5 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-27e (9.0 g, 24.3 mmol) as the starting material. LCMS (ES) m / z; 250.0 [M+H]+.

[0393] Step-7: 6-chloro-2,4,4,5-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-27g): To a stirred solution of I-27f (2.4 g, 9.61 mmol) in DMF (20.0 mL) was added NaH (60% suspension) (0.58 g, 14.4 mmol) at 0 °C and stirred for 30 min. To this was then added iodomethane (0.72 mL, 11.5 mmol) drop wise at 0° C and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of starting material, water (50 mL) was added to it and extraction was carried out using Et2O (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% EtOAc in hexane) to afford 6-chloro-2,4,4,5-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine I-27g (2.4 g) as a pale-yellow solid. LCMS (ES) m / z; 264.0 [M+H]+.

[0394] Step-8: N-(2,4,4,5-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-27h): I-27h (0.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-27g (0.7 g, 2.65 mmol) and cyclopropanecarboxamide (0.45 g, 5.31 mmol) as the starting materials. LCMS (ES) m / z; 313.0 [M+H]+.

[0395] Step-9: 2,4,4,5-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-27): I-27 (0.9 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-27h (1.7 g, 5.44 mmol) as the starting material. LCMS (ES) m / z; 245.1 [M+H]+.Example 28: Preparation of 2',5'-dimethyl-2',5'-dihydrospiro[cyclobutane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridin]-6'-amine (I-28):

[0396] Step-1: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclobutan-1-ol (I-28a): I-28a (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I- 16a (5.0 g, 20.8 mmol) and cyclobutanone (3.06 mL, 41.5 mmol) as the starting materials. LCMS (ES) m / z; 232.0 [M+H]+.

[0397] Step-2: 4-(1-azidocyclobutyl)-5-bromo-2-methyl-2H-1,2,3-triazole (I-28b): I-28b (1.0 g) was synthesized by following procedure as described for the synthesis of I-27 (step-2) using I- 28a (1.0 g, 4.31 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 4.17 (s, 3H); 2.50- 2.45 (m, 2H); 2.73-2.66 (m, 2H); 2.03-1.98 (m, 1H); 1.79-1.74 (m, 1H).

[0398] Step-3: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclobutan-1-amine (I-28c): I-28c (0.8 g) was synthesized by following procedure as described for the synthesis of I-27 (step-3) using I-28b (1.0 g, 3.89 mmol) as the starting material. LCMS (ES) m / z; 231.0 [M+H]+.

[0399] Step-4: tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclobutyl)carbamate (I-28d): I-28d (1.1 g) was synthesized by following procedure as described for the synthesis of I- 27 (step-4) using I-28c (0.8 g, 3.46 mmol) as the starting material. LCMS (ES) m / z; 231.1 [(M- Boc)+H]+.

[0400] Step-5: tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)cyclobutyl)carbamate (I-28e): I-28e (4.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-28d (8.0 g, 24.2 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (10.6 g, 60.4 mmol) as the starting materials. LCMS (ES) m / z; 382.0 [M+H]+.

[0401] Step-6: 6'-chloro-2'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridine] (I-28f): I-28f (1.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-28e (2.7 g, 7.07 mmol) as the starting material. LCMS (ES) m / z; 262.1 [M+H]+.

[0402] Step-7: 6'-chloro-2',5'-dimethyl-2',5'-dihydrospiro[cyclobutane-1,4'- [1,2,3]triazolo[4,5-c][1,7]naphthyridine] (I-28g): I-28g (0.9 g) was synthesized by following procedure as described for the synthesis of I-27 (step-7) using I-28f (1.0 g, 3.82 mmol) as the starting material. LCMS (ES) m / z; 276.1 [M+H]+.

[0403] Step-8: N-(2',5'-dimethyl-2',5'-dihydrospiro[cyclobutane-1,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-28h): I-28h (1.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-28g (2.0 g, 7.25 mmol) and cyclopropanecarboxamide (1.23 g, 14.5 mmol) as the starting materials. LCMS (ES) m / z; 325.1 [M+H]+.

[0404] Step-9: 2',5'-dimethyl-2',5'-dihydrospiro[cyclobutane-1,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-amine (I-28): I-28 (1.3 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-28h (1.8 g, 5.55 mmol) as the starting material. LCMS (ES) m / z; 257.2 [M+H]+.Example 29: Preparation of 2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-amine (I-29):

[0405] Step-1: N-(3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)-2-methylpropane- 2-sulfinamide (I-29a): To a stirred solution of I-16a (10 g, 41.5 mmol) in anhydrous THF (100 mL) was added a 2M solution of n-BuLi in cyclohexane (18.7 mL, 37.5 mmol) at -30 °C and stirred for 30 min at -78 °C. To this was then added 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (7.28 g, 41.5 mmol) at -78 °C. The reaction mixture was stirred at the same temperature for another 30 min. After completion, it was quenched with addition of saturated NH4Cl solution (50 mL), and extraction was carried out using EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-30% EtOAc in Hexane) to afford desired compound N-(3-(5-bromo-2-methyl-2H-1,2,3-triazol-4- yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide I-29a (9.0 g) as an off-white solid. LCMS (ES) m / z; 337.1 [M+H]+.

[0406] Step-2: 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-amine (I-29b): To a stirred solution of I-29a (9.0 g, 26.7 mmol) in MeOH (100 mL) was added a 4M solution of HCl in 1,4-dioxane (30 mL) at 0 °C and the reaction mixture was stirred for 15 min. After complete consumption of starting material, saturated NaHCO3solution (30 mL) was added to it and washed using EtOAc (20 mL x 3). The aqueous NaHCO3solution containing 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-amine I-29b was carried forward for the next step without further purification. LCMS (ES) m / z; 230.9 [M-H]+.

[0407] Step-3: tert-butyl (3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)carbamate (I-29c): A solution of (Boc)2O (12.2 mL, 53.2 mmol) in THF (60 mL) was added to the aqueous NaHCO3solution containing I-29b and the reaction mixture was stirred at room temperature for 16 h. After completion, water (50 mL) was added to it and extraction was carried out using EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi- Flash (using gradient elution of 0-40% EtOAc in hexane) to afford tert-butyl (3-(5-bromo-2- methyl-2H-1,2,3-triazol-4-yl)oxetan-3-yl)carbamate I-29c (8.0 g) as an off-white solid. LCMS (ES) m / z; 333.1 [M+H]+.

[0408] Step-4: tert-butyl (3-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4- yl)oxetan-3-yl)carbamate (I-29d): I-29d (1.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-29c (3.0 g, 9.0 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (3.95 g, 22.5 mmol) as the starting materials. LCMS (ES) m / z; 384.1 [M+H]+.

[0409] Step-5: 6'-chloro-2'-methyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridine] (I-29e): I-29e (4.74 g) was synthesized by following procedure as described for the synthesis of I-5 (step-2) using I-29d (6.9 g, 18.0 mmol) as the starting material. LCMS (ES) m / z; 264.1 [M+H]+.

[0410] Step-6: 6'-chloro-2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridine] (I-29f): To a stirred solution of I-29e (2.5 g, 9.48 mmol) in DMF (20.0 mL) was added NaH (60% suspension) (0.57 g, 14.2 mmol) at 0 °C and stirred for 30 min. To this was then added iodomethane (0.71 mL, 11.4 mmol) drop wise at 0° C and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of starting material, water (50 mL) was added to it and extraction was carried out using Et2O (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% EtOAc in hexane) to afford 6'-chloro-2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5-c][1,7]naphthyridine] I- 29f (2.5 g) as a pale-yellow solid. LCMS (ES) m / z; 278.1 [M+H]+.

[0411] Step-7: N-(2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-29g): I-29g (1.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-29f (2.5 g, 9.0 mmol)and cyclopropanecarboxamide (1.53 g, 18.0 mmol) as the starting materials. LCMS (ES) m / z; 327.0 [M+H]+.

[0412] Step-8: 2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c][1,7]naphthyridin]-6'-amine (I-29): I-29 (1.0 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-29g (1.8 g, 5.52 mmol) as the starting material. LCMS (ES) m / z; 259.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 5.2 Hz, 1H); 6.81 (d, J = 5.2 Hz, 1H); 6.06 (s, 2H); 4.79 (d, J = 6.4 Hz, 2H); 4.60 (d, J = 6.4 Hz, 2H); 4.27 (s, 3H); 2.24 (s, 3H). Example 30: Preparation of 2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c]quinol

[0413] Step-1: tert-butyl (3-(5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4- yl)oxetan-3-yl)carbamate (I-30a): I-30a (4.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-29c (7.0 g, 21.0 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.4 g, 31.5 mmol) as the starting materials. LCMS (ES) m / z; 394.2 [M+H]+.

[0414] Step-2: 2'-methyl-6'-nitro-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c]quinoline] (I-30b): I-30b (1.65 g) was synthesized by following procedure as described for the synthesis of I-5 (step-2) using I-30a (4.0 g, 10.18 mmol) as the starting material. LCMS (ES) m / z; 274.1 [M+H]+.

[0415] Step-3: 2',5'-dimethyl-6'-nitro-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5- c]quinoline] (I-30c): I-30c (2.7 g) was synthesized by following procedure as described for the synthesis of I-27 (step-7) using I-30b (2.8 g, 10.2 mmol) as the starting material. LCMS (ES) m / z; 288.1 [M+H]+.

[0416] Step-4: 2',5'-dimethyl-2',5'-dihydrospiro[oxetane-3,4'-[1,2,3]triazolo[4,5-c]quinolin]- 6'-amine (I-30): I-30 (0.8 g) was synthesized by following procedure as described for the synthesis of I-16 (step-6) using I-30c (3.3 g, 11.4 mmol) as the starting material. LCMS (ES) m / z; 258.1 [M+H]+. Example 31: Preparation of 3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridin-6-amine (I-31):

[0417] Step-1: 4-bromo-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (I-31b): I-31b (13.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-1) using I-31a (16.8 g, 69.7 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H); 4.32 (s, 3H). LCMS (ES) m / z; 189.9 [M+H]+.

[0418] Step-2: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol (I-31c): I-31c (12.0 g) was synthesized by following procedure as described for the synthesis of I-3 (step-1) using I-31b (13.0 g, 68.4 mmol) as the starting material. LCMS (ES) m / z; 206.1 [M+H]+.

[0419] Step-3: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-one (I-31d): I-31d (8.8 g) was synthesized by following procedure as described for the synthesis of I-3 (step-2) using I-31c (12.0 g, 58.2 mmol) as the starting material.1H NMR (400 MHz, CDCl3) δ 4.26 (s, 3H); 2.71 (s, 3H). LCMS (ES) m / z; 204.0 [M+H]+.

[0420] Step-4-5: tert-butyl (1-(4-bromo-1-methyl-1H-1,2,3-triazol-5- yl)ethyl)(methyl)carbamate (I-31f): I-31f (12.0 g) was synthesized by following procedure as described for the synthesis of I-3 (step-3-4) using I-31d (8.8 g, 43.1 mmol) as the starting material. LCMS (ES) m / z; 319.1 [M+H]+.

[0421] Step-6: 5-[1-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-(2-chloro-3-fluoro-4- pyridyl)-1-methyl-1H-1,2,3-triazole (I-31g): I-31g (7.1 g) was synthesized by following procedure as described for the synthesis of I-18 (step-1) using I-31f (12.0 g, 37.6 mmol) and (2- chloro-3-fluoropyridin-4-yl)boronic acid (16.5 g, 94.0 mmol) as the starting material. LCMS (ES) m / z; 370.1 [M+H]+.

[0422] Step-7: 6-chloro-3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5- c][1,7]naphthyridine (I-31h): I-31h (3.6 g) was synthesized by following procedure as described for the synthesis of I-18 (step-2) using I-31g (7.1 g, 19.2 mmol) as the starting material. LCMS (ES) m / z; 250.1 [M+H]+.

[0423] Step-8: N-(3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- yl)cyclopropanecarboxamide (I-31i): I-31i (4.8 g) was synthesized by following procedure as described for the synthesis of I-18 (step-3) using I-31h (3.6 g, 14.4 mmol) and cyclopropanecarboxamide (1.84 g, 21.6 mmol) as the starting materials. LCMS (ES) m / z; 299.0 [M+H]+.

[0424] Step-9: 3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6- amine (I-31): I-31 (1.2 g) was synthesized by following procedure as described for the synthesis of I-18 (step-4) using I-31i (4.8 g, 6.44 mmol) as the starting material. LCMS (ES) m / z; 231.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 5.2 Hz, 1H); 7.17 (d, J = 5.2 Hz, 1H); 4.77 (s, 2H); 4.23 (q, J = 7.2 Hz, 1H); 3.99 (s, 3H); 2.49 (s, 3H); 1.11 (d, J = 6.8 Hz, 3H).

[0425] Note: Racemate I-31 (1.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm X 20 mm X 5 µm) Mobile phase: n-Hexane:Ethanol with 0.1% DEA (50:50) Flow rate : 19.0 mL / min] to afford two enantiomers {I-31A (0.43 g): peak-1; Rt; 7.11 min and I-31B (0.43 g): peak-2; Rt; 8.80 min}, which were used further without their absolute configuration determination.Example 32: Preparation of 3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6- amine (I-32):

[0426] Step-1: tert-butyl (1-(4-(2-fluoro-3-nitrophenyl)-1-methyl-1H-1,2,3-triazol-5- yl)ethyl)(methyl)carbamate (I-32a): I-32a (3.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-31f (6.47 g, 20.3 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.1 g, 30.5 mmol) as the starting materials. LCMS (ES) m / z; 380.2 [M+H]+.

[0427] Step-2: 1-(4-(2-fluoro-3-nitrophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethan- 1-amine (TFA salt) (I-32b): I-32b (6.0 g) was synthesized by following procedure as described for the synthesis of I-19 (step-5) using I-32a (6.0 g, 21.0 mmol) as the starting material. LCMS (ES) m / z; 280.1 [M+H]+.

[0428] Step-3: 3,4,5-trimethyl-6-nitro-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinoline (I-32c): I-32c (2.0 g) was synthesized by following procedure as described for the synthesis of I-5 (step-5) using I-32b (3.2 g, 10.1 mmol) as the starting material. LCMS (ES) m / z; 260.0 [M+H]+.

[0429] Step-4: 3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-32): I-32 (2.7 g) was synthesized by following procedure as described for the synthesis of I-16 (step-6) using I-32c (4.0 g, 15.4 mmol) as the starting material. LCMS (ES) m / z; 230.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.00 (d, J = 7.6 Hz, 1H); 6.92 (t, J = 8.0 Hz, 1H); 6.63 (d, J = 7.6 Hz, 1H); 4.96 (br s, 2H); 4.49 (q, J = 7.2 Hz, 1H); 4.04 (s, 3H); 2.40 (s, 3H); 1.05 (t, J = 6.8 Hz, 3H).

[0430] Note: Racemate I-32 (2.7 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IJ (250 mm x 20 mm x 5 μm); Mobile phase: n-Hexane: IPA in 0.1% DEA (70:30); Flow rate: 18 mL / min)] to afford two enantiomers {I-32A (0.8 g): peak-1; Rt; 13.96 min and I-32B (0.7 g): peak-2; Rt; 15.76 min}, which were used further without their absolute configuration determination.Example 33: Preparation of 3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6- amine (I-33):

[0431] Step-1-2: tert-butyl ((4-bromo-1-methyl-1H-1,2,3-triazol-5- yl)methyl)(methyl)carbamate (I-33b): I-33b (15.0 g) was synthesized by following procedure as described for the synthesis of I-16 (step-2 and 3) using I-31b (16.0 g, 84.2 mmol) and methyl amine hydrochloride (11.4 g, 168.0 mmol) as the starting materials. LCMS (ES) m / z; 205.0 [(M- Boc)+H]+.

[0432] Step-3: tert-butyl ((4-(2-fluoro-3-nitrophenyl)-1-methyl-1H-1,2,3-triazol-5- yl)methyl)(methyl)carbamate (I-33c): I-33c (2.5 g) was synthesized by following procedure as described for the synthesis of I-16 (step-4) using I-33b (1.8 g, 5.99 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.36 g, 88.5 mmol) as the starting materials. LCMS (ES) m / z; 366.2 [M+H]+.

[0433] Step-4: 3,5-dimethyl-6-nitro-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinoline (I-33d): I-33d (1.2 g) was synthesized by following procedure as described for the synthesis of I-16 (step-5) using I-33c (1.8 g, 4.93 mmol) as the starting material. LCMS (ES) m / z; 246.0 [M+H]+.

[0434] Step-5: 3,5-dimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-33): I- 33 (0.7 g) was synthesized by following procedure as described for the synthesis of I-16 (step-6) using I-33d (1.2 g, 4.87 mmol) as the star...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, 4, 5, or 6; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; V1is -NR5-, -O-, -S-, -S(=O)-, or -SO2-; R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2- C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -S(=O)R7, -SO2R7, or -SO2N(R6)2; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR7, -C(=O)R6, - CO2R6, -C(=O)N(R6)2, -N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; R4is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with t instances of R8; each R8is independently halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, -N(R6)2, - NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; or two R8groups on adjacent atoms of Ring B are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6- membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6- membered monocyclic heterocycle; t is 1, 2, 3, or 4; or R4is -C(=O)R9, -C(=O)NR9R10, or -C(=O)OR9; R9is hydrogen, unsubstituted or substituted C1-C6alkyl, C1-C6deuteroalkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R10is hydrogen, C1-C6alkyl, or C1-C6fluoroalkyl; Z is -NR11-, -O-, -S-, -S(=O)-, or -SO2-; R11is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen, halogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, - N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2; B1is N or CR13a; B2is N or CR13b; R13aand R13bare each independently hydrogen, halogen, unsubstituted or substituted C1- C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2- C6alkynyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR7, -C(=O)R6, -CO2R6, -C(=O)N(R6)2, - N(R6)2, -NR6C(=O)R7, -SR6, -S(=O)R7, -SO2R7, or -SO2N(R6)2;R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, or monocyclic heterocycle; each R6is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R6on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; and each R7is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, - C(=O)N(R15)2, -CH2C(=O)N(R15)2, -N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, - CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, -SR15, -CH2SR15, -S(=O)R16, - CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or -CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6- membered heteroaryl.

2. The compound of claim 1 further defined as a compound of Formula (I-A):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: m is 0, 1, 2, 3, or 4; q and r are each independently 0, 1, or 2, provided the sum of q and r is at least 2; n is 0, 1, or 2; p is 0 or 1; V1is -NR5-, -O-, or -S-; R5is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl; each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OR6, -N(R6)2, or -SR6, wherein: each R6is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from thegroup consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, - C(=O)N(R15)2, -CH2C(=O)N(R15)2, -N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, - CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, -SR15, -CH2SR15, -S(=O)R16, - CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or -CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6- membered heteroaryl.

3. The compound of either claim 1 or claim 2 further defined as a compound of Formula (I-B):Formula (I-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R11is methyl or trideuteromethyl;X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR15, -CH2OR15, -CO2R15, -CH2CO2R15, - C(=O)N(R15)2, -CH2C(=O)N(R15)2, -N(R15)2, -CH2N(R15)2, -NR15C(=O)R15, - CH2NR15C(=O)R15, -NR15SO2R16, -CH2NR15SO2R16, -SR15, -CH2SR15, -S(=O)R16, - CH2S(=O)R16, -SO2R16, -CH2SO2R16, -SO2N(R15)2, or -CH2SO2N(R15)2; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R15groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R16is independently selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6- membered heteroaryl.

4. A compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 1 or 2; p is 0 or 1;Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N; each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, and substituted deuteroalkyl, is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -CH2CN, -OR15, -CH2OR15, - N(R15)2, -CH2N(R15)2, -SR15, and -CH2SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl.

5. A compound of Formula (III): Formula (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: t is 1, 2, 3, or 4; Het is monocyclic heteroaryl;each R8is independently unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, or unsubstituted or substituted C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, -CN, -OR15, -N(R15)2, or -SR15; each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C1- C6heteroalkyl.

6. The compound of claim 5, wherein t is 1 or 2.

7. The compound of either claim 5 or claim 6, wherein Het is pyrazolyl, imidazolyl, or pyridyl.

8. The compound according to any one of claims 5–7, wherein each R8is independently unsubstituted or substituted C1-C6alkyl or unsubstituted or substituted heterocycloalkyl.

9. The compound according to any one of claims 5–7, wherein each R8is independently methyl, 2-(dimethylamino)ethyl, 2-hydroxypropan-2-yl, 1-methylazetidin-3-yl, or morpholinopyridin-2-yl.

10. A compound of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl, wherein at least one of Y1and Y2is C1-C6alkyl, C1- C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; R1is unsubstituted or substituted C2-C6alkyl, unsubstituted or substituted C2-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1- C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; and R11is methyl or trideuteromethyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

11. A compound of Formula (V): Formula (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl;or , wherein: R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl;R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

12. The compound of claim 11 further defined as:Formula (V-A) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; andeach R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

13. The compound of claim 11 further defined as:Formula (V-B) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substitutedwith one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

14. The compound of claim 11 further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein:each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

15. The compound of claim 11 further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R1is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substitutedC1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

16. The compound of claim 11 further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl; or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl;R1and R18are each independently hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

17. The compound of claim 11 further defined as:Formula (V-F) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: n is 0, 1, or 2; p is 0 or 1; Y1and Y2are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, or C1-C6heteroalkyl;or Y1and Y2are taken together with the carbon atom to which they are attached to form C=O, C3-C6monocyclic cycloalkyl, or 3- to 6-membered monocyclic heterocycloalkyl; R18is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C1-C6deuteroalkyl, unsubstituted or substituted C1-C6fluoroalkyl, unsubstituted or substituted C1-C6heteroalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl, wherein: each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted heteroalkyl, substituted cycloalkyl, and substituted heterocycloalkyl is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, C1-C6alkyl, -CN, -OR15, -N(R15)2, and -SR15; and each R15is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, and C1-C6heteroalkyl; R3is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl; R11is methyl or trideuteromethyl; each R17is fluoro; or two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl; X1, X2, and X3are each independently CR12or N, wherein: each R12is independently hydrogen or halogen; B1is N or CH; and R14is hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, or C1-C6fluoroalkyl.

18. The compound according to any one of claims 11–13, 16, and 17, wherein R18is hydrogen, unsubstituted or substituted C1-C6alkyl, or unsubstituted or substituted cycloalkyl.

19. The compound according to any one of claims 11–13 and 16–18, wherein R18is hydrogen, methyl, or cyclopropyl.

20. The compound according to any one of claims 2–3 and 10–19, wherein n is 0 or 1.

21. The compound according to any one of claims 2–3 and 10–20, wherein n is 0.

22. The compound according to any one of claims 2–4 and 10–20, wherein n is 1.

23. The compound according to any one of claims 2–4 and 10–19, wherein n is 2.

24. The compound according to any one of claims 2–4, 10–20, 22, and 23, wherein each R17is fluoro.

25. The compound according to any one of claims 2–4, 10–19, and 23, wherein two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form an unsubstituted or substituted C3-C6cycloalkyl.

26. The compound according to any one of claims 2–4, 10–19, 23, and 25, wherein two R17attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

27. The compound according to any one of claims 2–4 and 10–26, wherein p is 0.

28. The compound according to any one of claims 2–4 and 10–26, wherein p is 1.

29. The compound according to any one of claims 4–28, wherein Y1is hydrogen, methyl, or (methoxy)methyl.

30. The compound according to any one of claims 4–29, wherein Y2is hydrogen, methyl, or (methoxy)methyl.

31. The compound according to any one of claims 4–30, wherein Y1is methyl or (methoxy)methyl and Y2is hydrogen.

32. The compound according to any one of claims 4–31, wherein Y1is methyl and Y2is hydrogen.

33. The compound according to any one of claims 11–30, wherein Y1and Y2are both hydrogen.

34. The compound according to any one of claims 11–28, wherein Y1and Y2are taken together with the carbon atom to which they are attached to form a 3- to 6-membered monocyclic heterocycloalkane.

35. The compound according to any one of claims 11–28 and 34, wherein Y1and Y2are taken together with the carbon atom to which they are attached to form 3-oxetane.

36. The compound according to any one of claims 1–12, 14–16, and 18–35, wherein R1is unsubstituted or substituted C2-C6alkyl.

37. The compound according to any one of claims 1–12, 14–16, and 18–36, wherein R1is ethyl, 2-methoxyethyl, 2-fluoroethyl, or 2,2-difluoroethyl.

38. The compound according to any one of claims 1–9, 11, 12, 14–16, and 18–35, wherein R1is C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl.

39. The compound according to any one of claims 1–9, 11, 12, 14–16, 18–35, and 38, wherein R1is methyl, difluoromethyl, or trideuteromethyl.

40. The compound according to any one of claims 1, 10–12, 14–16, and 18–35, wherein R1is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocycloalkyl.

41. The compound according to any one of claims 1, 10–12, 14–16, 18–35, and 40, wherein R1is cyclopropyl or oxetan-3-yl.

42. The compound according to any one of claims 1–41, wherein R3is C1-C6deuteroalkyl.

43. The compound according to any one of claims 1–42, wherein R3is trideuteromethyl.

44. The compound of claim 1, wherein R11is C1-C6alkyl or C1-C6deuteroalkyl.

45. The compound according to any one of claims 1–44, wherein R11is methyl or trideuteromethyl.

46. The compound according to any one of claims 1–45, wherein X1is CR12.

47. The compound according to any one of claims 1–46, wherein X2is CR12.

48. The compound according to any one of claims 1–47, wherein X3is CR12.

49. The compound according to any one of claims 1–47, wherein X3is N.

50. The compound according to any one of claims 1–49, wherein each R12is independently hydrogen or halogen.

51. The compound according to any one of claims 1–50, wherein each R12is hydrogen or fluoro.

52. The compound according to any one of claims 1–51, wherein B1is N.

53. The compound according to any one of claims 1–52, wherein R14is hydrogen or C1-C6alkyl.

54. The compound according to any one of claims 1–53, wherein R14is hydrogen.

55. The compound of claim 1, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

56. The compound of claim 4, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

57. The compound of claim 5, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

58. The compound of claim 10, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

59. The compound of claim 11 or claim 12, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

60. The compound of claim 11 or claim 13, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

61. The compound of claim 11 or claim 14, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

62. The compound of claim 11 or claim 15, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

63. The compound of claim 11 or claim 16, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

64. The compound of claim 11 or claim 17, wherein the compound is further defined as:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

65. A compound of the formula:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

66. A compound of the formula:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

67. A pharmaceutical composition comprising the compound of any one of claims 1–66, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

68. A method of treating a TYK2-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1–66, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

69. A method of treating an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1–66, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

70. The method of claim 68 or claim 69, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

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