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.

Description

TYK2 INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 604,080, filed on November 29, 2023, and US Provisional Application No. 63 / 717,459, filed on November 7, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE DISCLOSURE

[0002] The present disclosure 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 IFNa signaling. Additional aspects of the disclosure 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-P, IFN-K, IFN-5, IFN-s, IFN-T, IFN-CO, and IFN- (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). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.SUMMARY OF THE DISCLOSURE

[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 bloodbrain 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:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N; each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substitutedheterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is a group of the formula:wherein: each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is unsubstituted or substituted bicyclic carbocycle and unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3- Ce cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-G, cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, - CH2OR18, -CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, - CH2N(R18)2, -NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, - CH2NR18SO2R19, -SR18, -CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, - CH2SO2R19, -SO2N(R18)2, or -CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-Ce heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6- membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, or 3.

[0006] In some embodiments, the compound of Formula (I) is further defined as a compound of Formula (I- A):Formula (I- A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0007] In some embodiments, the compound of Formula (I-A) is further defined as a compound of Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0008] In another aspect, the present disclosure provides compounds of Formula (II):Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -O-, -S-, -S(=O)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1is CF or N, X2is CH or CF, and X3is N; or X1is N, X2is CH or CF, and X3is CH or CF;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, - OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, - S(=O)R17, -SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-Ce cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, - OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, - CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, - NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, - CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-Ce heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided when X1is N, X2is CH, and X3is N, then

[0009] In some embodiments, the compound of Formula (II) is further defined as a compound of Formula (II-A):Formula (II-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0010] In some embodiments, the compound of Formula (II-A) is further defined as a compound of Formula (II-B):Formula (II-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0011] In still another aspect, the present disclosure provides compounds of Formula (III):Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -O-, -S-, -S(=O)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N; each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ceheteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, - OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, - S(=O)R17, -SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle;or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-Ce cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, - CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, - NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, - CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; m is 1, 2, 3, or 4; p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided that when m is 1, then

[0012] In some embodiments, the compound of Formula (III) is further defined as a compound of F ormul a (III-A) :Formula (III- A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0013] In some embodiments, the compound of Formula (III-A) is further defined as a compound of Formula (III-B):Formula (III-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0014] 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.

[0015] 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 for administration 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.

[0016] Described herein are compounds of Formulae (I)-(III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof useful in the treatment of TYK2 -mediated disorders. Described herein are compounds of Formulae (I)-(III), 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: multiple sclerosis, such as relapsing or relapsing-remitting multiple sclerosis; stroke; epilepsy; encephalomyelitis, such as acute disseminated encephalomyelitis; polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy; encephalitis, such as autoimmune encephalitis; or a neuromyelitis optica spectrum disorder, such as neuromyelitis optica.

[0017] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formulae (I)-(III), 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.

[0018] 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, thecompound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0019] In any of the embodiments disclosed herein, the mammal is a human.

[0020] In some embodiments, compounds provided herein are orally administered to a human.

[0021] 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.

[0022] 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 DISCLOSURE

[0023] 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.

[0024] 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, scleroderma; or diseases and conditions of the eye, such as Sjogren’s syndrome, uveitis, and dry eye.

[0025] 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.

[0026] 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, furthersuggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. Various type I IFN signaling pathways dependent on TYK2 signaling have implicated TYK2 in SLE and other autoimmune diseases and conditions.

[0027] 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.

[0028] 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.

[0029] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-P (AP) peptide. Decreased TYK2 phosphorylation of STAT3 following Ap administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer’s patients.

[0030] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

[0031] 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 sideeffects associated with the inhibition of JAK2. For example, compounds with increased activity or increased selectivity over other JAK kinases (especially JAK2). The present disclosure relatesto compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2) and inhibit certain cytokine signaling, in particular IL-23 and IFNa 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.

[0032] 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

[0033] 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, a compound described herein exhibits improved blood-brain barrier penetration relative to previously disclosed TYK2 inhibitors.

[0034] In one aspect, the present disclosure provides compounds of Formula (I):Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -S02-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N; each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=0)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=0)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is a group of the formula:wherein: each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Cealkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, - N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is unsubstituted or substituted bicyclic carbocycle and unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-Ce cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, - OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, - CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, - NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, - CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, or 3.

[0035] In another aspect, the present disclosure provides compounds of Formula (II):Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8;each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1is CF or N, X2is CH or CF, and X3is N; or X1is N, X2is CH or CF, and X3is CH or CF;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=0)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, - S(=O)R17, -SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-Ce cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, - OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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; andeach R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, - CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, - NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, - CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided when X1is N, X2is CH, and X3is N, then

[0036] In still another aspect, the present disclosure provides compounds of Formula (III):Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci- Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N; each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substitutedheterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci- Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, - OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, - S(=O)R17, -SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-Ce cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, - CO2R18, -CH2CO2R18, -C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, - NR18C(=O)R18, -CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, - CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; m is 1, 2, 3, or 4;p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided that when m is 1, thennot

[0037] In some embodiments, R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is hydrogen, Ci- Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is C1-C4 alkyl, Ci-Ce heteroalkyl, C1-C4 deuteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is C1-C4 alkyl, C1-C4 deuteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R4is C1-C4 alkyl, Ci-Ce heteroalkyl, or C1-C4 deuteroalkyl. In some embodiments, R4is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R4is Ci- C4 deuteroalkyl. In some embodiments, R4is 2,2,2-trideuterioeth-l-yl.

[0038] In some embodiments, R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl. In some embodiments, R1is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R1is hydrogen or Ci-Ce alkyl. In some embodiments, R1is hydrogen or C1-C4 alkyl. In some embodiments, R1is hydrogen.

[0039] In some embodiments, R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. In some embodiments, R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R5is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C4 cycloalkyl. In some embodiments, R5is hydrogen or C1-C4 alkyl. In some embodiments, R5is hydrogen.

[0040] In some embodiments, B1is CR12aand B2is CR12b; or B1is N and B2is CR12b; or B1is CR12aand B2is N; or B1is N and B2is N. In some embodiments, B1is CR12aand B2is CR12b. In some embodiments, B1is N; and B2is CR12b. In some embodiments, B1is CR12aand B2is N.

[0041] In some embodiments, R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2.

[0042] In some embodiments, R12aand R12bare each independently hydrogen, halogen, Ci-Ce alkyl, Ci-C6fluoroalkyl, -CN, -OH, -OR17, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -SO2R17, or -SO2N(R16)2. In some embodiments, R12aand R12bare each independently hydrogen, halogen, Ci- C6alkyl, Ci-C6fluoroalkyl, -CN, -OH, -OR17, -C(=O)N(R16)2, -N(R16)2, or -SO2N(R16)2. In some embodiments, R12aand R12bare each independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, -CN, -OH, -OR17, -N(R16)2. In some embodiments, R12aand R12bare each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR17, or -N(R16)2. In some embodiments, R12aand R12bare each independently hydrogen, halogen, C1-C4 alkyl, Ci- C4 fluoroalkyl, or -CN. In some embodiments, R12aand R12bare each independently hydrogen, halogen, or -CN. In some embodiments, R12aand R12bare each independently hydrogen or halogen. In some embodiments, R12aand R12bare each hydrogen.

[0043] In some embodiments, B1is CH. In some embodiments, B2is CH. In some embodiments, B1and B2are each CH.

[0044] In some embodiments, Z is -NR10-, -O-, -S-, -S(=O)-, or -SO2-. In some embodiments, Z is -NR10-, -O-, -S-, or -SO2-. In some embodiments, Z is -NR10-, -O-, or -SO2-. In some embodiments, Z is -NR10-, -O-, 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 -S(=O)-. In some embodiments, Z is -SO2-. In some embodiments, Z is -NR10- or -O-. In some embodiments, Z is -NR10-.

[0045] In some embodiments, R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl. In some embodiments, R10is Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocycloalkyl. In some embodiments, R10is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R10is C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R10is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R10C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R10is Ci-Ce alkyl. In some embodiments, R10is C1-C4 alkyl. In some embodiments, R10is methyl.

[0046] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0047] In some embodiments, the compound of Formula (I) is further defined as a compound of Formula (I- A):Formula (I- A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0048] In some embodiments, the compound of Formula (II) is further defined as a compound of Formula (II- A):Formula (II-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0049] In some embodiments, the compound of Formula (III) is further defined as a compound of F ormul a (III- A) :Formula (III- A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0050] In some embodiments, Ring A is an unsubstituted or substituted carbocyclic ring whereinA1and A2are both C, wherein if Ring A is substituted then Ring A is substituted with pinstances of R8. In further embodiments, Ring A is an unsubstituted or substituted phenyl, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

[0051] In some embodiments, Ring A is an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

[0052] In some embodiments, Ring A is an unsubstituted or substituted 5- or 6-membered heterocycloalkyl ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted 5-membered heterocycloalkyl ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted 6-membered heterocycloalkyl ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

[0053] In some embodiments, Ring A is an unsubstituted or substituted triazolone, unsubstituted or substituted pyridone, unsubstituted or substituted pyridazinone, unsubstituted or substituted imidazolidinone, or unsubstituted or substituted oxazolidinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted triazolone, unsubstituted or substituted pyridone, or unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted triazolone or an unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with 1 R8. In some embodiments, Ring A is an unsubstituted or substituted triazolone, wherein if Ring A is substituted then Ring A is substituted with 1 R8. In some embodiments, Ring A is an unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with 1 R8.

[0054] In some embodiments, Ring A is an unsubstituted or substituted triazolone, unsubstituted or substituted pyridone, unsubstituted or substituted imidazolidinone, or unsubstituted or substituted oxazolidinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted triazolone or unsubstituted or substituted pyridone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted triazolone, wherein if Ring A is substituted then Ring A is substituted with 1 R8.

[0057] In some embodiments, Ring A is an unsubstituted or substituted 5- or 6-membered heteroaryl ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

[0058] In some embodiments, Ring A is an unsubstituted or substituted 5-membered heteroaryl ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrrole, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted oxazole, unsubstituted or substituted isoxazole, unsubstituted or substituted thiazole, unsubstituted or substituted isothiazole, unsubstituted or substituted triazole, unsubstituted or substituted oxadiazole, unsubstituted or substitutedthiadiazole, unsubstituted or substituted tetrazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridazine, or unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted oxazole, unsubstituted or substituted thiazole, unsubstituted or substituted triazole, unsubstituted or substituted tetrazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridazine, or unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted thiazole, unsubstituted or substituted triazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridazine, or unsubstituted or substituted pyridazinone, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted thiazole, unsubstituted or substituted triazole, or unsubstituted or substituted pyridazine, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted thiazole, or unsubstituted or substituted triazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, unsubstituted or substituted thiazole, or unsubstituted or substituted triazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole or unsubstituted or substituted triazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted pyrazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8. In some embodiments, Ring A is an unsubstituted or substituted triazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.some embodiments, Ring A isIn some embodiments, Ring A issome embodiments, Ring A isIn some embodiments, Ring A issome embodiments, Ring A isIn some embodiments, Ring A issome embodiments, Ring A isIn some embodiments, Ring A issome embodiments, Ring A isIn some embodiments, Ring A is

[0060] In some embodiments,wherein A1and A2are each independently N or C; and A3, A4, and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is not C, or at least one of A3, A4, and A5is not -CR8-.

[0061] In some embodiments, the compound of Formula (I- A) is further defined as a compound of Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0062] In some embodiments, the compound of Formula (II- A) is further defined as a compound of Formula (II-B):Formula (II-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0063] In some embodiments, the compound of Formula (III- A) is further defined as a compound of Formula (III-B):Formula (III-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

[0064] In some embodiments, A1is C; A2is N or C; A3is N, CR8, or C=O; A4is N, NR8, S, or CR8; and A5is N, NR8, S, or CR8. In some embodiments, A1is C; A2is N or C; A3is N, CR8, or C=O; A4is NR8or CR8; and A5is N, NR8, S, or CR8. In further embodiments, A1is C; A2is N or C; A3is N or C=O; A4is NR8or CR8; and A5is N, S, or CR8.

[0065] In some embodiments:A1is C; A2is C; A3is N; A4is NR8, O, or S; and A5is CR8; or A1is C; A2is C; A3is N; A4is NR8, O, or S; and A5is N; or A1is C; A2is C; A3is NR8, O, or S; A4is N; and A5is N; or A1is C; A2is C; A3is NR8, O, or S; A4is N; and A5is CR8; or A1is N; A2is C; A3is N; A4is N; and A5is CR8; or A1is C; A2is C; A3is N; A4is N; and A5is NR8; or A1is C; A2is N; A3is N; A4is CR8; and A5is N; or A1is C; A2is N; A3is N; A4is N; and A5is N; or A1is N; A2is C; A3is N; A4is N; and A5is N; or A1is C; A2is N; A3is N; A4is CR8; and A5is CR8; or A1is C; A2is N; A3is N; A4is N; and A5is CR8; or A1is C; A2is N; A3is CR8; A4is N; and A5is CR8; or A1is C; A2is N; A3is CR8; A4is CR8; and A5is N; or A1is N; A2is C; A3is N; A4is CR8; and A5is CR8; or A1is C; A2is C; A3is N; A4is CR8; and A5is NR8, O, or S; or A1is C; A2is C; A3is NR8, O, or S; A4is CR8; and A5is N;or A1is C; A2is N; A3is C=O; A4is NR8; and A5is N; or A1is C; A2is C; A3is N or CR8; A4is NR8; and A5is N; or A1is C; A2is N; A3is CR8; A4is N; and A5is N.

[0066] In some embodiments: A1is C; A2is C; A3is N; A4is N or NR8; and A5is N or NR8.In some embodiments:A1is C; A2is C; A3is N; A4is NR8; and A5is N; or A1is C; A2is C; A3is N; A4is N; and A5is NR8.

[0067] In some embodiments, A1is C; A2is C; A3is N; A4is NR8; and A5is N. In some embodiments, A1is C; A2is C; A3is N; A4is N; and A5is NR8.

[0068] In some embodiments: A1is C; A2is C; A3is N; A4is NR8; and A5is N or CR8. In some embodiments:A1is C; A2is C; A3is N; A4is NR8; and A5is N; or A1is C; A2is C; A3is N; A4is NR8; and A5is CR8.

[0069] In some embodiments, A1is C; A2is C; A3is N; A4is NR8; and A5is N. In some embodiments, A1is C; A2is C; A3is N; A4is NR8; and A5is CR8.

[0070] In some embodiments, A1is C; A2is C; A3is N; A4is NR8; and A5is N.

[0071] In some embodiments, each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci- Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH.

[0072] In some embodiments, each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci- Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; wherein ifR8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH.

[0073] In some embodiments, each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R16, - CO2R16, or -C(=O)N(R16)2; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH.

[0074] In some embodiments, each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted heterocycle; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle or unsubstituted or substituted heterocycle; or two R8attached to the same carbon atom are taken together to form =0.

[0075] In some embodiments, each R8is independently unsubstituted or substituted Ci-Ce alkyl. In some embodiments, each R8is independently methyl.

[0076] In some embodiments, at least one R8is not methyl.

[0077] In some embodiments, each R8is independently hydrogen, halogen, unsubstituted or substituted C2-C6 alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted heterocycle; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle or unsubstituted or substituted heterocycle; or two R8attached to the same carbon atom are taken together to form =0.

[0078] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, or 3. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 0, 2, or 3. In some embodiments, p is 0 or 1. In some embodiments, p is 0 or 2. In some embodiments, p is 0 or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0; and Ring A is therefore unsubstituted.

[0079] In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR17, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SO2R17, or -SO2N(R16)2. In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR17, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SO2R17, or - SO2N(R16)2. In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, -CN, -OH, - OR17, and -N(R16)2.In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, -CN, -OH, -OR17, and - N(R16)2. In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, or Ci-Ce heteroalkyl. In some embodiments, each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, or Ci-Ce deuteroalkyl. In some embodiments, each R6and R7is independently hydrogen, deuterium, Ci-Ce alkyl, Ci-Ce deuteroalkyl, or Ci-Ce heteroalkyl. In some embodiments, each R6and R7is independently hydrogen, deuterium, Ci-Ce alkyl, or Ci-Ce deuteroalkyl. In some embodiments, each R6and R7is independently hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuteroalkyl, or Ci-Ce heteroalkyl. In some embodiments, each R6and R7is independently hydrogen or C1-C4 alkyl. In some embodiments, each R6and R7is independently hydrogen or methyl. In some embodiments, each R6and R7is independently hydrogen. In some embodiments, each R6and R7is independently methyl. In some embodiments, one R6or R7is hydrogen or methyl. In some embodiments, one R6or R7is hydrogen. In some embodiments, one R6or R7is methyl. In some embodiments, one R6is hydrogen or methyl. In some embodiments, one R6is hydrogen. In some embodiments, one R6is methyl. In some embodiments, one R7is hydrogen or methyl. In some embodiments, one R7is hydrogen. In some embodiments, one R7is methyl. In some embodiments, each R6and R7is hydrogen. In some embodiments, each R6is methyl and each R7is hydrogen. In some embodiments, each R6is hydrogen and each R7is methyl. In some embodiments, one R6is methyl and one R7is hydrogen. In some embodiments, one R6is hydrogen and one R7is methyl.

[0080] In some embodiments, one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane. In some embodiments, one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O. In some embodiments, one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkane. In some embodiments, one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkane. In some embodiments, one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropane.

[0081] In some embodiments, each R6and R7is independently hydrogen, deuterium, Ci-Ce alkyl, Ci-Ce deuteroalkyl, or Ci-Ce heteroalkyl; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkane. In some embodiments, each R6and R7is independently hydrogen or methyl; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropane. In some embodiments, each R6and R7is independently hydrogen or methyl.

[0082] In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0083] In some embodiments:X1is CR11, X2is CR11, and X3is CR11; or X1is CR11, X2is CR11, and X3is N; or X1is CR11, X2is N, and X3is CR11; or X1is CR11, X2is N, and X3is N; or X1is N, X2is CR11, and X3is CR11; or X1is N, X2is CR11, and X3is N; or X1is N, X2is N, and X3is CR11.

[0084] In some embodiments, X1is CR11, X2is CR11, and X3is N.

[0085] In some embodiments, each R11is independently hydrogen, halogen, Ci-Ce alkyl, Ci- Ce fluoroalkyl, -CN, -OH, -OR17, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -SO2R17, or -SO2N(R16)2. In some embodiments, each R11is independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, -CN, -OH, -OR17, -C(=O)N(R16)2, -N(R16)2, or -SO2N(R16)2. In some embodiments, each R11is independently hydrogen, halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, -CN, -OH, -OR17, or -N(R16)2. In some embodiments, each R11is independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR17, or -N(R16)2. In some embodiments, each R11isindependently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, each R11is independently hydrogen, halogen, Ci-Ce alkyl, or -CN. In some embodiments, each R11is independently hydrogen, halogen, or -CN. In some embodiments, each R11is independently hydrogen, halogen, or Ci-Ce alkyl. In some embodiments, each R11is independently hydrogen or halogen. In some embodiments, each R11is independently hydrogen or fluoro. In some embodiments, each R11is hydrogen. In some embodiments, at least one R11is hydrogen. In some embodiments, at least one R11is fluoro.

[0086] In some embodiments:X1is CH, X2is CH, and X3is N; or X1is CF, X2is CH, and X3is N; or X1is N, X2is CH, and X3is N; or X1is N, X2is CH, and X3is CH.

[0087] In some embodiments, X1is CH, X2is CH, and X3is N.

[0088] In some embodiments:X1is CF, X2is CH, and X3is N; or X1is N, X2is CH, and X3is N; or X1is N, X2is CH, and X3is CH.

[0089] In some embodiments, X1is CF, X2is CH, and X3is N. In some embodiments, X1is N, X2is CH, and X3is N. In some embodiments, X1is N, X2is CH, and X3is CH.

[0090] In some embodiments, R2is 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 q instances of R13; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14.

[0091] In some embodiments, R2is 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 q instances of R13. In some embodiments, R2is 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 q instances of R13.

[0092] In some embodiments, R2is 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 q instances of R13.

[0093] In some embodiments, R2is 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 q instances of R13.

[0094] In some embodiments, R2is 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 q instances of R13. In some embodiments, R2is 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 q instances of R13.

[0095] In some embodiments, R2is 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 q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, or unsubstituted or substituted tetrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, or unsubstituted or substituted tetrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, or unsubstituted or substituted pyrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13.

[0096] In some embodiments, R2is 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 q instances of R13.

[0097] In some embodiments, R2is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted orsubstituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13.

[0098] In some embodiments, R2is 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 q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyridinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In some embodiments, R2is a Ring B that is an unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13.

[0099] In further embodiments, R2is 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 q instances of R13. In still further embodiments, R2is 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 q instances of R13. In yet further embodiments, R2is 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 q instances of R13. In further embodiments, R2is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In other embodiments, R2is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13. In further embodiments, R2is a Ring B that is an unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R13.

[0100] In some embodiments:and q is 0, 1, 2, 3, or 4.

[0101] In some embodiments:2, 3, or 4.

[0102] In further embodiments:

[0103] In some embodiments:, wherein q is 0, 1, 2, or 3.

[0104] In still further embodiments:

[0105] In some embodiments, R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14; or a group of. , ; g p. In some embodiments, R2is -C(=O)R14; or a group of the formula:embodiments, R2is -C(=O)R14; or a group of the

[0106] In some embodiments, R2is a group of the formula:embodiments, R2is a group of the formula:some embodiments, R2is a group of the formula:some embodiments, R2is a group of the formula:some embodiments, R2is a group of the formula:

[0107] In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0, 1, or 3. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0, 2, or 3. In some embodiments, q is 0 or 1. In some embodiments, q is 0 or 2. In some embodiments, q is 0 or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 1. In further embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 0 and Ring B is therefore unsubstituted.

[0108] In some embodiments, each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SO2R17, or -SO2N(R16)2. In some embodiments, each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R16, -CO2R16, or -C(=O)N(R16)2. In some embodiments, each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, or unsubstituted or substituted heterocycle. In some embodiments, each R13is independently halogen or unsubstituted or substituted Ci-Ce alkyl. In some embodiments, each R13is independently halogen or unsubstituted or substituted heterocycle. In some embodiments, each R13is independently unsubstituted or substituted Ci-Ce alkyl or unsubstituted or substituted heterocycle. In some embodiments, each R13is independently halogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R16, -CO2R16, or -C(=O)N(R16)2. In some embodiments, each R13is independently halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, each R13is independently halogen. In some embodiments, each R13is independently unsubstituted or substituted Ci-Ce alkyl. In some embodiments, at least one R13is independently unsubstituted or substituted Ci-Ce alkyl. In further embodiments, each R13is independently unsubstituted C1-C4 alkyl. In further embodiments, at least one R13is independently unsubstituted C1-C4 alkyl. In still further embodiments, each R13is methyl. In some embodiments, at least one R13is methyl. In some embodiments, each R13is independently unsubstituted or substituted heterocycle. In some embodiments, each R13is independently unsubstituted or substituted heterocycloalkyl. In some embodiments, each R13is independently unsubstituted heterocycloalkyl.

[0109] In some embodiments, R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14. In some embodiments, R2is -C(=O)R14.

[0110] In some embodiments, R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, or unsubstituted or substituted monocyclic carbocycle. In some embodiments, R14is unsubstituted or substituted Ci- Ce alkyl or unsubstituted or substituted monocyclic carbocycle. In some embodiments, R14is unsubstituted or substituted monocyclic carbocycle. In some embodiments, R14is unsubstituted or substituted C3-C8 cycloalkyl. In some embodiments, R14is unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R14is unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R14is unsubstituted or substituted cyclopropyl. In some embodiments, R14is cyclopropyl.

[0111] In some embodiments, R14is unsubstituted or substituted bicyclic carbocycle and unsubstituted or substituted bicyclic heterocycle. In some embodiments, R14is unsubstituted or substituted bicyclic heterocycle. In some embodiments, R14is unsubstituted or substituted bicyclic carbocycle. In some embodiments, R14is C5-C12 bicyclic carbocycle. In some embodiments, R14is C5-C12 bicyclic cycloalkyl.

[0112] In some embodiments, R14is a group of the formula:wherein:x and y are each independently 0, 1, 2, 3, 4, wherein the sum of x and y is at least 1; and z is 1, 2, 3, 4, 5, 6, 7, or 8.

[0113] In some embodiments, R14is a group of the formula:wherein: x and y are each independently 0, 1, or 2, wherein the sum of x and y is at least 1; and z is 1, 2, 3, or 4.

[0114] In some embodiments, R14is a group of the formula:wherein: x and y are each independently 0 or 1, wherein the sum of x and y is at least 1; and z is 1.

[0115] In some embodiments, x and y are each independently 0, 1, 2, 3, or 4, wherein the sum of x and y is at least 1. In some embodiments, x and y are each independently 0, 1, 2, or 3, wherein the sum of x and y is at least 1. In some embodiments, x and y are each independently 0, 1, or 2, wherein the sum of x and y is at least 1. In some embodiments, x and y are each independently 0 or 1, wherein the sum of x and y is at least 1.

[0116] In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, z is 1, 2, 3, or 4. In some embodiments, z is 1, 2, or 3. In some embodiments, z is 1 or 2. In some embodiments, z is 1.

[0117] In some embodiments,

[0118] In some embodiments, each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two R16on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, each R16is independently hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two R16on the same N atom are taken together with the N atom to which they are attached to form a 4- to 6-membered N- containing heterocycloalkyl.

[0119] In some embodiments, each R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, each R17is independently Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0120] In some embodiments, compounds described herein have the following structure:

[0121] In some embodiments, R2, A1, A2, Ring A, R8, and p are as described herein. In some embodiments, R2, A1, A2, Ring A, R8, and p are as described in Table 1. In some embodiments, A1, A2, Ring A, R8, and p are as described in Table 1 or Table 2. In some embodiments, A1, A2, Ring A, R8, and p are as described in Table 1.

[0122] In some embodiments, compounds described herein have the following structure:

[0123] In some embodiments, X1, X3, A1, A2, Ring A, R8, and p are as described herein. In some embodiments, X1, X3, A1, A2, Ring A, R8, and p are as described in Table 2. In some embodiments, A1, A2, Ring A, R8, and p are as described in Table 1 or Table 2. In some embodiments, A1, A2, Ring A, R8, and p are as described in Table 2.

[0124] Exemplary compounds described herein include the compounds described in the following tables:Table 1* = Single isomer obtained by chiral separation of racemic compound. Absolute configuration not determined. = Obtained as a racemic mixture, = Obtained as a mixture of diastereomers.

[0125] Compounds in Table 1 are named:1: rac-(R)-l-methyl-4-((5-(propanoyl-3,3,3-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(lH)-one;5: (S)-l-methyl-4-((5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1.2.3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(lH)-one;8: rac-(R)-N-(5-(propanoyl-3,3,3-d3)-4-(((S)-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-yl)amino)pyridin-2-yl)spiro[2.2]pentane-l-carboxamide; and9: rac-(R)-N-(5-(propanoyl-3,3,3-d3)-4-(((R)-2,4,5-trimethyl-4,5-dihydro-2H-[1.2.3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridin-2-yl)spiro[2.2]pentane-l- carboxamide.

[0126] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound described in Table 1.Table 2* = Single isomer obtained by chiral separation of racemic compound. Absolute configuration not determined. = Obtained as a racemic mixture, = Obtained as a mixture of diastereomers.

[0127] Compounds in Table 2 are named:2: rac-(R)-N-(4-((9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide;3: rac-(R)-N-(4-((9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-yl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide;10: (S)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide;11: rel-(R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H- pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide;12: rel-(R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,5]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; and13: rel-(R)-N-(5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,5]naphthyridin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide.

[0128] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound described in Table 2.

[0129] In some embodiments, the compound described herein has the following structure:

[0130] Compound 4 is named: N-(4-((2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-l, d'fl, 2, 3]triazolo[4, 5-c][l, 7]naphthyridin]-6'-yl)amino)-5-(propanoyl-3, 3, 3-d3)pyri din-2- yl)cyclopropanecarboxamide. In some embodiments, provided herein is a pharmaceutically acceptable salt of Compound 4.

[0131] 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.

[0132] “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.

[0133] 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 / Zurich: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 thesalt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0134] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formulae (I)-(III) with an acid. In some embodiments, the compound of Formulae (I)-(III) (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, l-hydroxy-2-naphthoic acid; 2, 2-di chloroacetic acid; 2 -hydroxy ethanesulfonic 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-l,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; naphthal ene-l,5-disulfonic acid; naphthal ene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ( / ?); and undecylenic acid.

[0135] In some embodiments, a compound of Formulae (I)-(III) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0136] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formulae (I)-(III) with a base. In some embodiments, the compound of Formulae (I)-(III) is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formulae (I)-(III) 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, di cyclohexylamine, 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, thecompounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0137] 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.

[0138] The methods and formulations described herein include the use of A-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formulae (I)-(III), as well as active metabolites of these compounds having the same type of activity.

[0139] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formulae (I)-(III) 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.

[0140] 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.

[0141] 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,170,35S,18F,36C1,123I,124I,125I,1311,32P 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.

[0142] In some embodiments, the compounds of Formulae (I)-(III) 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)-(III) exists in the R configuration. In some embodiments, the compound of Formulae (I)-(III) 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.

[0143] 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)-(III) 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 by chromatography 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.

[0144] 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, aprodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0145] 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. etal., 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.

[0146] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formulae (I)-(III) 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.

[0147] 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.

[0148] 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.

[0149] 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 reductivereactions 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.

[0150] 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:all of which are encapsulated within the group, “substituted pyridines.” Similarly, triazolones could exist in the following tautomeric forms, which include zwitterionic forms:all of which are encapsulated within the group, “substituted 5-membered heteroaryl.” Similarly, pyrazidinones could exist in the following tautomeric forms, which include zwitterionic forms:all of which are encapsulated within the group, “substituted 6-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.General Synthesis of the Compounds of the Present Disclosure

[0151] Compounds of Formulae (I)-(III) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0152] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0153] 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.

[0154] In some embodiments, compounds described herein are prepared as described in Scheme A, or analogously thereto.Scheme A:Variables are as defined in Formulae (I)-(III).

[0155] 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 group with 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.

[0156] In some embodiments, compounds are prepared as described in the Examples.Certain Terminology

[0157] 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.

[0158] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “Ci-Ce” 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-C4 alkyl” 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, Ao-propyl, / / -butyl, iso- butyl, ec-butyl, and / -butyl.

[0159] 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 Ci- Cioalkyl. 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 Ci-Ce alkyl. 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.

[0160] 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 Ci-Ce alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0161] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0162] The term “alkylamine” refers to the -N(alkyl)xHygroup, 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.

[0163] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a Ci-C4hydroxy alkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.

[0164] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a Ci-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and the like.

[0165] 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 ordifferent. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (z.e., vinyl), propenyl (z.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Nonlimiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and -CH2CH=CH2.

[0166] 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, -OCCH3 - OCCH2CH3, -CH2OCH.

[0167] 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 Ci-Ce heteroalkyl.

[0168] The term “deuteroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a deuterium atom. In one aspect, a deuteroalkyl is a Ci-Cedeuteroalkyl.

[0169] The term “aromatic” refers to a planar ring having a delocalized 7t-electron system containing 4n+2 71 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.

[0170] 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 carbocyclic from “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. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems.

[0171] 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 Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0172] 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, a bicyclic cycloalkyl is fused, spirocyclic, or bridged. 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. In some embodiments, 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 bicyclo[l.l.l]pentyl. In some embodiments, a cycloalkyl is a Cs-Cecycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.

[0173] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0174] 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 Ci-Cefluoroalkyl.

[0175] The term “fluoroalkoxy” refers to a (fluoroalkyl)O- group, where fluoroalkyl is as defined herein.

[0176] 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-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)- onyl, isoindoline-1, 3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-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 TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV- attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-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 (=0) 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.

[0177] 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 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl.

[0178] 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-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some embodiments, aheterocycloalkyl 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.

[0179] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties 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.

[0180] 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.

[0181] 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(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), - C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci- C4alkyl, C3-Cecycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-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 (=0).

[0182] In some embodiments, each substituted alkyl, substituted deuteroalkyl, 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, Ci-Ce alkyl, 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, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-Ce cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryland 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 Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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 the desired 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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)-(III), 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)-(III), 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 two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0192] The terms “article of manufacture” and “kit” are used as synonyms.

[0193] 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 animalsincluding rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0194] 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

[0195] 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. 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’sPharmaceutical 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 & Wilkinsl999), herein incorporated by reference for such disclosure.

[0196] 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.

[0197] 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-P, IFN-K, IFN-5, IFN-s, IFN-T, IFN-CO, and IFN- (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. In some embodiments, the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratorydisease or disorder, type 1 diabetes, and interferonopathies such as Alcardi-Goutieres syndrome, or combinations thereof.

[0198] 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.

[0199] 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, Sjogren’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.

[0200] 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 effected by 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).

[0201] 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.

[0202] 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 cores are 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 beadded to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0203] 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 multidose 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.

[0204] 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.

[0205] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present disclosure 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.

[0206] Pharmaceutical compositions suitable for topical administration include liquid or semiliquid 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.

[0207] 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 orinsufflation, 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.

[0208] 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

[0209] 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-a, IFN- P, IFN-K, IFN-5, IFN-s, IFN-T, IFN-CO, and IFN-^ (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).

[0210] 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-a / p, 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.

[0211] Additionally, increased levels of IL-12 and IL-23 have been found in MS lesions, and IFN-y 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 pl9 are resistant to EAE; and systemic injection of recombinant IL- 12 or intracerebral injection of an IL-23 encoding adenoviral vector induces clinical relapses of EAE. Accordingly, use of a TYK2 inhibitor can interrupt this important pathology in MS and other CNS disorders.

[0212] TYK2 -mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-P (AP) peptide, which demonstrates its role in potential treatment ofAlzheimes’s Disease (AD). Decreased TYK2 phosphorylation of STAT3 following Ap 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).

[0213] In some embodiments, certain TYK2 inhibitors described herein penetrate the bloodbrain barrier. In some embodiments, certain TYK2 inhibitors described herein have a mean braimplasma ratio of at least 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean braimplasma ratio of more than 0.3. In some embodiments, certain TYK2 inhibitors described herein have a mean braimplasma ratio of at least 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean braimplasma ratio of more than 0.5. In some embodiments, certain TYK2 inhibitors described herein have a mean braimplasma 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.

[0214] 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.

[0215] In one aspect, the present disclosure provides methods of treating a 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, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition is a TYK2 -mediated disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is a neuroinflammatory disease or condition. In some embodiments, the disease or condition is a neurodegenerative disease or condition. In some embodiments, the disease or condition isselected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, the multiple sclerosis is relapsing or relapsing-remitting. In some embodiments, the disease or condition is a neuromyelitis optica spectrum disorder. In some embodiments, the disease or condition is neuromyelitis optica. In some embodiments, the disease or condition is encephalomyelitis. In some embodiments, the disease or condition is acute disseminated encephalomyelitis. In some embodiments, the disease or condition is polyneuropathy. In some embodiments, the disease or condition is chronic inflammatory demyelinating polyneuropathy. In some embodiments, the disease or condition is encephalitis. In some embodiments, the disease or condition is autoimmune encephalitis. In some embodiments, the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren’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.Methods of Dosing and Treatment Regimens

[0216] 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 such treatment, 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.

[0217] 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.

[0218] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorderor 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.

[0219] 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.

[0220] 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.

[0221] 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 to the 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.

[0222] 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.

[0223] 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, therequirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0224] 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 LD50 and 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.

[0225] 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.

[0226] 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.

[0227] 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

[0228] 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.

[0229] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (z.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.

[0230] 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.

[0231] 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.

[0232] 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 or condition being treated and so forth. In additional embodiments, when coadministered 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.

[0233] 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).

[0234] 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, thecompounds 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

[0235] As used above, and throughout the description of the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:Abbreviations:ACN acetonitrileCAN ceric ammonium nitrateDCM dichloromethaneDIBAL diisobutylaluminum hydrideDIPEA N,N-diisopropylethylamineDMA dimethylacetamideDMF N,N-dimethylformamideDMSO dimethylsulfoxideEtOAc ethyl acetateEGTA ethylene glycol-bis(P-aminoethyl ether)-N,N,N’,N’ -tetraacetic acidES electrosprayFBS fetal bovine serumGST glutathione S-transferaseHEK human embryonic kidneyHEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acidHMDS bis(trimethylsilyl)amideHPLC high pressure liquid chromatographyHTRF homogenous time resolved fluorescenceIC50 half maximal inhibitory concentrationIFN interferonIL interleukinIPA isopropyl alcoholJAK Janus kinaseLCMS liquid chromatography-mass spectrometryMDI metered drug inhalantMW micro waveNMR nuclear magnetic resonanceSEAP secreted embryonic alkaline phosphataseSTAT signal transducer and activator of transcriptionT3P propanephosphonic acid anhydrideTBAF tetra-n-butylammonium fluorideTBDMS tert-butyldimethylsilylTBDPS tert-butyldiphenylsilylTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin-layer chromatographyTYK non-receptor tyrosine-protein kinase

[0236] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.I. Synthesis of CompoundsExample 1: Preparation of (S)-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-amine (1-1): i) CH3NH2 HCI, TEAi) 4 M HCI / 1 ,4-dioxane0 °C-rt, 16 h cyclopropanecarboxamidePd2(dba)3, [(t-Bu)3PH]BF4ii) DIPEA, 1 ,4-dioxane Pd2(dba)3, Xantphos, Cs2CO3CsF, THF, 70 °C, 16 h 80 °C, 12 h 1 ,4-dioxane, 130 °C, 16 hStep-4Step-5 Step-6

[0237] Step-1: l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (I-lb): To a stirred solution of I-la (40 g, 166 mmol) in anhydrous THF (300 mL) was added 2M solution of isopropylmagnesium chloride in THF (91.3 mL, 183 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMA (77 mL, 830 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4CI solution (100 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 0-10% EtOAc in heptane) to afford desired compound l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one I- 1b (19 g) as a white solid. 'HNMR (400 MHz, DMSO-< / 6) 84.23 (s, 3H), 2.59 (s, 3H).

[0238] Step-2: l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)-N-methylethan-l-amine (I-lc): To a stirred solution of I-lb (17 g, 83.3 mmol) in MeOH (80 mL) was added TEA (23.2 mL, 167 mmol) and methylamine hydrochloride (11.3 g, 167 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. It was then cooled to 0 °C and NaBHj (6.3 g, 167 mmol) was added to it portion-wise. The reaction mixture was allowed to warm to room temperature over 2 h. After completion (as indicated by LCMS), saturated NaHCCh solution (30mL) was added to it and washed with EtOAc (20 mL x 2). The aqueous NaHCCh solution containing l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)-N-methylethan-l-amine I-lc was used for the next step without further purification.

[0239] Step-3: tert-butyl (l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol- 4-yl)ethyl)(methyl)carbamate (I-ld): A solution of (Boc)2O (35.7 mL, 155 mmol) in THF (100 mL) was added to the aqueous NaHCCL solution containing I-lc and the reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and water (50 mL) was added to it. Extraction was carried out using EtOAc (50 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 heptane) to afford tert-butyl (l-(5-(2-chl oro-3 - fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)(methyl)carbamate I-ld (16.0 g) as a colorless thick oil. LCMS (ES) m / z 220.1 [(M-100)+H]+.

[0240] Step-4: tert-butyl (l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol- 4-yl)ethyl)(methyl)carbamate (I-le): Argon gas was purged through a stirred suspension of I- Id (18.0 g, 56.4 mmol), (2-chloro-3-fhioropyridin-4-yl)boronic acid (24.7 g, 141.0 mmol) and CsF (25.7 g, 169 mmol) in THF (50 mL) for 15 min before addition of tri -tertbutylphosphonium tetrafluoroborate (0.98 g, 3.38 mmol) and Pd2(dba)s (2.58 g, 2.82 mmol). The reaction mixture was then stirred at 70 °C for 16 h in a sealed tube. After complete consumption of starting material, it was cooled to room temperature and the reaction mixture was filtered through celite bed. The residue was washed with EtOAc (50 mL x 2) and the combined filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford tert-butyl (l-(5-(2-chloro-3- fhioropyridin-4-yl)-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)(methyl)carbamate I-le (14 g) as a pale yellow gum. LCMS (ES) m / z 370.0 [M+H]+.

[0241] Step-5: 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridine (I-lf): A 4M solution of HC1 in 1,4-dioxane (140 mL) was added to I-le (14 g, 37.9 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After complete consumption of starting material, volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane). To this was added 1,4-dioxane (60 mL) and DIPEA (31.3 mL, 180.0 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 12 h. After complete consumption of starting material, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in hexane) to afford the desired compound 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridine I-lf (8 g) as an off-white solid. LCMS (ES) m / z 250.0 [M+H]+.

[0242] Step-6: N-(2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c] [l,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-lg): Argon gas was purged through a stirred suspension of I-lf (8 g, 32.0 mmol), cyclopropanecarboxamide (5.45 g, 64.1 mmol) and CS2CO3 (31.3 g, 96.1 mmol) in 1,4-di oxane (80 mL) for 15 min before addition of [5-(diphenylphosphanyl)-9,9- dimethyl-9H-xanthen-4-yl]diphenylphosphane (1.85 g, 3.2 mmol) and Pd2(dba)s (2.93 g, 3.2 mmol). The reaction mixture was then stirred at 130 °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 2). The filtrate was concentrated under reduced pressure and the residue was purified by Combi- Flash (using gradient elution of 0-80% EtOAc in Hexane) to afford N-(2,4,5-trimethyl-4,5- dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl)cyclopropanecarboxamide I-lg (8 g) as a pale yellow solid. LCMS (ES) m / z 299.2 [M+H]+.

[0243] Step-7: 2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6- amine (I-lh): To a stirred solution of I-lg (9.0 g, 30.2 mmol) in THF (300 mL) was added an aqueous solution of LiOH (3.61 g, 17.6 mmol, in 100 mL water) at room temperature. It was then stirred at 50 °C for 5 h. After completion, it was cooled to room temperature and water (20 mL) was added to it. Extraction was carried out using 10% MeOH in DCM (100 mL x 2); the combined organic extracts were washed with brine (50 mL), dried over anhydrous ISfeSCU, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% MeOH in DCM) to afford desired compound 2,4,5-trimethyl-4,5- dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-amine I-lh (4.4 g) as an off-white solid. LCMS (ES) m / z; 231.2 [M+H]+.

[0244] Note: Racemate I-lh (4.4 g) was resolved by chiral HPLC separation [Column: CHIRALCEL OJ H (250 mm x 30 mm x 5 pm); Mobile phase: n-Hexane: Ethanol with 0.1% DEA (80:20); Flow rate: 40 mL / min] to afford two enantiomers {I-li (1.8 g): peak-1; Rt; 6.8 min and 1-1 (1.8 g): peak-2; Rt; 9.44 min}, the desired enantiomer 1-1 was used further without confirming the absolute configuration.Example 2: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-amine (1-2):

[0245] Step-1: tert-butyl methyl(l-(2-methyl-5-(tributylstannyl)-2H-l,2,3-triazol-4- yl)ethyl)carbamate (I-2a): Argon gas was purged through a stirred suspension of I-ld (15.0 g, 47 mmol) in hexabutyl ditin ( 24.5 mL, 73.8 mmol) for 15 min. To this was then added Pd(OAc)2 (0.15 g, 0.67 mmol) and tri cyclohexylphosphine (0.38 g, 1.34 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 0-20% EtOAc in heptane) to afford desired compound tert-butyl methyl(l-(2-methyl-5-(tributylstannyl)-2H-l,2,3-triazol-4-yl)ethyl)carbamate I-2a (9.2 g) as a pale yellow semi-solid.

[0246] Step-2: tert-butyl (l-(5-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2-methyl-2H- l,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-2b): Argon gas was purged through a stirred suspension of I-2a (7 g, 13.2 mmol), 2-chloro-3,5-difluoro-4-iodopyridine (5.46 g, 19.8 mmol) and LiCl (1.29 g, 30.4 mmol) in DMF (70.0 mL) for 15 min. To this was then added Pd(PPhs)4 (1.53 g, 1.33 mmol) and Cui (1.26 g, 6.61 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 extraction was carried out using 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 0-30% EtOAc in heptane) to afford tert-butyl (l-(5-(2-chloro-3-fluoro-5- methylpyridin-4-yl)-2-methyl-2H- 1,2, 3 -triazol -4-yl)ethyl)(methyl)carbamate I-2b (3 g) as a colourless liquid. LCMS (ES) m / z 330.2 [(M-Boc)+H]+.

[0247] Step-3: 6-chloro-9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridine (I-2c): TFA (10 mL) was added to a solution of I-2b (3 g, 7.74 mmol) in DCM (30 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material, volatiles were removed under reduced pressure and the residue was dried (co-evaporation with 1,4-dioxane). To this was then added 1,4-dioxane (20 mL) and DIPEA (6.82 mL, 38.2 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution of 0-35% EtOAc in heptane) to afford the desired compound 6-chloro-9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H- [l,2,3]triazolo[4,5-c][l,7]naphthyridine I-2c (0.6 g) as white solid. LCMS (ES) m / z 268.1 [M+H]+.

[0248] Step-4: N-(9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-2d): I-2d (0.5 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-6) using I-2c (0.8 g, 2.99 mmol) and cyclopropanecarboxamide (0.5 g, 5.98 mmol) as the starting materials. LCMS (ES) m / z 317.1 [M+H]+.

[0249] Step-5: 9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-amine (1-2): 1-2 (0.36 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-7) using I-2d (0.5 g, 1.58 mmol) as the starting material. LCMS (ES) m / z; 249.0 [M+H]+.

[0250] Note: Racemate 1-2 (0.94 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 20 mm x 5 pm) Mobile phase: n-Hexane:IPA with 0.1% DEA (50:50) Flow rate : 40.0 mL / min] to afford two enantiomers {I-2A (0.11 g): peak-1; Rt; 6.2 min and I-2B (0.11 g): peak-2; Rt; 9.8 min}, which were used further without their absolute configuration determination.Example 3: Preparation of 2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-l,4'- [l,2,3]triazolo[4,5-c] [l,7]naphthyridin]-6'-amine (1-3):

[0251] Step-1: 5-bromo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde (I-3a): To a stirred solution of I-la (10 g, 41.6 mmol) in THF (100 mL) was added a 2M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMF (16.08 mL, 208 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4CI solution (30 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 0-10% EtOAc in heptane) to afford desired compound 5-bromo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde I-3a (6 g) as an off-white solid. 'HNMR (400 MHz, DMSO-6) 8 9.95 (s, 1H); 4.26 (s, 3H).

[0252] Step-2: (5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (3b): To a stirred solution of I-3a (9.3 g, 48.9 mmol) in MeOH (100 mL) at 0 °C was added sodium borohydride (2.78 g, 73.4 mmol) and the mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was quenched with addition of water (100 mL) and MeOH was concentrated underreduced pressure. Extraction was then carried out using EtOAc (2 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30 % EtOAc in n-heptane) to afford (5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)methanol I-3b (8.0 g) as colorless thick oil. LCMS (ES) m / z; 192.9 [M+H]+. 'HNMR (400 MHz, CDC13) d 4.63 (s, 2H), 4.10 (s, 3H), 2.22 (bs, 1H).

[0253] Step-3: 4-bromo-5-(bromomethyl)-2-methyl-2H-l,2,3-triazole (I-3c): To a stirred solution of I-3b (8.0 g, 41.7 mmol) in DCM (80 mL) was added CBn (18.0 g, 54.2 mmol) and triphenylphosphine (14.2 g, 54.2 mmol) at 0 °C and the reaction was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), water (100 mL) was added to it and extracted with DCM (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by Combi-Flash (using gradient elution of 0-15 % EtOAc in n- heptane) to afford 4-bromo-5-(bromomethyl)-2-methyl-2H-l,2,3-triazole I-3c (10.2 g) as a colourless oil. 'HNMR (400 MHz, CDCI3) d 4.44 (s, 2H), 4.15 (s, 3H).

[0254] Step-4: 2-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)acetonitrile (I-3d): To a stirred solution of I-3c (10.2 g, 40.0 mmol) in ACN (100 mL) was added TMSCN (7.51 mL, 60.0 mmol) and tetrabutylammonium fluoride (1.0 M in THF) (60.0 mL, 60.0 mmol) and the reaction mixture was stirred for 1 h at room temperature. After completion of the reaction (as indicated by TLC), the reaction mixture was diluted with EtOAc (200 mL) and was washed with water (100 mL). Aqueous layer was again extracted with EtOAc (250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-30 % EtOAc in n- heptane) to afford (5- 2-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)acetonitrile I-3d (7.4 g) as a white solid. 'HNMR (400 MHz, CDCI3) d 4.18 (s, 3H), 3.74 (s, 2H).

[0255] Step-5: l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)cyclopropane-l-carbonitrile (I- 3e): To a stirred solution of I-3d (7.4 g, 36.8 mmol) in DMF (70 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C and stirred for 30 min before addition of 1,2-dibromoethane (6.37 mL, 73.6 mmol). The reaction was stirred for 2 h at room temperature, while monitoring reaction progress by TLC. After completion of the reaction, it was quenched with addition of ice cold water (100 mL). Extraction was carried out using EtOAc (2 x 250 mL); the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-20 % EtOAc in n- heptane) to afford l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)cyclopropane-l-carbonitrile I-3e(7.1 g) as a colourless oil. LCMS (ES) m / z; 227.0 [M+H]+. 'HNMR (400 MHz, CDC13) (5 4.13 (s, 3H), 1.77-1.70 (m, 2H), 1.58 -1.51 (m, 2H).

[0256] Step-6: l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)cyclopropane-l-carboxylic acid (I-3f): A suspension of I-3e (10.5 g, 46.2 mmol) in 10% aqueous NaOH solution (250 mL) was stirred at 100 °C for 16 h, while monitoring reaction progress by TLC. After completion of the reaction, the homogeneous solution was washed with EtOAc (300 mL) and the aqueous layer was then acidified using 6 M aqueous HC1 (~ pH 3). Extraction was carried out using 10% MeOH in DCM (2 x 500 mL); the combined organic extracts were dried over anhydrous sodium sulfate, filtered and dried under reduced pressure to afford l-(5-bromo-2-methyl-2H-l,2,3- triazol-4-yl)cyclopropane-l -carboxylic acid I-3f (11.3 g) as an off-white solid. LCMS (ES) m / z; 245.9 [M+H]+. 'HNMR (400 MHz, DMSO ) 3 12.64 (bs, 1H), 4.09 (s, 3H), 1.52-1.49 (m, 2H), 1.21-1.18 (m, 2H).

[0257] Step-7: tert-butyl (l-(5-bromo-2-methyl-2H-l,2,3-triazol-4- yl)cyclopropyl)carbamate (I-3g): To a solution of I-3f (12.2 g, 49.6 mmol) in t-butanol (250 mL) was added triethylamine (10.5 mL, 74.4 mmol) and DPPA (11.3 mL, 59.5 mmol). The resulting mixture was heated at 100 °C for 16 h, while monitoring reaction progress by LCMS. After completion, the reaction mixture was cooled to room temperature and volatile were removed under reduced pressure. The residue was dissolved in EtOAc (500 mL) and was washed with 10% citric acid (100 mL) and water (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-25 % EtOAc in n-heptane) to afford tert-butyl (l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)cyclopropyl)carbamate I-3g (9.3 g) as an off-white solid. LCMS (ES) m / z; 263.0 [(M-56)+H]+. 'H NMR (400 MHz, CDC13) 3 5.31 (bs, 1H), 4.07 (s, 3H), 1.42 (s, 9H), 1.38-133 (m, 2H), 1.21 (bs, 2H).

[0258] Step-8: tert-butyl (l-(5-bromo-2-methyl-2H-l,2,3-triazol-4- yl)cyclopropyl)(methyl)carbamate (I-3h): To a stirred solution of I-3g (2.7 g, 8.51 mmol) in DMF (30 mL) was added sodium hydride (0.41 g, 10.2 mmol) at 0 °C and was stirred for 20 min at 0 °C. Then iodomethane (0.64 mL, 10.2 mmol) was added and the reaction was stirred at room temperature for 1 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with addition of ice cold water (50 mL) and extraction was carried out using EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using gradient elution of 0-20 % EtOAc in n-heptane) to afford tert-butyl (l-(5- bromo-2-methyl-2H-l,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate I-3h (2.8 g) as colourlessthick oil. LCMS (ES) m / z; 277.0 [(M-56)+H]+.1H NMR (400 MHz, CDC13) (5 4.06 (s, 3H), 2.94 (s, 3H), 1.43 (s, 11H), 1.30 (s, 2H).

[0259] Step-9: tert-butyl (l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol- 4-yl)cyclopropyl)(methyl)carbamate (I-3i): I-3i (2.7 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-3h (2.8 g, 8.45 mmol) and (2- chloro-3-fluoropyridin-4-yl)boronic acid (3.71 g, 21.1 mmol) as the starting materials. LCMS (ES) m / z; 382.1 [M+H]+.

[0260] Step-10: 6'-chloro-2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-l,4'-[1.2.3]triazolo[4,5-c][l,7]naphthyridine] (I-3j): I-3j (1.5 g) was synthesized by following procedure as described for the synthesis of 1-2 (step-3) using I-3i (2.7 g, 6.36 mmol) as the starting material. LCMS (ES) m / z 262.2 [M+H]+.

[0261] Step-11: N-(2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-l,4'-[1.2.3]triazolo[4,5-c] [l,7]naphthyridin]-6'-yl)cyclopropanecarboxamide (I-3k): I-3k(1.4 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-6) using I-3j (1.5 g, 5.73 mmol) and cyclopropanecarboxamide (0.97 g, 11.5 mmol) as the starting materials. LCMS (ES) m / z 311.1 [M+H]+.

[0262] Step-12: 2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-l,4'-[l,2,3]triazolo[4,5- c][l,7]naphthyridin]-6'-amine (1-3): 1-3 (0.99 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-7) using I-3k (1.4 g, 4.51 mmol) as the starting material. LCMS (ES) m / z; 243.1 [M+H]+.Example 4: Preparation of 3,4,5-trimethyl-4,5-dihydro-3H-[l,2,3]triazolo[4,5- c][l,7]naphthyridin-6-amine (1-4):

[0263] Step-1: 4-bromo-l-methyl-lH-l,2,3-triazole-5-carbaldehyde (I-4b): To a stirred solution of I-4a (20 g, 83 mmol) in THF (200 mL) was added 2M solution of isopropylmagnesium chloride in THF (49.8 mL, 99.6 mmol) at -30 °C and stirred for 1 h at the same temperature. To this was then added DMF (32.1 mL, 415 mmol) at -30 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h. After completion, it was quenched with addition of saturated NH4CI solution (100 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 heptane) to afford desired compound 4-bromo-l-methyl-lH-l,2,3-triazole-5-carbaldehyde I-4b (11 g) as an off white solid. 'HNMR (400 MHz, CDCI3) d 9.92 (s, 1H); 4.32 (s, 3H). LCMS (ES) m / z 189.9 [M+H]+.

[0264] Step-2: l-(4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)ethan-l-ol (I-4c): To a stirred solution of I-4b (10 g, 52.6 mmol) in anhydrous THF (100 mL) was added a 3M solution of MeMgBr in Et2O (26.3 mL, 78.9 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 NH4CI solution (100 mL) and extraction was carried out using EtOAc (70 mL x 3). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using gradient elution 0-30% EtOAc in heptane) to afford desired compound l-(4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)ethan-l-ol I-4c (9 g) as an off white solid. LCMS (ES) m / z 206.1 [M+H]+.

[0265] Step-3: l-(4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)ethan-l-one (I-4d): To a stirred solution of I-4c (9 g, 43.7 mmol) in DCM (90.0 mL) was added DMP (24.1 g, 56.8 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 (50 mL x 2). The resulting filtrate was washed with saturated NaHCCL solution (100 mL), water (100 mL), brine (70 mL), dried over anhydrous ISfeSCh, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in hexane) to afford desired compound l-(4-bromo-l-methyl-lH-l,2,3- triazol-5-yl)ethan-l-one I-4d (7.0 g) as an off-white solid. LCMS (ES) m / z 204.0 [M+H]+.

[0266] Step-4: l-(4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)-N-methylethan-l-amine (I-4e): To a stirred solution of I-4d (17 g, 83.3 mmol) in THF (150 mL) was added titanium(IV) isopropoxide (49.3 mL, 152.70 mmol) in a sealed tube at 0 °C. To this was then added a 2M solution of MeNH2 in THF (76.3 mL, 167. 0 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 (170 mL) and to this was added NaBHj (9.46 g, 250 mmol) at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, saturated NaHCCh solution (100 mL) was added to it and washed with EtOAc (30 mL x 2). The aqueous NaHCCh solution containing l-(4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)-N-methylethan-l-amine I-4e was carried forward for the next step.

[0267] Step-5: tert-butyl (l-(4-bromo-l-methyl-lH-l,2,3-triazol-5- yl)ethyl)(methyl)carbamate (I-4f): I-4f (18 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-3) using I-4e as the starting material. LCMS (ES) m / z 319.0 [M+H]+.

[0268] Step-6: 5-[l-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-(2-chloro-3-fluoro- 4-pyridyl)-l-methyl-lH-l,2,3-triazole (I-4g): I-4g (7.1 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-4f (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]+.

[0269] Step-7: 6-chloro-3,4,5-trimethyl-4,5-dihydro-3H-[l,2,3]triazolo[4,5- c][l,7]naphthyridine (I-4h): I-4h (3.6 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-5) using I-4g (7.1 g, 19.2 mmol) LCMS (ES) m / z 250.1 [M+H]+.

[0270] Step-8: N-(3,4,5-trimethyl-4,5-dihydro-3H-[l,2,3]triazolo[4,5-c] [l,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-4i): I-4i (4.8 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-6) using I-4h (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]+.

[0271] Step-9: 3,4,5-trimethyl-4,5-dihydro-3H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6- amine (1-4): 1-4 (1.2 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-7) using I-4i (4.8 g, 6.44 mmol) as the starting material. LCMS (ES) m / z 231.1 [M+H]+. 'HNMR (400 MHz, CDC13) 3 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).

[0272] Note: Racemate 1-4 (1.2 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 20 mm x 5 pm) Mobile phase: n-Hexane: Ethanol with 0.1% DEA (50:50) Flow rate : 19.0 mL / min] to afford two enantiomers {I-4A (0.43 g): peak-1; Rt; 7.11 min and I-4B (0.43 g): peak-2; Rt; 8.80 min}, which were used further without their absolute configuration determination.Example 5: Preparation of 2,3,4, 5-tetramethyl-4,5-dihydro-2H-pyrazolo [4,3- c][l,7]naphthyridin-6-amine (1-5):

[0273] Step-1: 3-bromo-5-methyl-lH-pyrazole-4-carbaldehyde (I-5b): To a stirred solution of I-5a (6.7 g, 68.3 mmol) in N,N-dimethylformamide (18.1 mL, 232 mmol) at 0 °C was added POBrs (66.6 g, 232 mmol) and the reaction mixture was heated at 120 °C for 1 h. The progress of the reaction mixture was monitored by TLC and LC-MS. After completion of the reaction, it was cooled to 0 °C and quenched with addition of saturated sodium bicarbonate solution (100 mL). Extraction was carried out using EtOAc (50 mL x 3) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford desired compound 3-bromo-5-methyl- lH-pyrazole-4-carbaldehyde I-5b (9.5 g mmol) as a white solid. LCMS (ES) m / z 189.0 [M+H]+.

[0274] Step-2: 3-bromo-l,5-dimethyl-lH-pyrazole-4-carbaldehyde (I-5c): To a solution of I-5b (3 g, 15.9 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.14 g, 1.8 eq., 28.6 mmol) at 0 °C under nitrogen atmosphere and allowed to stir for 15 min. Then iodomethane (1.19 mL, 19 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with addition of sodium bicarbonate solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-30% EtOAc in heptane) to afford desired compound 3-bromo-l,5-dimethyl-lH-pyrazole-4-carbaldehyde I-5c (0.4 g) as a white solid. LCMS (ES) m / z 202.9 [M+H]+.

[0275] Step-3: l-(3-bromo-l,5-dimethyl-lH-pyrazol-4-yl)ethan-l-ol (I-5d): I-5d (2.7 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-2) using I-5c (3.0 g, 14.8 mmol) as the starting material. LCMS (ES) m / z 218.9 [M+H]+.

[0276] Step-4: l-(3-bromo-l,5-dimethyl-lH-pyrazol-4-yl)ethan-l-one (I-5e): I-5e (2.0 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-3) using I-5d (2.7 g, 12.3 mmol) as the starting material. LCMS (ES) m / z 216.9 [M+H]+.

[0277] Step-5: l-(3-bromo-l,5-dimethyl-lH-pyrazol-4-yl)-N-methylethan-l-amine (I-5f):I-5f (2 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-4) using I-5e (2.0 g, 9.21 mmol) as the starting material. LCMS (ES) m / z 232.1 [M+H]+.

[0278] Step-6: tert-butyl (l-(3-bromo-l,5-dimethyl-lH-pyrazol-4- yl)ethyl)(methyl)carbamate (I-5g): I-5g (1.6 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-3) using I-5f (2.0 g, 9.21 mmol) as the starting material. LCMS (ES) m / z; 332.1 [M+H]+.

[0279] Step-7: tert-butyl (l-(3-(2-chloro-3-fluoropyridin-4-yl)-l,5-dimethyl-lH-pyrazol- 4-yl)ethyl)(methyl)carbamate (I-5h): I-5h (4.2 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-5g (6.0 g, 18.1 mmol) as the starting material. LCMS (ES) m / z; 383.0 [M+H]+.

[0280] Step-8: 6-chloro-2,3,4,5-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridine (I-5i): I-5i (1.7 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-5) using I-5h (4.2 g, 11 mmol) as the starting material. LCMS (ES) m / z; 263.1 [M+H]+.

[0281] Step-9: N-(2,3,4,5-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin- 6-yl)cyclopropanecarboxamide (I-5j): I-5j (1.7 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-6) using I-5i (1.7 g, 6.47 mmol) as the starting material. LCMS (ES) m / z; 312.2 [M+H]+.

[0282] Step-10: 2,3,4,5-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][l,7]naphthyridin-6- amine (1-5): 1-5 (0.75 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-7) using I-5j (1.2 g, 3.85 mmol) as the starting material. LCMS (ES) m / z 244.1 [M+H]+.

[0283] Note: Racemate 1-5 (0.75 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 20 mm x 5 pm) Mobile phase: n-Hexane: Ethanol with 0.1% DEA (80:20) Flow rate : 40.0 mL / min] to afford two enantiomers {I-5A (0. 3 g): peak-1; Rt; 10.71min and I-5B (0.3 g): peak-2; Rt; 12.77 min}, which were used further without their absolute configuration determination.Example 6: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3',4':4,5]pyrido[3,2- d]pyrimidin-6-amine (1-6):

[0284] Step-1: l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethan-l-ol (I-6b): I-6b (23 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-2) using I-6a (25 g, 132.3 mmol) as the starting material.. LCMS (ES) m / z 205 [M+H]+.

[0285] Step-2: l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethan-l-one (I-6c): I-6c 10 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-3) using I-6b (15 g, 73.2 mmol) as the starting material.. LCMS (ES) m / z 203 [M+H]+.

[0286] Step-3: l-(3-bromo-l-methyl-lH-pyrazol-4-yl)-N-methylethan-l-amine (I-6d): I- 6d (15 g) was synthesized by following procedure as described for the synthesis of 1-4 (step-4) using I-6c (15.5 g, 76.35 mmol) as the starting material. LCMS (ES) m / z 218 [M+H]+.

[0287] Step-4: tert-butyl (l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethyl)(methyl)carbamate (I-6e): I-6e (19 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-3). LCMS (ES) m / z; 318.0 [M+H]+.

[0288] Step-5: tert-butyl methyl(l-(l-methyl-3-(tributylstannyl)-lH-pyrazol-4- yl)ethyl)carbamate (I-6f): I-6f (3.5 g) was synthesized by following procedure as described for the synthesis of 1-2 (step-1) using I-6e (6 g, 18.9 mmol) as the starting material.. LCMS (ES) m / z; 530.3 [M+H]+.

[0289] Step-6: tert-butyl (l-(3-(6-chloro-5-fluoropyrimidin-4-yl)-l-methyl-lH-pyrazol-4- yl)ethyl)(methyl)carbamate (I-6g): I-6g (5 g) was synthesized by following procedure asdescribed for the synthesis of 1-2 (step-2) using I-6f (10 g, 18.9 mmol) as the starting material. LCMS (ES) TWZZ; 370.1 [M+H]+.

[0290] Step-7 : 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo [3', 4' : 4,5] pyrido [3,2- djpyrimidine (I-6h): I-6h (1.5 g) was synthesized by following procedure as described for the synthesis of 1-3 (step-10) using I-6g (5 g, 13.5 mmol) as the starting material. LCMS (ES) m / z 250.0 [M+H]+.

[0291] Step-8: 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidin- 6-amine (1-6): A mixture of I-6h (1.3 g, 5.21 mmol) and ammonium hydroxide (20 mL) in a steel bomb was stirred at 100 ° C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with 5% MeOH in DCM (50 mL x 2). The combined organic extracts were dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by Combi- Flash (using gradient elution of 0-10% MeOH in DCM) to afford desired compound 2,4,5- trimethyl-4,5-dihydro-2H-pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidin-6-amine 1-6 (0.850 g) as off white solid. LCMS (ES) m / z; 231.2 [M+H]+.Example 7: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,5]naphthyridin-6-amine (1-7):

[0292] Step-1: tert-butyl (l-(3-(4-chloro-3-fluoropyridin-2-yl)-l-methyl-lH-pyrazol-4- yl)ethyl)(methyl)carbamate (I-7a): I-7a (5.2 g) was synthesized by following procedure as described for the synthesis of 1-2 (step-2) using I-6f (15 g, 28.4 mmol) as the starting material.LCMS (ES) m / z; 369.1 [M+H]+.

[0293] Step-2: 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,5]naphthyridine (I-7b): I-7b (2.5 g) was synthesized by following procedure as described for the synthesis of 1-3 (step-10) using I-7a (5.2 g, 14.1 mmol) as the starting material. LCMS (ES) m / z; 249.1 [M+H]+.

[0294] Step-3: N-(2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,5]naphthyridin-6- yl)cyclopropanecarboxamide (I-7c): I-7c (2.5 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-6) using I-7b (2.5 g, 10.1 mmol) as the starting material. LCMS (ES) m / z; 298.1 [M+H]+.

[0295] Step-4: 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,5]naphthyridin-6-amine(1-7): 1-7 (1.1 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-7) using I-7c (2.4 g, 8.07 mmol) as the starting material. LCMS (ES) m / z 230.1 [M+H]+.

[0296] Note: Racemate 1-7 (1.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm X 20 mm X 5 pm) Mobile phase: Methanol with 0.1% DEA (100%) Flow rate: 38.0 mL / min] to afford two enantiomers {I-7A (0. 45 g): peak-1; Rt; 5.25 min and I- 7B (0.47 g): peak-2; Rt; 10.47 min}, which were used further without their absolute configuration determination.Example 8: Preparation of N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2- yl)cyclopropanecarboxamide (A-l):

[0297] Step 1: 4,6-dichloro-N-methoxy-N-methylnicotinamide (A-lb): To a stirred solution of A- la (20.0 g, 104.0 mmol) in DCM (50.0 mL) were added TEA (43.6 mL, 313.0 mmol) and HATU (39.6 g, 104 mmol) at 0 °C. To this was then added N,O- dimethylhydroxylamine hydrochloride (15.9 g, 260.0 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. After complete consumption of starting material,water (100 mL) was added and extraction was carried out using DCM (100 x 2 mL). 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 (0-15% EtOAc in Heptane) to afford 4,6-dichloro-N-methoxy-N-methylnicotinamide A-lb (18.0 g) as a colorless liquid. LCMS (ES) m / z 235.1 [M+H]+.

[0298] Step-2: l-(4,6-dichloropyridin-3-yl)ethan-l-one (A-lc): To a stirred solution of A- 1b (15 g, 63.8 mmol) in anhydrous THF (50.0 mL) was added a 3M solution of MeMgBr in Et2O (45 mL, 134 mmol) at 0 °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 NH4CI solution (100 mL) and extraction was carried out using EtOAc (100 mL x 2). The combined extracts were washed with water (100 mL), brine (100 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 l-(4,6-dichloropyridin-3-yl)ethan-l-one A-lc (10.0 g) as a thick yellow liquid.LCMS (ES) m / z; 190.1 [M+H]+.

[0299] Step-3: methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoate (A-ld): To a stirred solution of A-lc (10 g, 52.6 mmol) in dimethyl carbonate (150 mL) was added NaH (60% suspension) (6.31 g, 158 mmol) in portion-wise at 0 °C. The reaction mixture was the stirred at room temperature for 3 h. After complete consumption of starting material, it was quenched with addition of 2N aqueous HC1 solution (20 mL) and extraction was carried out using EtOAc (100 mL x 2). The combined organic extracts were washed with water (100 mL), brine (100 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 desired compound methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoate A-ld (8.6 g) as a yellow solid. LCMS (ES) m / z 244.1 [M+H]+.

[0300] Step-4: methyl 2-(6-chloro-4-methoxynicotinoyl)propanoate-3,3,3-d3 (A-le): To a stirred solution of A-ld (8.6 g, 35.3 mmol) in DMF (50.0 mL) was added potassium carbonate (5.37 g, 38.8 mmol) at 0 °C, and stirred for 5 min. To this was then added iodomethane-d^ (2.45 mL, 38.8 mmol) drop wise at 0 °C and the reaction mixture was stirred at room temperature for 6 h. After completion, water (80 mL) was added to it and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-8% EtOAc in hepatane) to afford methyl 2- (6-chloro-4-methoxynicotinoyl)propanoate-3,3,3-d3 A-le (5.6 g) as on off-white solid. LCMS (ES) m / z; 261.1 [M+H]+.

[0301] Step-5: l-(6-chloro-4-hydroxypyridin-3-yl)propan-l-one-3,3,3-d3 (A-lf): To a solution of A-le (5.6 g, 21.5 mmol) in AcOH (40 mL) was added hydrogen chloride (80 mL) at room temperature. The reaction mixture was then stirred at 130 °C for 16 h. After completion (as indicated by LCMS), it was quenched with water (100 mL) and extraction was carried out using EtOAc (100 x 2 mL). The combined organic extracts were washed brine (100 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 hepatane) to afford l-(6- chloro-4-hydroxypyridin-3-yl)propan-l-one-3,3,3-d3 A-lf (3.8 g). LCMS (ES) m / z 189.6 [M+H]+.

[0302] Step-6: l-(4,6-dichloropyridin-3-yl)propan-l-one-3,3,3-d3 (A-lg): To a solution of A-lf (3.8 g, 20.1 mmol) in ACN (15 mL) was added POCI3 (7 mL) at room temperature. The reaction mixture was then heated to 85 °C for 1 h. After complete consumption of starting material, volatiles were removed under reduced pressure and saturated NaHCOs solution (20 mL) was added to the residue. Extraction was carried out using EtOAc (3 x 30 mL); the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% EtOAc in hepatane) to afford 11 -(4,6- dichloropyridin-3-yl)propan-l-one-3,3,3-d3 (A-lg) (2.6 g). LCMS (ES) m / z 207.1 [M+H]+.

[0303] Step-7 : N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (A-l): Argon gas was purged through a stirred suspension of A-lg (3.0 g, 14.5 mmol), cyclopropanecarboxamide (1.11 g, 13.0 mmol) and CS2CO3 (9.44 g, 29.0 mmol) in 1,4-dioxane (50.0 mL) for 15 min. To this was then added rac-BINAP (0.9 g, 1.45 mmol) and Pd2(dba)3- CHCI3 (1.5 g, 1.45 mmol). The reaction mixture was then heated at 110 °C for 2 h in a sealed tube. After completion, it was cooled to room temperature and filtered through Celite bed. It is washed with EtOAc (50 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-25% EtOAc in heptane) to afford desired compound N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2- yl)cyclopropanecarboxamide A-l (1.8 g) as a yellow solid. LCMS (ES) m / z 256.6 [M+H]+.Example 9: Preparation of N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2- yl)spiro[2.2]pentane-l-carboxamide (A-2):

[0304] Step 1: spiro[2.2]pentane-l-carboxamide (A-2b): To a solution of A-2a (0.75 g, 6.69 mmol) in DCM (6 mL) at 0 °C was added oxalyl chloride (1.75 mL, 20.1 mmol) dropwise over period of 15 minutes followed by addition of catalytic amount of DMF. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and cooled to 0 °C. To this was then added a solution of ammonia in MeOH (10.0 mL). The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was concentrated under reduced pressure and the residue was triturated with 10% EtOAc in hexane to afford desired spiro[2.2]pentane-l-carboxamide A-2b (0.72 g) as off white solid. LCMS (ES) m / z 112.1 [M+H]+.

[0305] Step 2: N-(4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)spiro[2.2]pentane-l- carboxamide (A-2): A-2 (0.13 g) was synthesized by following procedure as described for the synthesis of A-l (step-7) using A-2b (0.27 g, 2.41 mmol) and A-lg (0.5 g, 2.41 mmol) as the starting materials. LCMS (ES) m / z 282.1 [M+H]+.Example 10: Preparation of 4-((4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)amino)-l- methylpyrimidin-2(lH)-one (A-3):

[0306] Step-1: 4-amino-l-methylpyrimidin-2(lH)-one (A-3b): To a solution of A-3a (3 g, 27 mmol) in dichloromethane (90.0 mL, 1.41 mol) was added tetrabutylammonium hydroxide (17 mL, 27 mmol) and iodomethane (6.72 mL, 108 mmol); and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with water (150 ml) and was washed with DCM (100 mL). The aqueous layer was then concentrated under reduced pressureand the product was recrystallized from residue using EtOh to afford l-methyl-2-oxo-4- pyrimidinylamine A-3b (2.6 g) as a white solid. LCMS (ES) m / z 126.2 [M+H]+.

[0307] Step-2: 4-((4-chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)amino)-l- methylpyrimidin-2(lH)-one (A-3): A-3 (0.48 g) was synthesized by following procedure as described for the synthesis of A-l (step-7) using A-3b (0.3 g, 2.41 mmol) and A-lg (0.5 g, 2.41 mmol) as the starting materials. LCMS (ES) m / z 296.1 [M+H]+.Example 11: Preparation of (S)-l-methyl-4-((5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl- 4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridin-2- yl)amino)pyrimidin-2(lH)-one (Compound 5):

[0308] Argon gas was purged through a stirred suspension of 1-1 (0.1 g, 0.434 mmol), A-3 (0.154 g, 0.52 mmol) and CS2CO3 (0.35 g, 1.09 mmol) in 1,4-dioxane (5.0 mL) for 15 min before addition of rac-BINAP (0.027 g, 0.043 mmol) and Pd2(dba)3-CHCh (0.045 g, 0.043 mmol). The reaction mixture was then stirred at 110 °C for 4 h in a sealed tube, while monitoring reaction progress by TLC. After completion, it was cooled to room temperature and filtered through celite bed. It is washed with DCM (40 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0- 50% EtOAc in heptane). The solid thus obtained was further purified by preparative HPLC to afford desired compound (S)-l-methyl-4-((5-(propanoyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5- dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridin-2-yl)amino)pyrimidin- 2(lH)-one 5 (0.14 g) as pale yellow solid. LCMS (ES) m / z = 490.5 [M+H]+.1HNMR (400 MHz, DMSO ): 3 12.19 (s, 1H); 10.36 (s, 1H); 10.06 (s, 1H); 8.94 (s, 1H); 8.29 (d, J= 4.8 Hz, 1H); 7.89 (d, J= 6.8 Hz, 1H); 7.31 (d, J= 4.8 Hz, 1H); 6.53 (d, = 6.8 Hz, 1H); 4.59 (q, J= 6.8 Hz, 1H); 4.25 (s, 3H); 3.32 (s, 3H); 3.12 (s, 2H); 2.56 (s, 3H); 1.18 (d, J= 6.8 Hz, 3H). Note: Single isomer prepared, but absolute configuration not determined.

[0309] The following compounds were synthesized following the procedures as described above, using appropriate intermediates and starting materials.

[0310] The “orl” 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 “orl”) but absolute stereochemistry is not known. For example, compounds with a single “orl” in the structure or either pure (R) or pure (S), not a racemic mixture.

[0311] The “&1” designation in the structures throughout this application refers to stereocenters which exist as a mixture of two enantiomers. For example, compounds with a “&1” in the structure represent a mixture of both (R) and (S). The mixture can be in any ratio; and the racemic mixture (1 : 1 ratio) is included.II. Biological EvaluationExample B-l: HEK-Blue™ IL-23 and IFNa / p Reporter Assays for Profiling TYK2 Pseudokinase (JH2) Inhibition

[0312] HEK-Blue™ IL-23 and IFNa / p cells with a stably-integrated cytokine receptor and STAT3 or STAT1 express STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. These cells are plated in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U / mL PenStrep (Gibco) at 37 °C under 5% CO2 conditions for 20-22 hours. The cells are then pretreated with serially diluted test compounds for 60 min prior to stimulation with either 10 ng / mL human recombinant IL-23 (Miltenyl Biotech) or 1 ng / mL human recombinant IFNa (InvivoGen) for 22-24 hours for IL-23 or 16-18 h for IFNa. SEAP induction is measured using the QUANTI Blue™ Solution (InvivoGen) according to the manufacturer's instructions. Inhibition data are calculated by comparison to no inhibitor control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves are generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by non-linear regression analysis.

[0313] Table B-l provides TYK2 inhibitory activity of illustrative compounds, where A means IC50 < 30 nM; B means IC50 is between 30 and 300 nM; C means IC50 is between 300 and 1000 nM; D means IC50 > 1000 nM; n / a means no observed activity at 1000 nM; and n.d. means not determined.Table B-l: Representative TYK2 Inhibitory Activity

[0314] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N;each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2- Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is a group of the formula:wherein: each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, - CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, - SO2R17, or -SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is unsubstituted or substituted bicyclic carbocycle and unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-G, cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, -CO2R18, -CH2CO2R18, - C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, -NR18C(=O)R18, - CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, -CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, or 3.

2. A compound of Formula (II):Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen,unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -O-, -S-, -S(=O)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1is CF or N, X2is CH or CF, and X3is N; or X1is N, X2is CH or CF, and X3is CH or CF;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=0)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=0)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; or two R13groups on adjacent atoms of Ring B are taken together with the intervening atoms to which they are attached to form an unsubstituted orsubstituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-G, cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R6and R7is independently hydrogen, deuterium, halogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, - NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C=O or a C3-C6 cycloalkane; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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- noeach R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, -CO2R18, -CH2CO2R18, - C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, -NR18C(=O)R18, - CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, -CH2SR18, - S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided when X1is N, X2is CH, and X3is N, then- I l l -A compound of Formula (III):Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, or an unsubstituted or substituted 5- or 6-membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8; each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, 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; or two R8attached to the same carbon atom are taken together to form =0, =S, or =NH;Z is -NR10-, -0-, -S-, -S(=0)-, or -SO2-;R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle;X1, X2, and X3are each independently CR11or N; each R11is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2;B1is N or CR12a;B2is N or CR12b;R12aand R12bare each independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, - C(=O)R16, -CO2R16, -C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or -SO2N(R16)2;R1is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl;R2is 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 q instances of R13; each R13is independently halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR17, -C(=O)R16, -CO2R16, - C(=O)N(R16)2, -N(R16)2, -NR16C(=O)R17, -SR16, -S(=O)R17, -SO2R17, or - SO2N(R16)2; or two R13groups 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; or R2is -C(=O)R14, -C(=O)NR14R15, or -C(=O)OR14;R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted C2-Ce alkenyl, unsubstituted or substituted C2-Ce alkynyl, unsubstituted or substituted Ci-Ce heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;R15is hydrogen, Ci-Ce alkyl, or Ci-Ce fluoroalkyl; or R14and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; or R1and R15are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;R4is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl; or R4and R12aare taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted Cs-G, cycloalkyl;R5is hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle; each R16is independently hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R16on 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 R17is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce fluoroalkyl, substituted or unsubstituted Ci-Ce heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, 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, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR18, -CH2OR18, -CO2R18, -CH2CO2R18, - C(=O)N(R18)2, -CH2C(=O)N(R18)2, -N(R18)2, -CH2N(R18)2, -NR18C(=O)R18, - CH2NR18C(=O)R18, -NR18SO2R19, -CH2NR18SO2R19, -SR18, -CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or - CH2SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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 Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; m is 1, 2, 3, or 4; p is 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; provided that when m is 1, thennot4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4is C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 deuteroalkyl, or C3-C6 cycloalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4is C1-C4 deuteroalkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R4is 2,2,2-trideuterioeth-l-yl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1is hydrogen or C1-C4 alkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R1is hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R5is hydrogen or C1-C4 alkyl.10 The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R5is hydrogen.11 The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein B1is CR12a.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R12ais hydrogen or unsubstituted or substituted Ci- Ce alkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R12ais hydrogen.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein B2is CR12b.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R12bis hydrogen or unsubstituted or substituted Ci- Ce alkyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R12bis hydrogen.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Z is -NR10-, -O-, or -S-.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Z is -NR10-.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10is hydrogen, Ci-Ce alkyl, Ci-Ce deuteroalkyl, Ci-Ce fluoroalkyl, or C3-C6 cycloalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10is Ci-Ce alkyl, Ci-Ce deuteroalkyl, or C3-C6 cycloalkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10is Ci-Ce alkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R10is methyl.

23. The compound of any one of claims 1, 2, and 4-22, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein n is 1.

24. The compound of any one of claims 1 and 4-23 further defined as Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

25. The compound of any one of claims 2 and 4-23 further defined as Formula (II-A):Formula (II-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

26. The compound of any one of claims 3-23 further defined as Formula (III-A):Formula (III-A), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

27. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted carbocyclic ring wherein A1and A2are both C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted phenyl, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted 5- or 6- membered heterocyclic ring wherein A1and A2are independently N or C, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted pyrrole, unsubstituted or substituted furan, unsubstituted or substituted thiophene, unsubstituted or substituted pyrazole, unsubstituted or substituted imidazole, unsubstituted or substituted oxazole, unsubstituted or substituted isoxazole, unsubstituted or substituted thiazole, unsubstituted or substituted isothiazole, unsubstituted or substituted triazole, unsubstituted or substituted oxadiazole, unsubstituted or substituted thiadiazole, unsubstituted or substituted tetrazole, unsubstituted or substituted triazolone, unsubstituted or substituted pyridine, unsubstituted or substituted pyrazine, unsubstituted or substituted pyridazine, unsubstituted or substituted pyridazinone, or unsubstituted or substituted pyrimidine, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted pyrazole or unsubstituted or substituted triazole, wherein if Ring A is substituted then Ring A is substituted with p instances of R8.

32. The compound of any one of claims 1 and 4-31 further defined as Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8;wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

33. The compound of any one of claims 1 and 4-32, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A1is C; A2is C; A3is N; A4is N or NR8; and A5is N or NR8.

34. The compound of any one of claims 1 and 4-33, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1is C; A2is C; A3is N; A4is NR8; and A5is N; or A1is C; A2is C; A3is N; A4is N; and A5is NR8.

35. The compound of any one of claims 2 and 4-31 further defined as Formula (II-B):Formula (II-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

36. The compound of any one of claims 2, 4-31, and 35, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A1is C; A2is C; A3is N; A4is NR8; and A5is N or CR8.

37. The compound of any one of claims 2, 4-31, 35, and 36 or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:A1is C; A2is C; A3is N; A4is NR8; and A5is N; or A1is C; A2is C; A3is N; A4is NR8; and A5is CR8.

38. The compound of any one of claims 3-31 further defined as Formula (III-B):Formula (III-B), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: A1and A2are each independently N or C;A3is S, O, N, NR8, CR8, or C=O; andA4and A5are each independently S, O, N, NR8, or CR8; wherein at least one of A1and A2is C, or at least one of A3, A4, and A5is CR8.

39. The compound of any one of claims 3-31 and 38, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A1is C; A2is C; A3is N; A4is NR8; and A5is N.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R8is independently hydrogen, halogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted heterocycle; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle or unsubstituted or substituted heterocycle; or two R8attached to the same carbon atom are taken together to form =0.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R8is independently unsubstituted or substituted Ci-Ce alkyl.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R8is methyl.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein at least one R8is not methyl.

44. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R8is independently hydrogen, halogen, unsubstituted or substituted C2-C6 alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted heterocycle; wherein if R8is attached to a nitrogen atom, then R8is hydrogen, unsubstituted or substituted Ci-Ce alkyl, unsubstituted or substituted Ci-Ce deuteroalkyl, unsubstituted or substituted Ci-Ce fluoroalkyl, unsubstituted or substituted carbocycle or unsubstituted or substituted heterocycle; or two R8attached to the same carbon atom are taken together to form =0.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein p is 1.

46. The compound of any one of claims 1, 2, and 4-45, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R6and R7is independently hydrogen, deuterium, Ci-Ce alkyl, Ci-Ce deuteroalkyl, or Ci-Ce heteroalkyl; or one R6and one R7attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkane.

47. The compound of any one of claims 1, 2, and 4-46, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R6and R7is independently hydrogen or methyl.

48. The compound of any one of claims 3-44, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein m is 1.

49. The compound of any one of claims 1 and 3-48, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:X1is CR11, X2is CR11, and X3is CR11; or X1is CR11, X2is CR11, and X3is N; or X1is CR11, X2is N, and X3is CR11; or X1is CR11, X2is N, and X3is N; or X1is N, X2is CR11, and X3is CR11; or X1is N, X2is CR11, and X3is N; or X1is N, X2is N, and X3is CR11.

50. The compound of any one of claims 1 and 3-49, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X1is CR11, X2is CR11, and X3is N.

51. The compound of any one of claims 1 and 3-50, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R11is independently hydrogen, halogen, Ci-Ce alkyl, Ci-C6fluoroalkyl, -CN, -OH, -OR17, -N(R16)2.

52. The compound of any one of claims 1 and 3-51, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R11is independently hydrogen53. The compound of any one of claims 1 and 3-52, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X1is CH, X2is CH, and X3is N.

54. The compound of any one of claims 2 and 4-48, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:X1is CF or N, X2is CH, and X3is N; or X1is N, X2is CH, and X3is CH.

55. The compound of any one of claims 2, 4-48, and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X1is CF, X2is CH, and X3is N.

56. The compound of any one of claims 2, 4-48, and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X1is X1is N, X2is CH, and X3is N.

57. The compound of any one of claims 2, 4-48, and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X1is N, X2is CH, and X3is CH.

58. The compound of any one of claims 2-57, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is 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 q instances of R13; or R2is -C(=O)R14.

59. The compound of any one of claims 2-58, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is -C(=O)R14.

60. The compound of any one of claims 2-59, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is hydrogen, unsubstituted or substituted Ci-Ce alkyl, or unsubstituted or substituted monocyclic carbocycle.

61. The compound of any one of claims 2-60, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14unsubstituted or substituted monocyclic carbocycle.

62. The compound of any one of claims 2-61, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is unsubstituted or substituted Cs-Cs cycloalkyl.

63. The compound of any one of claims 2-62, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is cyclopropyl.

64. The compound of any one of claims 1 and 4-57, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is a group of the formula:

65. The compound of any one of claims 1, 4-57, and 64, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is a group of the formula:

66. The compound of any one of claims 1, 4-57, 64, and 65, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is a group of the formula:

67. The compound of any one of claims 1-58, 64, and 65, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein q is 1.

68. The compound of any one of claims 1-58 and 64-67, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein at least one R13is unsubstituted or substituted Ci-C6alkyl.

69. The compound of any one of claims 1-58 and 64-68, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein at least one R13is methyl.

70. The compound of any one of claims 1, 4-24, 27-34, 40-47, and 49-53, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R2is -C(=O)R14.

71. The compound of any one of claims 1, 4-24, 27-34, 40-47, 49-53, and 70, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is unsubstituted or substituted bicyclic carbocycle.

72. The compound of any one of claims 1, 4-24, 27-34, 40-47, 49-53, 70, and 71, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is C5-C12 bicyclic carbocycle.

73. The compound of any one of claims 1, 4-24, 27-34, 40-47, 49-53, and 70-72, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is C5-C12 bicyclic cycloalkyl.

74. The compound of any one of claims 1, 4-24, 27-34, 40-47, 49-53, and 70-73, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is a group of the formula:wherein: x and y are each independently 0, 1, 2, 3, 4, wherein the sum of x and y is at least 1; and z is 1, 2, 3, 4, 5, 6, 7, or 8.

75. The compound of claim 74, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein x is 0 and y is 1.

76. The compound of claim 74 or claim 75, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein z is 1.

77. The compound of any one of claims 1, 4-24, 27-34, 40-47, 49-53, and 70-73, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R14is:

78. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

79. A compound selected from the group consisting of:or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

80. A pharmaceutical composition comprising the compound of any one of claims 1-79, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

81. A method of treating a 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 1-79, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, or a pharmaceutical composition of claim 80.

82. The method of claim 81, wherein the disease or condition is a TYK2 -mediated disease or condition.

83. The method of claim 81 or claim 82, wherein the disease or condition is an inflammatory disease or condition or an autoimmune disease or condition.

84. The method of claim 83, wherein the disease or condition is an inflammatory disease or condition.

85. The method of claim 84, wherein the inflammatory disease or condition is a neuroinflammatory disease or condition.

86. The method of any one of claims 81-85, wherein the disease or condition is a neurodegenerative disease or condition.

87. The method of any one of claims 81-86, wherein the disease or condition is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or a neuromyelitis optica spectrum disorder.

88. The method of claim 87, wherein the disease or condition is multiple sclerosis.

89. The method of claim 88, wherein the multiple sclerosis is relapsing or relapsingremitting.

90. The method of claim 87, wherein the disease or condition is a neuromyelitis optica spectrum disorder.

91. The method of claim 90, wherein the disease or condition is neuromyelitis optica.

92. The method of claim 87, wherein the disease or condition is encephalomyelitis.

93. The method of claim 82, wherein the disease or condition is acute disseminated encephalomy eliti s .

94. The method of claim 87, wherein the disease or condition is polyneuropathy.

95. The method of claim 94, wherein the disease or condition is chronic inflammatory demyelinating polyneuropathy.

96. The method of claim 87, wherein the disease or condition is encephalitis.

97. The method of claim 96, wherein the disease or condition is autoimmune encephalitis.

98. The method of any one of claims 81-86, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren’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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